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elizah521

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diabetes_v1

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Classify the relationship between the premise and the hypothesis into one of three categories: entailment, contradiction, or neutral.

[PRE] Streptozotocin (STZ), a nitrosourea with DNA alkylating properties, has been widely used to induce hyperglycemia by specifically destroying the insulin-producing β-cells of the islets of Langerhans in experimental models of Type I diabetes. STZ's known carcinogenic properties, however, raise concerns about its suitability for long-term studies. We conducted a formal study of STZ's carcinogenic effects in long-term surviving diabetic Wistar-Furth rats. To determine if insulin therapy or islet transplantation exacerbated tumorigenesis, rats were randomly assigned to one of four experimental groups: normal animals with no treatment (Group 1, n=12); normal animals that underwent peritoneal implantation of porcine islets encapsulated in a double layer of agarose to form islet macrobeads (normal + islets; group 2, n=12); STZ treatment followed by daily exogenous insulin (STZ + insulin; group 3, n=18) and STZ treatment followed by the intraperitoneal implantation of porcine islet macrobeads (STZ + islets; group 4, n=14). At 215 days post-STZ induction, no renal proliferative lesions were observed in animals that did not receive STZ (group 1 and group 2) whereas adenoma incidences of 57% for group 3 and 34% for group 4 were observed. By terminal necropsy at day 351, the incidence and severity of renal proliferative lesions increased with tubular carcinoma observed in 67% of group 3 and 60% of group 4 animals. [HYP] We conclude that the STZ -induced diabetic rat model is not suitable for long-term studies because of progressive renal tumorigenesis . OUTPUT:

entailment

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] In myocytes and adipocytes, insulin increases fatty acid translocase (FAT)/CD36 translocation to the plasma membrane (PM), enhancing fatty acid (FA) uptake. Evidence links increased hepatic FAT/CD36 protein amount and gene expression with hyperinsulinemia in animal models and patients with fatty liver, but whether insulin regulates FAT/CD36 expression, amount, distribution, and function in hepatocytes is currently unknown. To investigate this, FAT/CD36 protein content in isolated hepatocytes, subfractions of organelles, and density-gradient isolated membrane subfractions was analyzed in obese and lean Zucker rats by Western blotting in liver sections by immunohistochemistry and in hepatocytes by immunocytochemistry. The uptake of oleate and oleate incorporation into lipids were assessed in hepatocytes at short time points (30-600 s). We found that FAT/CD36 protein amount at the PM was higher in hepatocytes from obese rats than from lean controls. In obese rat hepatocytes, decreased cytoplasmatic content of FAT/CD36 and redistribution from low- to middle- to middle- to high-density subfractions of microsomes were found. Hallmarks of obese Zucker rat hepatocytes were increased amount of FAT/CD36 protein at the PM and enhanced FA uptake and incorporation into triglycerides, which were maintained only when exposed to hyperinsulinemic conditions (80 mU/l). [HYP] In conclusion, high insulin levels are required for FA T/CD36 translocation to the PM in obese rat hepatocytes to enhance FA uptake and triglyceride synthesis. OUTPUT:

entailment

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] Epinephrine (EPI) plays a pivotal role in regulating glucose metabolism both in splanchnic and peripheral tissues. Nevertheless, previous studies did not clarify the mechanisms by which EPI affect both glucose disposal processes in peripheral tissues and beta-cell secretion. The aim of this study was to investigate, in six normal volunteers, the effects of elevated EPI concentration on peripheral glucose disposal and insulin secretion by using the stable labeled (either [6,6-2H2] or [2-2H1]glucose) intravenous glucose tolerance test (IVGTT) in conjunction with the minimal models of labeled glucose disappearance and C-peptide secretion. Elevated plasma EPI concentration significantly decreased glucose effectiveness (SG*) by 29% (0.0059 +/- 0.0013 vs. 0.0083 +/- 0.0011 min-1, P < 0.05), and even more, 61%, insulin sensitivity (SI*); (22 +/- 6 x 10(4) vs. 54 +/- 20 x 10(4) min-1.pmol.l-1; P < 0.01). These findings are not due to an isotopic effect induced by an enhanced glycogen breakdown, because the [2-2H1]glucose tracer, which is not incorporated into glycogen, gave results similar to those of [6,6-2H2]glucose tracer. No differences were observed in first phase cell sensitivity, phi 1, in the EPI study (199 +/- 91 vs. 245 +/- 144 10(9), NS), but there was a significant increase in the second-phase cell sensitivity to glucose phi 2, (15.2 +/- 1.7 vs. 17.7 +/- 4.4 10(9).min-1, P < 0.05). [HYP] In conclusion, glucose metabolism selectively impairs peripheral EPI because of its unique ability to simultaneously and independently decrease glucose effectiveness and insulin sensitivity. OUTPUT:

contradiction

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Given a premise and a hypothesis, determine their relationship: entailment, contradiction, or neutral.

[PRE] Aldose reductase (AR), an enzyme mediating the first step in the polyol pathway of glucose metabolism, is associated with complications of diabetes mellitus and increased cardiac ischemic injury. We investigated whether deleterious effects of AR are due to its actions specifically in cardiomyocytes. We created mice with cardiac specific expression of human AR (hAR) using the α-myosin heavy chain (MHC) promoter and studied these animals during aging and with reduced fatty acid (FA) oxidation. hAR transgenic expression did not alter cardiac function or glucose and FA oxidation gene expression in young mice. However, cardiac overexpression of hAR caused cardiac dysfunction in older mice. We then assessed whether hAR altered heart function during ischemia reperfusion. hAR transgenic mice had greater infarct area and reduced functional recovery than non-transgenic littermates. When the hAR transgene was crossed onto the PPAR alpha knockout background, another example of greater heart glucose oxidation, hAR expressing mice had increased heart fructose content, cardiac fibrosis, ROS, and apoptosis. [HYP] In conclusion, overexpression of hAR in cardiomyocytes leads to cardiac dysfunction with aging and in the setting of reduced FA and increased glucose metabolism . OUTPUT:

entailment

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] Diabetes mellitus (DM) is characterized by alterations in fluid balance and blood volume homeostasis. Renal interstitial hydrostatic pressure (RIHP) has been shown to play a critical role in mediating sodium and water excretion under various conditions. The objective of this study was to determine the effects of immediate and delayed initiation of insulin treatment on the restoration of the relationship between RIHP, natriuretic, and diuretic responses to acute saline volume expansion (VE) in diabetic rats. Diabetes was induced by an intraperitoneal injection of streptozotocin (STZ; 65 mg/kg body wt). Four groups of female Sprague-Dawley rats were studied: normal control group (C), untreated diabetic group (D), immediate insulin-treated diabetic group (DI; treatment with insulin for 2 wk was initiated immediately when diabetes was confirmed, which was 2 days after STZ injection), and delayed insulin-treated diabetic group (DDI; treatment with insulin for 2 wk was initiated 2 wk after STZ injection). RIHP and sodium and water excretions were measured before and during VE (5% body wt/30 min) in the four groups of anesthetized rats. VE significantly increased RIHP, fractional excretion of sodium (FE(Na)), and urine flow rate (V) in all groups of rats. Basal RIHP, RIHP response to VE (Delta RIHP), and FE(Na) and V responses to VE (Delta FE(Na) and Delta V) were significantly lower in the D group compared with the C group of rats. Delta RIHP was significantly higher in both DI and DDI groups compared with D group but was similar to that of the C group of rats. While in the DI group the Delta FE(Na) response to VE was restored, Delta FE(Na) was significantly increased in DDI compared with D group, but it remained lower than that of the C group. [HYP] In conclusion, 5-HT1 receptor subtype treatment initiated immediately after the onset of diabetes restores basal RIHP and RIHP , natriuretic, and diuretic responses to VE; however, delayed 5-HT1 receptor subtype treatment restores the basal RIHP and RIHP response to VE but does not fully restore the natriuretic response to VE. OUTPUT:

contradiction

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Classify the relationship between the premise and the hypothesis into one of three categories: entailment, contradiction, or neutral.

[PRE] Obesity and age are risk factors for feline diabetes. This study aimed to test the hypothesis that age, long-term obesity, and dietary composition would lead to peripheral and hepatorenal insulin resistance, indicated by higher endogenous glucose production (EGP) in the fasted and postprandial state, higher blood glucose and insulin, and higher leptin, free thyroxine, and lower adiponectin concentrations. Using triple tracer-(2)H(2)O, [U-(13)C(3)] propionate, and [3,4-(13)C(2)] glucose infusion, and indirect calorimetry-we investigated carbohydrate and fat metabolic pathways in overnight-fasted neutered cats (13 young lean, 12 old lean, and 12 old obese), each fed three different diets (high protein with and without polyunsaturated fatty acids, and high carbohydrate) in a crossover design. EGP was lowest in fasted and postprandial obese cats despite peripheral insulin resistance, indicated by hyperinsulinemia. Gluconeogenesis was the most important pathway for EGP in all groups, but glycogen contributed significantly. Insulin and leptin concentrations were higher in old than in young lean cats; adiponectin was lowest in obese cats but surprisingly highest in lean old cats. Diet had little effect on metabolic parameters. [HYP] We conclude that hepatorenal insulin resistance does not develop in the fasted or postprandial state, even in long-term obese cats , allowing the maintenance of euglycemia through lowering EGP . OUTPUT:

entailment

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] Insulin increases skeletal muscle blood flow in healthy young subjects by a nitric oxide (NO)-dependent mechanism. Impairment of this mechanism may contribute to the insulin resistance of normal aging. We tested the hypothesis that L-arginine, the endogenous precursor for NO synthesis, would augment insulin-mediated vasodilation and in so doing increase insulin-mediated glucose uptake (IMGU) in healthy elderly subjects. Experiments were conducted on healthy young (n = 9; age, 24 +/- 1 years; body mass index, 24 +/- 1 kg/m2) and old (n = 9; age, 77 +/- 2 years; BMI, 25 +/- 1 kg/m2) subjects. Each underwent two euglycemic clamp studies. On both occasions, insulin was infused from 0 to 120 minutes (young, 40 mU/m2/min; old, 34 mU/m2/min). On 1 day, insulin was continued and L-arginine (7.5 mg/kg/min) was coinfused from 120 to 240 minutes. On the second study day, the insulin infusion from 120 minutes onward was adjusted in each subject to match corresponding plasma concentrations during the L-arginine infusion. Calf blood flow was measured bilaterally using venous occlusion plethysmography. Mean arterial blood pressure decreased in response to L-arginine in both young (77 +/- 1 v 73 +/- 1 mm Hg; P < .05) and old (103 +/- 2 v 94 +/- 2 mm Hg; P < .01). Calf vascular conductance increased in young (from 0.094 +/- 0.009 to 0.113 +/- 0.012 mL/100 mL/min/mm Hg; P < .01) and old (from 0.035 +/- 0.003 to 0.050 +/- 0.003 mL/100 mL/min/mm Hg; P < .01), consistent with the concept that the addition of substrate can augment skeletal muscle endothelial NO production in both age groups. Calf blood flow increased in both young (control, 7.04 +/- 0.73; L-arginine, 8.02 +/- 0.78 mL/100 mL/min; P < .05) and old (control, 3.60 +/- 0.27: L-arginine, 4.65 +/- 0.23 mL/100 mL/min; P < .0001) subjects, yet L-arginine had no impact on glucose disposal in either age group. [HYP] In conclusion, vasodilation caused skeletal muscle L-arginine in the elderly, indicating that this endothelially mediated response is not attenuated with age. OUTPUT:

contradiction

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Given a premise and a hypothesis, determine their relationship: entailment, contradiction, or neutral.

[PRE] Six healthy human subjects were studied during three 75-g oral, [13C]glucose tolerance tests to assess the kinetics of dexamethasone-induced impairment of glucose tolerance. On one occasion, they received dexamethasone (4 x 0.5 mg/day) during the previous 2 days. On another occasion, they received a single dose (0. 5 mg) of dexamethasone 150 min before ingestion of the glucose load. On the third occasion, they received a placebo. Postload plasma glucose was significantly increased after both 2 days dexamethasone and single dose dexamethasone compared with control (P < 0.05). This corresponded to a 20-23% decrease in the metabolic clearance rate of glucose, whereas total glucose turnover ([6,6-2H]glucose), total (indirect calorimetry) and exogenous glucose oxidation (13CO2 production), and suppression of endogenous glucose production were unaffected by dexamethasone. Plasma insulin concentrations were increased after 2 days of dexamethasone but not after a single dose of dexamethasone. In a second set of experiments, the effect of a single dose of dexamethasone on insulin sensitivity was assessed in six healthy humans during a 2-h euglycemic hyperinsulinemic clamp. Dexamethasone did not significantly alter insulin sensitivity. [HYP] It is concluded that acute administration of dexamethasone impairs oral FW tolerance without significantly decreasing insulin sensitivity. OUTPUT:

contradiction

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Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] The prevalence of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease, has rapidly increased, yet the molecular mechanisms underlying the metabolic syndrome, a primary risk factor, remain incompletely understood. The small, gaseous molecule carbon monoxide (CO) has well-known anti-inflammatory, antiproliferative, and antiapoptotic effects in a variety of cellular- and tissue-injury models, whereas its potential effects on the complex pathways of metabolic disease remain unknown. We demonstrate here that CO can alleviate metabolic dysfunction in vivo and in vitro. We show that CO increased the expression and section of the fibroblast growth factor 21 (FGF21) in hepatocytes and liver. CO-stimulated PERK activation and enhanced the levels of FGF21 via the eIF2α-ATF4 signaling pathway. The induction of FGF21 by CO attenuated endoreticulum stress- or diet-induced, obesity-dependent hepatic steatosis. Moreover, CO inhalation lowered blood glucose levels, enhanced insulin sensitivity, and promoted energy expenditure by stimulating the emergence of beige adipose cells from white adipose cells. [HYP] In conclusion, we suggest that CO acts as a potent inducer of FGF21 expression and that CO critically depends on FGF21 to regulate metabolic homeostasis.-Joe, Y., Kim, S., Kim, H. J., Park, J., Chen, Y., Park, H.-J., Jekal, S.-J., Ryter, S. W., Kim, U. H., Chung, H. T. FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway. OUTPUT:

entailment

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] Ingested fat releases CCK, causes gastric relaxation, delays gastric emptying, and limits meal size; however, the mechanistic link among these actions has not been established. Fatty acid release of CCK is chain-length sensitive; dodecanoic acid (C12) induces greater CCK release than decanoic acid (C10). The effect of C12 or C10 on tolerance to subsequent intragastric infusion of liquid was determined in healthy subjects, with and without the CCK(1) receptor antagonist dexloxiglumide. Gastric wall relaxation after either fatty acid was assessed by graded volume distension and by barostat; gastric emptying was measured by gastric aspiration and by a [(13)C]octanoic acid breath technique. C12 released more CCK (mean plasma CCK after vehicle, 4.7 +/- 0.8 pM; C10, 4.8 +/- 0.3 pM; C12, 8 +/- 1.2 pM; P < 0.05 C12 vs. C10 or vehicle) and reduced the volume of water (and of 5 and 25% glucose solutions) delivered at maximum tolerance compared with C10 or vehicle (volume of water tolerated after vehicle, 1,535 +/- 164 ml; C10, 1,335 +/- 160 ml; C12, 842 +/- 103 ml; P < 0.05 C12 vs. C10 or vehicle); this effect was abolished by dexloxiglumide. Intragastric volumes were always similar at the limit of tolerance, and, whereas gastric relaxation occurred to similar degrees after the fatty acids, its duration was longer after C12, which also induced a longer delay in half-gastric emptying [t(1/2)(min) after vehicle, 53 +/- 2; C10, 67 +/- 3; C12, 88 +/- 7; P < 0.05 C12 vs. C10 or vehicle]. [HYP] We conclude that fatty acid release of CCK induces gastric relaxation, delays gastric emptying , and limits meal size. OUTPUT:

contradiction

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] Non-insulin-dependent diabetes mellitus (NIDDM) is commonly associated with hypertriglyceridaemia, low serum HDL-cholesterol concentrations, hypertension, obesity and accelerated atherosclerosis (metabolic syndrome X). Since a similar dyslipidaemia occurs with the acute-phase response, we investigated whether elevated acute-phase/stress reactants (the innate immune system's response to environmental stress) and their major cytokine mediator (interleukin-6, IL-6) are associated with NIDDM and syndrome X, and may thus provide a unifying pathophysiological mechanism for these conditions. Two groups of Caucasian subjects with NIDDM were studied. Those with any 4 or 5 features of syndrome X (n = 19) were compared with a group with 0 or 1 feature of syndrome X (n = 25) but similar age, sex distribution, diabetes duration, glycaemic control and diabetes treatment. Healthy non-diabetic subjects of comparable age and sex acted as controls. Overnight urinary albumin excretion rate, a risk factor for cardiovascular disease, was also assayed in subjects to assess its relationship to the acute-phase response. Serum sialic acid was confirmed as a marker of the acute-phase response since serum concentrations were significantly related to established acute-phase proteins such as alpha-1 acid glycoprotein (r = 0.82, p < 0.0001). There was a significant graded increase of serum sialic acid, alpha-1 acid glycoprotein, IL-6 and urinary albumin excretion rate amongst the three groups, with the lowest levels in non-diabetic subjects, intermediate levels in NIDDM patients without syndrome X and highest levels in NIDDM patients with syndrome X. C-reactive protein and cortisol levels were also higher in syndrome X-positive compared to X-negative patients and serum amyloid A was higher in both diabetic groups than in the control group. [HYP] We conclude that NIDDM is associated with an elevated acute-phase response, particularly in those with features of syndrome X. Abnormalities of the innate immune system may be a contributor to the hypertriglyceridaemia, low HDL cholesterol, hypertension, glucose intolerance, insulin resistance and accelerated atherosclerosis of NIDDM . OUTPUT:

entailment

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] In muscle, physiologic hyperinsulinemia, presumably acting on endothelial cells (ECs), dilates arterioles and regulates both total blood flow and capillary recruitment, which in turn influences glucose disposal. In cultured ECs, however, supraphysiological (e.g. >or=10 nM) insulin concentrations are typically used to study insulin receptor (IR) signaling pathways and nitric oxide generation. IGF-I receptors (IGF-IRs) are more abundant than IR in ECs, and they also respond to high concentrations of insulin. To address whether IR mediates responses to physiologic insulin stimuli, we examined the insulin concentration dependence of IR and IGF-IR-mediated insulin signaling in bovine aortic ECs (bAECs). We also assessed whether insulin/IGF-I hybrid receptors were present in bAECs. Insulin, at 100-500 pM, significantly stimulated the phosphorylation of IRbeta, Akt1, endothelial isoform of nitric oxide synthase, and ERK 1/2 but not the IGF-IRbeta subunit. At concentrations 1-5 nm or greater, insulin dose-dependently enhanced the tyrosine phosphorylation of IGF-IRbeta, and this was inhibited by IGF-IR neutralizing antibody. In addition, immunoprecipitation of IRbeta pulled down the IGF-IRbeta, and the IRbeta immunocytochemically colocalized with IGF-IRbeta, suggesting that ECs have insulin/IGF-I hybrid receptors. [HYP] In conclusion, bAECs possess IGF-IR s that mediate physiologic insulin signaling and nitric oxide generation. OUTPUT:

contradiction

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] We have previously shown that transport of plasma insulin into the central nervous system (CNS) is mediated by a saturable mechanism consistent with insulin binding to blood-brain barrier insulin receptors and subsequent transcytosis through microvessel endothelial cells. Since glucocorticoids antagonize insulin receptor-mediated actions both peripherally and in the CNS, we hypothesized that glucocorticoids also impair CNS insulin transport. Nine dogs were studied both in the control condition and after 7 days of high-dose oral dexamethasone (DEX) administration (12 mg/day) by obtaining plasma and cerebrospinal fluid (CSF) samples over 8 h for determination of immunoreactive insulin levels during a 90-min euglycemic intravenous insulin infusion (plasma insulin approximately 700 pmol/l). From these data, the kinetics of CNS insulin uptake and removal were determined using a mathematical model with three components (plasma-->intermediate compartment, hypothesized to be brain interstitial fluid-->CSF). DEX increased basal insulin levels 75% from 24 +/- 6 to 42 +/- 30 pmol/l (P < 0.005) and slightly increased basal glucose levels from 5.0 +/- 0.7 to 5.3 +/- 1.0 mmol/l (P < 0.05). DEX also lowered the model rate constant characterizing CNS insulin transport by 49% from 5.3 x 10(-6) +/- 4.0 x 10(-6) to 2.7 x 10(-6) +/- 1.2 x 10(-6) min-2 (P < or = 0.001). As glucocorticoids are known to reduce CSF turnover, we also hypothesized that the model rate constant associated with CSF insulin removal would be decreased by DEX. As expected, the model rate constant for CSF insulin removal decreased 47% from 0.038 +/- 0.013 to 0.020 +/- 0.088 min-1 (P < or = 0.0005) during DEX treatment. [HYP] We conclude that DEX impairs CNS insulin transport . OUTPUT:

entailment

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] Hyperglycemia was reported to enhance angiotensin (Ang) II generation in rat cardiomyocytes, and Ang II inhibition reduces cardiovascular morbidity and mortality in diabetic patients. In diabetic patients, the enhanced activation of intracellular pathways related with myocyte hypertrophy and gene expression might enhance the progression of cardiac damage. Therefore, we investigated the effects of glucose on Ang II-mediated activation of Janus-activated kinase (JAK)-2, a tyrosine kinase related with myocyte hypertrophy and cytokine and fibrogenetic growth factor overexpression, in ventricular myocytes isolated from nonfailing human hearts (n = 5) and failing human hearts (n = 8). In nonfailing myocytes, JAK2 phosphorylation was enhanced by Ang II only in the presence of high glucose (25 mmol/l) via Ang II type I (AT1) receptors (+79% vs. normal glucose, P < 0.05). JAK2 activation was prevented by inhibitors of reactive oxygen species (ROS) generation (diphenyleneiodonium [DPI], tiron, and apocynin). In myocytes isolated from failing hearts, JAK2 phosphorylation was enhanced by high glucose alone (+107%, P < 0.05). High glucose-induced JAK2 activation was blunted by both ACE inhibition (100 nmol/l ramipril) and AT1 antagonism (1 mumol/l valsartan), thus revealing that the effects are mediated by autocrine Ang II production. Inhibition of ROS generation also prevented high glucose-induced JAK2 phosphorylation. [HYP] In conclusion, in human nonfailing myocytes, high glucose allows Ang II to activate JAK2 signaling, whereas in failing myocytes, hyperglycemia alone is able to induce Ang II generation, which in turn activates JAK2 via enhanced oxidative stress. OUTPUT:

entailment

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] To investigate the mechanism of growth hormone-induced hyperglycemia in diabetes, two studies were done in insulin-dependent diabetic patients receiving intensive insulin therapy with the insulin pump. First, the metabolic response to a standard breakfast following a subcutaneous insulin bolus was examined before and after 20 hourly boluses of intravenous growth hormone in eight patients. Despite unchanged insulin therapy, growth hormone administration produced a marked rise in fasting glucose concentrations (197 +/- 21 v 96 +/- 11 mg/dL), as well as increases in fasting levels of free fatty acids and branched chain amino acids. Nevertheless, postprandial blood glucose increments were only slightly greater after growth hormone (36 +/- 14 v 20 +/- 12 mgdL). Moreover, the increased levels of other insulin-sensitive fuels induced by growth hormone fell to normal following the meal. In a second study, six patients received a low-dose insulin clamp (designed to reproduce the mean postprandial concentrations of glucose and insulin observed in the meal study) before and after growth hormone administration. Despite endogenous glucose overproduction after growth hormone, modest elevations in free insulin (40 to 50 microU/mL) were sufficient to suppress glucose production to an extent comparable to the control day (from 2.8 +/- 0.2 to 0.6 +/- 0.3 mg/kg min after growth hormone v 1.6 +/- 0.1 to 0.4 +/- 0.2 mg/kg min on the control day). However, the normal stimulation of glucose uptake by insulin was abolished by growth hormone. [HYP] We conclude that in insulin -dependent diabetic patients, insulin -stimulated glucose disposal is not impaired by growth hormone. OUTPUT:

contradiction

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] The natural sweetener stevioside, which is found in the plant Stevia rebaudiana Bertoni, has been used for many years in the treatment of diabetes among Indians in Paraguay and Brazil. However, the mechanism for the blood glucose-lowering effect remains unknown. To elucidate the impact of stevioside and its aglucon steviol on insulin release from normal mouse islets and the beta-cell line INS-1 were used. Both stevioside and steviol (1 nmol/L to 1 mmol/L) dose-dependently enhanced insulin secretion from incubated mouse islets in the presence of 16.7 mmol/L glucose (P < .05). The insulinotropic effects of stevioside and steviol were critically dependent on the prevailing glucose concentration, ie, stevioside (1 mmol/L) and steviol (1 micromol/L) only potentiated insulin secretion at or above 8.3 mmol/L glucose (P < .05). Interestingly, the insulinotropic effects of both stevioside and steviol were preserved in the absence of extracellular Ca2+. During perifusion of islets, stevioside (1 mmol/L) and steviol (1 micromol/L) had a long-lasting and apparently reversible insulinotropic effect in the presence of 16.7 mmol/L glucose (P < .05). To determine if stevioside and steviol act directly on beta cells, the effects on INS-1 cells were also investigated. Stevioside and steviol both potentiated insulin secretion from INS-1 cells (P < .05). Neither stevioside (1 to 100 micromol/L) nor steviol (10 nmol/L to 10 micromol/L) influenced the plasma membrane K+ adenosine triphosphate ((K+)ATP)-sensitive channel activity, nor did they alter cyclic adenosine monophosphate (cAMP) levels in islets. [HYP] In conclusion, stevioside and insulin secretion stimulate steviol via a direct action on beta cells. OUTPUT:

contradiction

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] Two animal models, the hypophysectomized (hypox) and the streptozotocin-diabetic rat, both of which are GH-deficient, were used to study the effects of infused IGF I and its molecular size distribution in serum, and to investigate whether GH and IGF I act identically on growth plate chondrocyte maturation. In hypox rats. IGF I (300 microg/rat per day) stimulated body weight gain, total growth plate height and longitudinal growth rate, although less than GH (200 mU/rat per day), and mimicked the effect of GH at all stages of chondrocyte differentiation. including stem cells. Infused IGF I was nearly exclusively found in a < 100 kDa IGF binding protein (IGFBP) complex, whereas free IGF I was barely detectable. These findings argue against the 'dual effector theory' in vivo which postulates priming of the stem cells by GH before IGF I stimulates proliferation. They also suggest that IGF I bound to the < 100 kDa IGFBP complex is bioavailable for growth. In diabetic rats infused with 2.5 mg/rat per day of IGF I, body weight, tibial epiphyseal width and accumulated bone growth increased dramatically despite persisting hyperglycemia. Insulin infusion (2.5 U/rat per day), which nearly normalized elevated blood sugar values, raised endogenous IGF I serum levels and stimulated growth parameters to a similar extent as IGF I, in line with a similar distribution of the infused exogenous and the insulin-induced endogenous IGF I between the free and the < 100 kDa-bound form. Since GH secretion is inhibited in diabetic rats and the animals are resistant to GH action, these results, like those in hypox rats, demonstrate that IGF I can act on growth independently of GH. [HYP] Because insulin restores GH secretion and the responsiveness of the liver to GH in diabetic rats, one may conclude that insulin acts on growth of diabetic rats mainly via restoration of the GH/IGF I axis. OUTPUT:

entailment

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Given a premise and a hypothesis, determine their relationship: entailment, contradiction, or neutral.

[PRE] Adipose tissue controls energy homeostasis and systemic insulin sensitivity through the elaboration of a series of cytokines and hormones, collectively termed "adipokines." We and others have identified Lcn2 as a novel adipokine, but its exact role in obesity-induced insulin resistance remains controversial. The aim of this study was to examine the metabolic phenotype of Lcn2(-/-) mice to clarify the role of Lcn2 in metabolism. Male and female Lcn2(-/-) and wild-type (WT) littermates were placed on either chow or high-fat diet (HFD) to characterize their metabolic phenotype. Studies included body weight and body composition, glucose and insulin tolerance tests, and adipokine expression studies in serum and in white adipose tissue (WAT). Neither chow nor HFD cohorts showed any differences in body weight or body composition. Chow-fed Lcn2(-/-) mice did not exhibit any difference in glucose homeostasis compared with WT mice. Fasting serum glucose levels were lower in the chow-fed Lcn2(-/-) mice, but this finding was not seen in the HFD cohort. Serum adiponectin, leptin, resistin, and RBP4 levels were not different between WT and Lcn2(-/-) on chow diet. HFD-fed male Lcn2(-/-) mice did display a small improvement in glucose tolerance, but no difference in insulin sensitivity was seen in either male or female Lcn2(-/-) mice on HFD. [HYP] We conclude that the global ablation of Lcn2 has a minimal effect on obesity -associated glucose intolerance but does not appear to affect either age- or obesity -mediated insulin resistance in vivo. OUTPUT:

entailment

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Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] Lipid-mediated injury plays an important role in the pathogenesis of many renal diseases including diabetic nephropathy. Liver X receptor-alpha (LXRalpha) is an intracellular sterol sensor that regulates expression of genes controlling cholesterol absorption, excretion, catabolism, and cellular efflux. The present study was aimed at examining the role of LXRalpha in cholesterol metabolism in glomerular mesangial cells. A 1,561-bp fragment of full-length rabbit LXR cDNA was cloned. The deduced protein sequence exhibited 92.4 and 89.2% identity to human and mouse LXRalpha, respectively. Tissue distribution studies showed that rabbit LXRalpha was expressed in the liver, spleen, and kidney. In situ hybridization and RT-PCR assays further indicated that LXRalpha mRNA was widely expressed in the kidney and present in every nephron segment including the glomeruli. To determine intrarenal regulation of LXRalpha, rabbits were treated with thiazolidinedione (TZD) peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, which have been previously shown to enhance LXRalpha expression via PPARgamma and increase cholesterol efflux in macrophages. The results showed that glomerular LXRalpha expression was markedly induced by TZDs. In cultured rabbit mesangial cells, LXRalpha mRNA and protein were detected by RT-PCR and immunoblotting. Treatment of mesangial cells with a specific LXRalpha agonist, TO-901317, significantly increased basal and apolipoprotein AI-mediated cholesterol efflux and markedly enhanced the promoter activity of an LXRalpha target gene, ATP-binding cassette transporter A1 (ABCA1). [HYP] In conclusion, cholesterol efflux is expressed in renal glomeruli and functionally present in mesangial cells where its activation mediates LXRalpha via ABCA1. OUTPUT:

contradiction

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] Hyperglycemia is responsible for many of the vascular complications and metabolic derangements seen in diabetes. One potential regulator of the effects of glucose is the hexosamine biosynthesis pathway (HBP). Glutamine: fructose-6-phosphate amidotransferase (GFA), the first and rate-limiting enzyme in this pathway, catalyzes the transfer of an amino group from glutamine to fructose-6-phosphate to form glucosamine-6-phosphate. Overexpression of GFA in rat-1 fibroblasts results in insulin resistance for glycogen synthase (GS) activity, and renders these cells more sensitive to the effects of glucose. Using rat-1 cells, we examine further the mechanisms whereby hexosamines lead to insulin resistance. Insulin stimulated GS activity was found to occur via a PI-3 kinase (PI-3K)-dependent pathway as wortmannin, an inhibitor of PI-3K, blocked insulin's ability to stimulate GS activity. Subsequently, we examined the effects of hexosamines on PI-3K and Akt/PKB activity. Cells were cultured in 1 mM glucose (low glucose, LG), 20 mM glucose (high glucose, HG), or 1 mM glucose plus 3 mM glucosamine (GlcN) for 16--20 h. After treatment with insulin (100 nM) for 5 min, cell extracts were assayed for IRS-1 associated and total PI-3K activity. At LG, insulin increased PI-3K activity by 43%. There was no insulin stimulation of PI-3K activity in cells cultured in HG or GlcN. There was a trend for IRS-1 protein levels to decrease in HG but not GlcN. PI-3K protein levels were not altered by HG or GlcN. Finally PKB activity was assayed. At LG, insulin stimulated PKB activity. Again, both HG and GlcN significantly reduced insulin's ability to stimulate PKB activity. [HYP] We conclude that the superoxide -mediated insulin resistance of GS activity seen in rat-1 cells is mediated by superoxide regulation of PI-3K and PKB. OUTPUT:

contradiction

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] We have studied the ability of dexamethasone to regulate the glucose transport system in primary cultured adipocytes and delineated the mechanisms of insulin resistance after both acute and chronic treatment. Acutely, 20 nM dexamethasone led to a 65% decrease in basal and a 31% decrement in maximally insulin-stimulated glucose transport (ED50 = 3-4 nM; t1/2 = 50 min). These effects were maximal by 90-120 min, and a plateau was maintained over an additional 1-1.5 h. Chronic dexamethasone exposure (24 h) led to a more profound decrease in basal (77%; ED50 = 0.4 nM) and maximally stimulated (55%; ED50 = 1.0 nM) rates of glucose transport and shifted the transport: insulin dose-response curve to the right by increasing the half-maximally effective insulin concentration from 0.2 to 0.4 ng/ml. Dexamethasone did not affect cell surface insulin binding over 24 h. Both the short and long term effects of dexamethasone were partially blocked by the combined presence of insulin during preincubation and were not modulated by glucose. We also assessed effects on the number and cellular distribution of glucose transporter proteins using the cytochalasin-B binding assay. After 2 h, dexamethasone (30 nM) decreased the number of glucose transporters in plasma membranes by 30% in basal cells and by 41% in maximally insulin-stimulated cells, while increasing the number of low density microsomal transporters by 22-23% (P = NS). Transporter number in a total cellular membrane fraction was unaltered by short term dexamethasone. Chronic dexamethasone exposure (24 h) decreased plasma membrane and low density microsomal transporters by 30-50% in both basal and insulin-stimulated cells and depleted transporters by 43% in a total cellular membrane fraction. [HYP] In conclusion, dexamethasone acutely and chronically decreases glucose transport in primary cultured adipocytes. OUTPUT:

contradiction

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] In this study, we have correlated the translocation of somatostatin (SRIF) receptors from the cell interior to the plasma membrane with the ability of SRIF to inhibit insulin release. Islets were perifused with glucose (30, 100, 165, 200, or 300 mg/dl) in the presence of sodium isethionate. Sodium isethionate inhibits insulin release, but not the recruitment of SRIF receptors. Thus, the recruitment of SRIF receptors to the surface membrane continued without the lysis of secretion vesicles. SRIF binding rose from 3.75 +/- 0.16 to 6.46 +/- 0.28 fmol/10 islets as glucose concentration increased. Sodium isethionate was then removed, islets perifused with low glucose (30 mg/dl), and challenged with 400 microM isobutylmethylxanthine (IBMX) with or without SRIF (5 micrograms/ml). In the islets perifused with high glucose concentration, IBMX lysed a greater number of vesicles and caused enhanced release of insulin. The greater the number of secretion vesicles marginated to the plasma membrane by glucose, the greater the response to IBMX. Colchicine (1 mM) prevented secretion vesicle migration and this potentiation effect of higher concentrations of glucose was eliminated. In experiments with IBMX and SRIF, the degree of inhibition of IBMX-induced insulin release by SRIF was proportional to the magnitude of SRIF binding to these islets. SRIF inhibited insulin release by 20 microU/100 islets initially perifused with low glucose (30 mg/dl) and by 875 microU/100 islets perifused with high glucose (300 mg/dl). The maximal effect of SRIF was observed when its binding reached a level of 5.4 fmol/10 islets. [HYP] We conclude that inhibition of insulin release by SRIF is proportional to the SRIF receptor concentration, and that translocation of SRIF receptors during exocytosis plays an important role in paracrine regulation of insulin secretion by rendering the islets more sensitive to SRIF . OUTPUT:

entailment

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Given a premise and a hypothesis, determine their relationship: entailment, contradiction, or neutral.

[PRE] The present study was conducted to determine the effect of chronic administration of the long-acting beta(2)-adrenergic agonist clenbuterol on rats that are genetically prone to insulin resistance and impaired glucose tolerance. Obese Zucker rats (fa/fa) were given 1 mg/kg of clenbuterol by oral intubation daily for 5 wk. Controls received an equivalent volume of water according to the same schedule. At the end of the treatment, rats were catheterized for euglycemic-hyperinsulinemic (15 mU insulin. kg(-1). min(-1)) clamping. Clenbuterol did not change body weight compared with the control group but caused a redistribution of body weight: leg muscle weights increased, and abdominal fat weight decreased. The glucose infusion rate needed to maintain euglycemia and the rate of glucose disappearance were greater in the clenbuterol-treated rats. Furthermore, plasma insulin levels were decreased, and the rate of glucose uptake into hindlimb muscles and abdominal fat was increased in the clenbuterol-treated rats. This increased rate of glucose uptake was accompanied by a parallel increase in the rate of glycogen synthesis. The increase in muscle glucose uptake could not be ascribed to an increase in the glucose transport protein GLUT-4 in clenbuterol-treated rats. [HYP] We conclude that chronic clenbuterol treatment reduces the insulin resistance of the obese Zucker rat by increasing insulin-stimulated muscle and adipose tissue glucose uptake . OUTPUT:

entailment

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] 3-Deoxyglucosone (3DG), a highly reactive dicarbonyl intermediate generated during glycation, has been confirmed to be markedly elevated in the plasma of patients with diabetes. Our previous study found that there is an association between increasing accumulation of plasma 3DG and impaired glucose regulation in non-diabetic seniors (females, >50 years old; males, >55 years old). It was also found that 3DG led to impaired plasma glucose homeostasis in healthy mice, however, the mechanisms underlying the deleterious effect of 3DG in diabetes remain to be fully elucidated. The present study aimed to investigate the ability of 3DG to cause hepatic insulin resistance in a cell model by assessing glucose uptake and glycogen content. In addition, the molecular signaling events, including the phosphoinositide 3‑kinase (PI3K)/AKT/glucose transporter 2 (GLUT2) and PI3K/AKT/glycogen synthase kinase‑3 (GSK‑3) pathways, which affect hepatic insulin resistance, were further investigated using Western blot analysis. The results showed that 3DG (10‑300 ng/ml) had no significant effect on HepG2 cell viability, however, the viability of the HepG2 cells decreased with exposure to concentrations of 500 and 1,000 ng/ml. Treatment with non‑cytotoxic 3DG concentrations resulted in decreased uptake of glucose and glycogen content with insulin stimulation, but not under basal conditions. The insulin‑induced expression of GLUT2 and p‑GSK‑3 were eliminated by 3DG (80 and 300 ng/ml), in addition to inhibiting the phosphorylation of downstream effectors of the insulin signaling pathway, including insulin receptor substrate 1, PI3K and AKT. [HYP] In conclusion, the findings of the present study indicated that the addition of exogenous 3DG directly contributed to the induction of GFA resistance by impairing GFA signaling in the HepG2 cells, which suggested that 3DG may be involved in worsening of the diabetic condition. OUTPUT:

contradiction

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] Monolayer cultures of neonatal rat pancreatic cells were examined to ascertain whether they synthesize prostaglandin E (PGE) and to determine the effects on insulin secretion caused by PGE and drugs that inhibit its synthesis. PGE release into the medium was observed. Sodium salicylate and ibuprofen (at drug concentrations similar to those achieved therapeutically in humans in vivo) inhibited PGE synthesis in a dose-responsive fashion to a maximum of 70-80% inhibition. Inhibition of PGE synthesis was accompanied by augmented insulin secretion. Both PGE synthesis inhibitors shifted the glucose dose-insulin response curves to the left at low glucose concentrations and augmented maximal insulin release at high glucose concentrations. Increments in glucose-induced insulin secretion induced by sodium salicylate correlated well (r = 0.89) with inhibition of PGE synthesis and addition of exogenous PGE1 to the cultures reversed the augmenting effects of the drug on insulin secretion. [HYP] It is concluded that cultures of pancreatic cells synthesize PGE and that a function of PGE in these cultures appears to be a tonic negative modulation of glucose -induced insulin secretion . OUTPUT:

entailment

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] In this study, the in vivo effects of insulin and chronic treatment with bis(maltolato)oxovanadium (IV) (BMOV) on protein kinase B (PKB) activity were examined in the liver and skeletal muscle from two animal models of diabetes, the STZ-diabetic Wistar rat and the fatty Zucker rat. Animals were treated with BMOV in the drinking water (0.75-1 mg/ml) for 3 (or 8) weeks and sacrificed with or without insulin injection. Insulin (5 U/kg, i.v.) increased PKBalpha activity more than 10-fold and PKBbeta activity more than 3-fold in both animal models. Despite the development of insulin resistance, insulin-induced activation of PKBalpha was not impaired in the STZ-diabetic rats up to 9 weeks of diabetes, excluding a role for PKBalpha in the development of insulin resistance in type 1 diabetes. Insulin-induced PKBalpha activity was markedly reduced in the skeletal muscle of fatty Zucker rats as compared to lean littermates (fatty: 7-fold vs. lean: 14-fold). In contrast, a significant increase in insulin-stimulated PKBalpha activity was observed in the liver of fatty Zucker rats (fatty: 15.7-fold vs. lean: 7.6-fold). Chronic treatment with BMOV normalized plasma glucose levels in STZ-diabetic rats and decreased plasma insulin levels in fatty Zucker rats but did not have any effect on basal or insulin-induced PKBalpha and PKBbeta activities. [HYP] In conclusion (i) in STZ-diabetic rats PKB activity was normal up to 8 weeks of diabetes; (ii) in fatty Zucker rats insulin -induced activation of PKBalpha (but not PKBbeta) was markedly altered in both tissues; (iii) changes in PKBalpha activity were tissue specific; (iv) the glucoregulatory effects of BMOV were independent of PKB activity. OUTPUT:

contradiction

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] Extreme copper deficiency has been shown to enhance CCl4-induced injury in rats. CCl4 hepatotoxicity was studied in rats with copper deficiency moderated by limiting deficiency periods to 5 or 6 weeks, using minimally adequate dietary zinc and including a marginal copper diet. Also, housing some rats in groups of six, rather than individually, was found to moderate the effects of low copper intake. Weanling male rats were fed copper at either 6, 2, or 0.2 mg/kg diet (adequate, marginal, deficient). Copper-zinc superoxide dismutase activity levels for singly and group-housed marginal rats were 80% and 93%, respectively, of adequate values. Values for deficient rats were 35% (singles) and 47% (group). In singly housed rats, a CCl4 dose of 400 microliters/kg intraperitoneally increased serum sorbitol dehydrogenase activities, indicators of cell membrane hepatotoxicity, in inverse proportion to dietary copper. A lower dose (100 microliters/kg) also produced smaller sorbitol dehydrogenase increases in adequate rats compared with deficients, but produced lowest increases in the marginals. The latter pattern also occurred in group-housed rats given the higher CCl4 dose, but the difference for adequate and marginal rats was not significant. The higher CCl4 dose, in singly housed rats, decreased liver glucose-6-phosphatase activities independently of copper intake. These activities are inversely proportional to microsomal lipid damage. [HYP] In conclusion, marginal copper deficiency enhanced CCl4 hepatotoxicity. OUTPUT:

contradiction

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] Increased activity of the hepatic glucose-glucose 6-phosphate (G/G-6-P) cycle is associated with hepatic and peripheral insulin resistance in acromegaly. To determine whether a similar association occurs after short-term growth hormone (GH) elevation within the physiological range, two-step euglycemic hyperinsulinemic clamps were performed in normal human males after 12-h GH (2.2 ng.kg-1 x h-1) and control infusions. G/G-6-P cycle activity and endogenous glucose production (EGP) were determined by [2-3H]- and [6-3H]-glucose using labeled exogenous glucose infusions and selective enzymatic detritiation. GH increased levels of circulating lipid intermediates despite a twofold increase in basal insulin (P < 0.005), but plasma glucose, EGP, and G/G-6-P cycle activity were unchanged. GH impaired insulin suppression of EGP and lipid intermediates and impaired insulin stimulation of glucose disposal, but G/G-6-P cycle activity was unchanged. [HYP] We conclude that increased activity of the G/G-6-P cycle does not contribute to the hepatic insulin resistance induced by GH under these conditions but that changes in fatty acid metabolism may be partly responsible for the impairment in hepatic and peripheral insulin action. OUTPUT:

entailment

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Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] We determined the role of cellular fibronectin (CFN) containing the alternatively spliced extra domain A (FN-EDA) in causing insulin resistance (IR) through toll-like receptor 4 (TLR4). Circulating FN-EDA level was evaluated in mouse and rat IR models. Specific anti-FN-EDA antibody and TLR4 inhibitor were used to study its role in IR in mice. CFN protein was injected to evaluate TLR4 dependent effect of FN-EDA in IR. Furthermore, FN-EDA was estimated in blood plasma and correlated with demographic and clinical characteristics in healthy human participants (n = 38). High-fat diet feeding significantly increased circulating FN-EDA in both mouse (P = 0.03) and rat (P = 0.02) IR models. Antibody against FN-EDA protected mice from IR by increasing glucose disposal rate following glucose (P = 0.02) and insulin (P = 0.01) tolerance tests. CFN protein injection caused IR, however, TLR4 inhibitor protected the mice from CFN induced IR. Multivariate regression analysis predicted an independent positive correlation between circulating FN-EDA and fasting plasma glucose (P = 0.003) in healthy human participants. [HYP] In conclusion, FN-EDA may cause IR through TLR4 by decreasing glucose disposal rate following glucose and insulin load. OUTPUT:

entailment

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] This open, prospective therapeutic trial studied the effects of regular moderate androgen supplementation on bone mineral density in eugonadal men with established osteoporosis, and collected data on the safety of androgen therapy used in this setting. 23 men, aged 34-73 years, with vertebral crush fractures and back pain, in whom secondary causes of osteoporosis had been excluded, were treated with fortnightly intramuscular injections of 250 mg testosterone esters (Sustanon 250(R)) for 6 months. Blood pressure was recorded monthly; fasting lipids, glucose, haematocrit, plasma viscosity, and testosterone levels were measured every 3 months. Psychological effects were assessed using the Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire (GHQ), together with questioning on libido changes. Principal outcomes measured were changes in bone mineral density at the hip and spine by dual-energy X-ray absorptiometry (DEXA) over the treatment period. 21 men completed the study period. Mean bone mineral density at the lumbar spine increased from 0.799 g/cm(2) to 0.839 g/cm(2) during treatment (p < 0. 001), a rise of 5% in 6 months. Bone mineral density at the hip did not change. There were significant, favorable changes in diastolic blood pressure (-4.7 mmHg, p < 0.01), serum triglyceride levels (-0.405 mmol/L,p < 0.01), and total cholesterol (-0.27 mmol/L, p < 0.05). Adverse changes included a fall in HDL cholesterol (-0.087 mmol/L, p < 0.05) and a rise in plasma viscosity which was significant at 3 months but not at 6 months. The expected rises in hematocrit (0.434 to 0.456) and FAI (0.504 to 0.887) occurred. [HYP] We conclude that testosterone supplementation significantly increased bone mineral density in this heterogeneous group of men with idiopathic primary osteoporosis , without an overall adverse effect on cardiovascular risk factors. OUTPUT:

entailment

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Given a premise and a hypothesis, determine their relationship: entailment, contradiction, or neutral.

[PRE] The present study examined, at identical daily nutrient intakes, the impact of separating protein and lactose intakes across two daily meals on the metabolic and endocrine status in heavy veal calves. Calves were assigned to one of six degrees of separating protein and lactose over the two meals (termed nutrient synchrony, SYN 1-6; 6 calves/treatment). They were fed the protein-rich (P-)meal and the lactose-rich (L-)meal at 06:00 and 18:00h, respectively, or vice versa. At SYN 1, calves were fed with 50% of the daily protein and 50% of the daily lactose intake in each meal. Protein and lactose were iso-energetically exchanged between the two daily meals from SYN 1 to 6. At SYN 6, 85% of the daily protein and 20% of the daily lactose was fed in the P-meal and the remainder in the L-meal. Blood samples were collected hourly during 24h. Mean 24h glucose concentrations increased and insulin concentrations decreased from SYN 1 to 6. Postprandial 5h areas under concentration curves (AUC(0-5h)) of glucose increased with increasing meal lactose content. AUC(0-5h) of non-esterified fatty acids increased after P- and L-meals from SYN 1 to 6. Urea concentrations increased after L-meals from SYN 1 to 6, but decreased after P-meals from SYN 1 to 6. Insulin AUC(0-5h) decreased after L-meals and after P-meals from SYN 1 to 6. Nutrient asynchrony did not affect insulin-like growth factor-1, glucagon, growth hormone, leptin, 3,5,3'-triiodothyronine and thyroxine. [HYP] In conclusion, separation of protein and lactose intake over meals inhibited insulin responses to a lactose -rich meal in heavy veal calves despite high plasma glucose concentrations. OUTPUT:

entailment

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Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] Diabetes mellitus causes endothelial dysfunction, which further exacerbates peripheral arterial disease (PAD). Improving endothelial function via reducing endothelial oxidative stress (OS) may be a promising therapy for diabetic PAD. Activation of liver X receptor (LXR) inhibits excessive OS and provides protective effects on endothelial cells in diabetic individuals. Therefore, we investigated the effects of LXR agonist treatment on diabetic PAD with a focus on modulating endothelial OS. We used a streptozotocin-induced diabetes mouse model combined with a hindlimb ischaemia (HLI) injury to mimic diabetic PAD, which was followed by LXR agonist treatment. In our study, the LXR agonist T0901317 protected against HLI injury in diabetic mice by attenuating endothelial OS and stimulating angiogenesis. However, a deficiency in endothelial Sirtuin1 (SIRT1) largely inhibited the therapeutic effects of T0901317. Furthermore, we found that the underlying therapeutic mechanisms of T0901317 were related to SIRT1 and non-SIRT1 signalling, and the isoform LXRβ was involved in LXR agonist-elicited SIRT1 regulation. [HYP] In conclusion, LXR agonist treatment protected against HLI injury in diabetic mice via mitigating endothelial OS and stimulating cellular viability and angiogenesis by LXRβ, which elicited both SIRT1-mediated and non-SIRT1-mediated signalling pathways. OUTPUT:

entailment

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] The aim of this study was to assess the possible relationship between serum levels of Type III procollagen peptide (PIIINP) and peripheral vascular disease (PVD) in diabetic patients. Ninety Type 2 diabetic patients being treated with sulfonylureas, and 37 non-diabetic subjects were studied using Doppler ultrasound. After an overnight fast, blood was taken for PIIINP, glucose, glucosylated hemoglobin (HbA1), C-peptide, and lipids. Data were analysed according to the non-paired Student's t-test and the correlation coefficient, after log transformation. PIIINP levels were significantly elevated in diabetics with PVD (n = 44), 4.3 micrograms/l (2.4-7.6, 95% confidence limits) compared with controls 3.1 micrograms/l (1.9-4.9), P < 0.001, and with diabetics without PVD (n = 46), 3.1 micrograms/l (1.9-5.0), P < 0.001. No correlation was found between PIIINP and HbA1, glucose, C-peptide, age or duration of diabetes. [HYP] We conclude that PIIINP levels are elevated in Type 2 diabetics with PVD . OUTPUT:

entailment

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] The serum pancreatic polypeptide response to intravenous Boots secretin (1.5 U/kg), glucose tolerance, and insulin responses have been studied in 25 patients with chronic alcohol induced pancreatitis of varying severity, and these results compared with a secretin-pancreozymin test, and the structural damage noted on pancreatography. For the pancreatic polypeptide response 16 healthy subjects acted as controls. There was a marked reduction in pancreatic polypeptide response in patients with advanced structural changes of chronic alcohol induced pancreatitis compared with patients with minimal/moderate changes (p less than 0.01) and with healthy controls (p less than 0.05) although there was no difference between the latter two groups. Similarly, while the ratio of peak to mean basal pancreatic polypeptide concentration was also significantly reduced in patients with advanced changes compared with healthy controls (p less than 0.05) there was a marked degree of overlap in patients with lesser degrees of structural damage and control subjects. For all patients with chronic alcohol induced pancreatitis, however, there was a significant correlation between the pancreatic polypeptide response and each parameter of the standard secretin-pancreozymin test and with glucose tolerance and the integrated insulin response. [HYP] We conclude therefore that while the secretin stimulated pancreatic polypeptide response correlates significantly with accepted tests of pancreatic structure and function, there is a significant degree of overlap in the response obtained in patients who have minimal/moderate damage and healthy controls making the test insufficiently sensitive for routine diagnostic use. OUTPUT:

entailment

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] Hypoxia-inducible factor-1α (HIF-1α) in adipose tissue is known to promote obesity. We hypothesized that HIF-1α interferes with brown fat thermogenesis, thus decreasing energy expenditure. To test this hypothesis, we compared transgenic mice constitutively expressing HIF-1α in adipose tissues (HIF-1α++) at usual temperature (22 °C), where brown fat is somewhat active, or at thermoneutrality (30 °C), where brown fat is minimally active. HIF-1α++ mice or control litter mates were separated into room temperature (22 °C) or thermoneutrality (30 °C) groups. We assessed weight gain, food intake, calorimetry, activity, and oxygen consumption and transcriptional changes in isolated white and brown adipocytes. At 22 °C, HIF-1α++ mice exhibited accelerated weight gain, cold and glucose intolerance, hyperglycemia, and decreased energy expenditure without changes in food intake or activity. These changes were absent or minimal at thermoneutrality. In brown adipocytes of HIF-1α++ mice, oxygen consumption decreased ~50 % in association with reduced mitochondrial content, uncoupling protein 2, and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1α). [HYP] In conclusion, adipose HIF-1 α overexpression inhibits thermogenesis and cellular respiration in brown adipose tissue, promoting obesity in the setting of reduced ambient temperature. OUTPUT:

entailment

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] The effect of insulin and glucose on fat-induced gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (7-36 amide) (GLP-1 (7-36 amide)) was studied in five healthy subjects during continuous glucose infusion (Protocol 1) and during hyperinsulinaemic euglycaemic blood glucose clamp (Protocol 2). In Protocol 1, 50 g fat was orally ingested and glucose was infused at a rate of 0.7 g/kg/h for 2 h continuously from the time of fat ingestion. Either glucose infusion alone or fat ingestion alone was carried out in the same subjects as the control. The release of GIP and GLP-1 (7-36 amide) was suppressed in the hyperglycaemic hyperinsulinaemic state. In protocol 2, 50 g of fat was ingested and insulin was infused at a rate of 0.1 U/kg/h with an artificial pancreas system to obtain the normoglycaemic hyperinsulinaemic state. The release of GIP was significantly suppressed in the normoglycaemic hyperinsulinaemic state as well as in the hyperglycaemic hyperinsulinaemic state. However, the release of GLP-1 (7-36 amide) was suppressed in the hyperglycaemic hyperinsulinaemic state but not in the euglycaemic hyperinsulinaemic state. [HYP] Thus, it is concluded that insulin inhibits fat -induced GIP , but not GLP-1 (7-36 amide), secretion and that glucose is likely to inhibit GLP-1 (7-36 amide) secretion. OUTPUT:

entailment

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] Streptococcus mutans is resistant to bacitracin, which is a peptide antibiotic produced by certain species of Bacillus. The purpose of this study was to clarify the bacitracin resistance mechanism of S. mutans. We cloned and sequenced two S. mutans loci that are involved in bacitracin resistance. The rgp locus, which is located downstream from rmlD, contains six rgp genes (rgpA to rgpF) that are involved in rhamnose-glucose polysaccharide (RGP) synthesis in S. mutans. The inactivation of RGP synthesis in S. mutans resulted in an approximately fivefold-higher sensitivity to bacitracin relative to that observed for the wild-type strain Xc. The second bacitracin resistance locus comprised four mbr genes (mbrA, mbrB, mbrC, and mbrD) and was located immediately downstream from gtfC, which encodes the water-insoluble glucan-synthesizing enzyme. Although the bacitracin sensitivities of mutants that had defects in flanking genes were similar to that of the parental strain Xc, mutants that were defective in mbrA, mbrB, mbrC, or mbrD were about 100 to 120 times more sensitive to bacitracin than strain Xc. In addition, a mutant that was defective in all of the mbrABCD genes and rgpA was more sensitive to bacitracin than either the RGP or Mbr mutants. [HYP] We conclude that RGP synthesis is related to mbr genes resistance in S. mutans and that the bacitracin modulate resistance to mbr genes via an unknown mechanism that is independent of RGP synthesis. OUTPUT:

contradiction

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Given a premise and a hypothesis, determine their relationship: entailment, contradiction, or neutral.

[PRE] Mineral acid infusion is used to investigate the effects of acidemia on the cardiovascular and respiratory systems. Previous studies have shown that small infusions of HCl increase mean arterial pressure (MAP), adrenocorticotropic hormone (ACTH), and cortisol without producing acidemia. We infused 1 meq/min of 1 N HCl intravenously into chronically catheterized conscious sheep with or without pretreatment with 1.1 mg/kg flunixin-N-methylglucamine, a cyclooxygenase inhibitor (n = 6). Acid infusion resulted in significant increases in heart rate (83 +/- 5 to 94 +/- 7 beats/min), MAP (84 +/- 3 to 104 +/- 6 mmHg), ACTH (97 +/- 23 to 285 +/- 101 pg/ml), cortisol (20 +/- 3 to 37 +/- 16 ng/ml), sodium (149.5 +/- 0.8 to 150.6 +/- 1.3 meq/l), potassium (3.96 +/- 0.09 to 4.31 +/- 0.19 meq/l), and thromboxane (Tx) B2 (stable metabolite of TxA2) (147 +/- 78 to 2,304 +/- 1,213 pg/ml), whereas these changes were prevented by flunixin. Plasma concentrations of 6-ketoprostaglandin F1 alpha (stable metabolite of prostacyclin), prostaglandin E2, interleukin-1 alpha, and hematocrit did not change in either group. Arterial pH decreased, whereas arterial partial pressure of CO2 increased significantly in both groups. Arterial partial pressure of O2 declined in both groups, but the decrease was significantly greater in the group not receiving flunixin. [HYP] We conclude that a cyclooxygenase metabolite, most likely TxA2, mediates the MAP, heart rate, ACTH, and Metformin responses to mineral acid infusion. OUTPUT:

contradiction

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] Eight GH-deficient subjects received both subtilisin-cleaved human GH (hGH-S) and intact hGH (hGH-I) during short term balance studies to compare the potency of these two forms of GH. Both forms caused nitrogen retention, calciuria, postassium retention, and elevation of blood glucose. The effects on plasma insulin concentrations were inconstant at the doses used. hGH-S was more potent than hGH-I, as measured by nitrogen and potassium retention, and the differences reached levels of statistical significance. hGH-S also caused greater calciuria and increases in fasting the postprandial blood glucose and in postprandial insulin in absolute terms, but these differences did not reach levels of statistical significance. [HYP] In no instance was potassium -I significantly more potent than potassium -S. We conclude potassium -S, a two-chain form of potassium , caused significantly greater nitrogen and hGH retention in human subjects in short term balance studies than potassium -I. OUTPUT:

contradiction

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Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] To evaluate the contribution of gluconeogenesis to epinephrine-stimulated glucose production, we infused epinephrine (0.06 micrograms X kg-1 X min-1) for 90 min into normal humans during combined hepatic vein catheterization and [U-14C]alanine infusion. Epinephrine infusion produced a rise in blood glucose (50-60%) and plasma insulin (30-40%), whereas glucagon levels increased only at 30 min (19%, P less than 0.05). Net splanchnic glucose output transiently increased by 150% and then returned to base line by 60 min. In contrast, the conversion of labeled alanine and lactate into glucose increased fourfold and remained elevated throughout the epinephrine infusion. Similarly, epinephrine produced a sustained increase in the net splanchnic uptake of cold lactate (four- to fivefold) and alanine (50-80%) although the fractional extraction of both substrates by splanchnic tissues was unchanged. [HYP] We conclude that a) gluconeogenesis is a potent stimulator of epinephrine in humans, and b) this effect is primarily mediated by mobilization of lactate and alanine from extrasplanchnic tissues. OUTPUT:

contradiction

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] The main objective of this study was to examine the relation between adverse events and degree of metabolic control and multiple-dose treatment. A total of 139 children, aged between 1 and 18 y, prospectively registered severe hypoglycaemia with or without unconsciousness, as well as hospitalized ketoacidosis, during 1994-95. Treatment from onset was multiple-dose insulin (> 95% > or = 4 doses) combined with intense training and psychosocial support. Median HbA1c was 6.9% (ref. 3.6-5.4%). The incidence of severe hypoglycaemia with unconsciousness was 0.17 events per patient-year, having decreased from the 1970s to the 1990s, parallel to a change from 1-2 to > or = 4 doses per day. There was no correlation or association to the year mean HbA1c for severe hypoglycaemia. Severe hypoglycaemic episodes in 1995 correlated to severe hypoglycaemic episodes in 1994 (r=0.38; p<0.0001). Severe hypoglycaemia with unconsciousness increased during the spring season, and according to case records the assumed causes were mainly mistakes with insulin, food and exercise. Ketoacidosis was rare: 0.015 episodes per patient-year. [HYP] We conclude that multiple-dose insulin therapy from the very onset of diabetes, combined with adequate self-control, active problem-based training and psycho-social support, may limit severe hypoglycaemia and ketoacidosis . OUTPUT:

entailment

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] Ipragliflozin is a novel and selective sodium-glucose cotransporter 2 (SGLT2) inhibitor that induces sustained increases in urinary glucose excretion by inhibiting renal glucose reabsorption and thereby exerting a subsequent antihyperglycemic effect. Here, we examined the effect of ipragliflozin on body weight in high-fat diet-induced (HFD) obese rats. Treatment of ipragliflozin (10mg/kg once daily) reduced body weight despite a slight increase in food intake. Dual-energy X-ray absorptiometry and computed tomography demonstrated that the reduction in body weight was accompanied by reduced visceral and subcutaneous fat masses but not lean mass or bone mineral content. Analysis of plasma and urinary parameters suggested the possibility that ipragliflozin enhanced lipolysis and fatty acid oxidation, and indirect calorimetry showed that ipragliflozin decreased the heat production rate from glucose but increased the rate from fat and lowered the respiratory exchange ratio. [HYP] In conclusion, these data demonstrate that ipragliflozin-induced urinary glucose excretion specifically reduces fat mass with steady calorie loss by promoting the use of fatty acids instead of glucose as an energy source in HFD rats. OUTPUT:

entailment

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Classify the relationship between the premise and the hypothesis into one of three categories: entailment, contradiction, or neutral.

[PRE] Proglycosyn and resorcinol stimulate glycogen synthesis and inhibit glycolysis in hepatocytes. The former effect is attributed to inactivation of phosphorylase mediated by glucuronidated metabolites. This study investigated the mechanism by which resorcinol inhibits glycolysis. Resorcinol (150 microM) inhibited glycolysis in hepatocytes incubated with glucose (15-35 mM) but not with dihydroxyacetone (10 mM). The inhibition of glycolysis at elevated glucose concentration was associated with inhibition of glucose-induced dissociation of glucokinase and aldolase. The resorcinol concentration that caused half-maximal inhibition (20-43 microM) increased with increasing glucose concentration (15-35 mM). Resorcinol inhibited the translocation of glucokinase and the stimulation of detritiation of [2-3H]glucose and [3-3H]glucose caused by sorbitol (10-200 microM), but it potentiated the stimulation of glycogen synthesis. The inhibition of glycolysis by resorcinol could not be accounted for by diversion of substrate to glycogen. The glucose 6-phosphate content correlated with the free glucokinase activity. Resorcinol counteracted the increase in glucose 6-phosphate and fructose 2,6-bisphosphate caused by elevated glucose concentration or by sorbitol. The suppression of glucose 6-phosphate at high glucose concentration (15-35 mM) could be explained by the low activity of free glucokinase. However, the suppression at 5 mM glucose was due in part to an independent mechanism. The effect of resorcinol on glucokinase translocation was partly counteracted by galactosamine, which suppresses UDP-glucose and inhibits glucuronide formation, and was mimicked by phenol and p-nitrophenol but not by p-nitrophenylglucuronide. [HYP] It is concluded that resorcinol promotes glycolysis at elevated glucose concentration or when stimulated by sorbitol through increased glucokinase binding. OUTPUT:

contradiction

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Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] The objective of this study was to investigate the effects of different forms of Se supplementation on the antioxidant defense and glucose homeostasis in experimental diabetes. Sodium selenate (SS) or selenomethionine (SM) were administered (2 micromol Se kg(-1) day(-1)) via orogastric route to streptozotocine (STZ)-induced diabetic rats in addition to basal diet for 12 weeks. Glucose levels in whole blood, glutathione peroxidase (GSH-Px) activity in erythrocytes, Se and fructosamine levels in plasma were evaluated monthly. Plasma Se levels increased significantly in all diabetic groups compared to basal measurements, being more prominent in SM group [p(SM(3)/SM(0)) = 0.018]. The increase in GSH-Px activities was significant at the end of the second month in SS [p(SS(2)/SS(0)) = 0.028], whereas at the end of the third month in SM the value was lower [p(SM3/SM0) = 0.018] and the unsupplemented diabetic control (DC) groups, p(DC(3)/DC(0)) = 0.012. Glucose increased significantly only in DC group. Fructosamine increased gradually in all diabetic groups, being significant in DC and SS groups. At the end of the third month, highest fructosamine levels were observed in SS group, which were significantly higher than the SM group [p(SM/SS) = 0.010]. [HYP] We conclude that Se supplementation in experimental diabetes enhances oxidative stress by increasing GSH-Px activity. OUTPUT:

contradiction

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] Aging and obesity are characterized by decreased beta-cell sensitivity and defects in the potentiation of nutrient-stimulated insulin secretion by GIP. Exercise and diet are known to improve glucose metabolism and the pancreatic insulin response to glucose, and this effect may be mediated through the incretin effect of GIP. The purpose of this study was to assess the effects of a 12-wk exercise training intervention (5 days/wk, 60 min/day, 75% Vo(2 max)) combined with a eucaloric (EX, n = 10) or hypocaloric (EX-HYPO, pre: 1,945 +/- 190, post: 1,269 +/- 70, kcal/day; n = 9) diet on the GIP response to glucose in older (66.8 +/- 1.5 yr), obese (34.4 +/- 1.7 kg/m(2)) adults with impaired glucose tolerance. In addition to GIP, plasma PYY(3-36), insulin, and glucose responses were measured during a 3-h, 75-g oral glucose tolerance test. Both interventions led to a significant improvement in Vo(2 max) (P < 0.05). Weight loss (kg) was significant in both groups but was greater after EX-HYPO (-8.3 +/- 1.1 vs. -2.8 +/- 0.5, P = 0.002). The glucose-stimulated insulin response was reduced after EX-HYPO (P = 0.02), as was the glucose-stimulated GIP response (P < 0.05). Furthermore, after the intervention, changes in insulin (DeltaI(0-30)/DeltaG(0-30)) and GIP (Delta(0-30)) secretion were correlated (r = 0.69, P = 0.05). The PYY(3-36) (Delta(0-30)) response to glucose was increased after both interventions (P < 0.05). [HYP] We conclude that 1) a combination of caloric restriction and exercise reduces the GIP response to ingested glucose , 0.02) GIP may mediate the attenuated glucose -stimulated insulin response after exercise/diet interventions, and 3) the increased PYY(3-36) response represents an improved capacity to regulate satiety and potentially body weight in older, obese, insulin -resistant adults. OUTPUT:

contradiction

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] Portal infusion of glucose at rates approximating endogenous glucose production (EGP) causes paradoxical hypoglycemia in wild-type but not GLUT2 null mice, implying activation of a specific portal glucose sensor. To determine whether this occurs in humans, glucose containing [3-3H]glucose was infused intraduodenally at rates of 3.1 mg. kg-1. min-1 (n = 5), 1.55 mg. kg-1. min-1 (n = 9), or 0/0.1 mg. kg-1. min-1 (n = 9) for 7 h in healthy nondiabetic subjects. [6,6-2H2]glucose was infused intravenously to enable simultaneous measurement of EGP, glucose disappearance, and the rate of appearance of the intraduodenally infused glucose. Plasma glucose concentrations fell (P < 0.01) from 90 +/- 1 to 84 +/- 2 mg/dl during the 0/0.1 mg. kg-1. min-1 id infusions but increased (P < 0.001) to 104 +/- 5 and 107 +/- 3 mg/dl, respectively, during the 1.55 and 3.1 mg. kg-1. min-1 id infusions. In contrast, insulin increased (P < 0.05) during the 1.55 and 3.0 mg. kg-1. min-1 infusions, reaching a peak of 10 +/- 2 and 18 +/- 5 micro U/ml, respectively, by 2 h. Insulin concentrations then fell back to concentrations that no longer differed by study end (7 +/- 1 vs. 8 +/- 1 micro U/ml). This resulted in comparable suppression of EGP by study end (0.84 +/- 0.2 and 0.63 +/- 0.1 mg. kg-1. min-1). Glucose disappearance was higher (P < 0.01) during the final hour of the 3.1 than 1.55 mg. kg-1. min-1 id infusion (4.47 +/- 0.2 vs. 2.6 +/- 0.1 mg. kg-1. min-1), likely because of the slightly, but not significantly, higher glucose and insulin concentrations. [HYP] In conclusion, the paradoxical hypoglycemia caused by portal glucose infusion in wild-type but not GLUT2 null mice occurs in healthy nondiabetic subjects despite activation of a specific portal glucose sensor. OUTPUT:

contradiction

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] In isolated rat pancreatic alpha-cells, glucose, arginine, and the sulfonylurea tolbutamide stimulated glucagon release. The effect of glucose was abolished by the KATP-channel opener diazoxide as well as by mannoheptulose and azide, inhibitors of glycolysis and mitochondrial metabolism. Glucose inhibited KATP-channel activity by 30% (P<0.05; n=5) and doubled the free cytoplasmic Ca2+ concentration. In cell-attached recordings, azide opened KATP channels. The N-type Ca2+-channel blocker omega-conotoxin and the Na+-channel blocker tetrodotoxin inhibited glucose-induced glucagon release whereas tetraethylammonium, a blocker of delayed rectifying K+ channels, increased secretion. Glucagon release increased monotonically with increasing K+ concentrations. omega-Conotoxin suppressed glucagon release to 15 mM K+, whereas a combination of omega-conotoxin and an L-type Ca2+-channel inhibitor was required to abrogate secretion in 50 mM K+. Recordings of cell capacitance revealed that glucose increased the exocytotic response evoked by membrane depolarization 3-fold. This correlated with a doubling of glucagon secretion by glucose in intact rat islets exposed to diazoxide and high K+. In whole-cell experiments, exocytosis was stimulated by reducing the cytoplasmic ADP concentration, whereas changes of the ATP concentration in the physiological range had little effect. [HYP] We conclude that glucose stimulates glucagon release from isolated rat alpha-cells by KATP-channel closure and stimulation of Ca2+ influx through N-type Ca2+ channels. OUTPUT:

entailment

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] The aim of this study was to examine the effects of chronic (8-day) oral treatment with the dual angiotensin-converting enzyme (ACE) and neutral endopeptidase 24-11 (NEP) inhibitor mixanpril (25 mg/kg twice a day), compared with the ACE inhibitor captopril (25 mg/kg twice a day), on whole body insulin-mediated glucose disposal in young (10-week) and old (19-week) obese Zucker rats (ZOs). Moreover, the effects of chronic mixanpril administration on femoral blood flow at rest and during an insulin infusion were assessed. In the young ZOs, mixanpril decreased the glucose response during an IV glucose tolerance test more effectively than did captopril (-49 and -30%, respectively, p < 0.05). Incremental glucose area under the curve in mixanpril-treated ZOs was then no longer different from that observed in vehicle-treated lean rats (1,592 +/- 175 and 1, 470 +/- 104 mg/dl x min, respectively). The beneficial effects resulting from mixanpril or captopril administration were observed in ZOs but not in lean littermates. In the old ZOs, mixanpril induced higher glucose infusion rates to maintain euglycemia than did captopril during a hyperinsulinemic euglycemic clamp test (+92 and +35%, respectively, p < 0.001). However, the glucose infusion rates in mixanpril-treated ZOs remained much lower than that observed in vehicle-treated lean rats (9.4 +/- 0.7 mg/kg/min vs 28.6 +/- 1.0 mg/kg/min, p < 0.001). Mixanpril did not affect resting femoral vascular bed hemodynamics but restored the femoral blood flow response to insulin infusion. [HYP] In conclusion, in ZOs, chronic dual ACE/NEP inhibition improves whole body insulin -mediated glucose disposal more effectively than does ACE inhibition alone. OUTPUT:

entailment

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] The participation of calcium-activated, phospholipid-dependent protein kinase in the phosphorylation of endogenous islet proteins following the exposure of cultured, neonatal pancreatic islets to stimulatory glucose concentrations was investigated by two techniques. In the first technique, islets were prelabeled with 32Pi. The major endogenous substrates for glucose-induced phosphorylation had apparent molecular masses of 130,100 +/- 1010, 100,000 +/- 700, 80,400 +/- 890, 58,100 +/- 1200, 39,800 +/- 700, and 29,400 +/- 700 Da. In the presence of 12-O-tetradecanoylphorbol 13-acetate (2 microM), an activator of calcium-activated phospholipid-dependent kinase, there was enhanced phosphorylation of proteins of 80,000, 40,000, and 29,000 Da. In the second technique, exogenous phosphorylation by [gamma-32P]ATP of proteins in a postnuclear particulate fraction was studied in the presence and absence of cofactors for Ca2+-activated, phospholipid-dependent protein kinase (Ca2+, phosphatidylserine, and unsaturated diolein). These studies were performed in islets preexposed to low (1.7 mM) or high (16.7 mM) glucose concentration prior to preparation of the postnuclear particulate fraction. Following exposure of islets to low glucose concentration, three substrates (apparent molecular masses 40,500 +/- 600, 57,100 +/- 700, and 79,400 +/- 600 Da) in the postnuclear particulate fraction exhibited enhanced phosphorylation in the presence of calcium ions, phosphatidylserine, and unsaturated diolein. In preparations of islets preexposed to 16.7 mM glucose, the phosphorylation of the protein of molecular mass about 40,000 Da was significantly reduced, indicating prior phosphorylation of the acceptor sites on this substrate in response to glucose exposure. [HYP] It is concluded that stimulation of neonatal cultured islets by glucose induces the acute changes in phospholipid ion, calcium , and diacylglycerol concentration required to activate the phospholipid -activated calcium -dependent protein kinase and that the islet postnuclear particulate fraction contains at least one specific substrate for this kinase. OUTPUT:

contradiction

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut hormones that act via the enteroinsular axis to potentiate insulin secretion from the pancreas in a glucose-dependent manner. Both GLP-1 receptor and GIP receptor knockout mice (GLP-1R(-/-) and GIPR(-/-), respectively) have been generated to investigate the physiological importance of this axis. Although reduced GIP action is a component of type 2 diabetes, GIPR-deficient mice exhibit only moderately impaired glucose tolerance. The present study was directed at investigating possible compensatory mechanisms that take place within the enteroinsular axis in the absence of GIP action. Although serum total GLP-1 levels in GIPR knockout mice were unaltered, insulin responses to GLP-1 from pancreas perfusions and static islet incubations were significantly greater (40-60%) in GIPR(-/-) than in wild-type (GIPR(+/+)) mice. Furthermore, GLP-1-induced cAMP production was also elevated twofold in the islets of the knockout animals. Pancreatic insulin content and gene expression were reduced in GIPR(-/-) mice compared with GIPR(+/+) mice. Paradoxically, immunocytochemical studies showed a significant increase in beta-cell area in the GIPR-null mice but with less intense staining for insulin. [HYP] In conclusion, GIPR(-/-) mice exhibit altered islet structure and topography and increased islet sensitivity to GLP-1 despite a decrease in pancreatic insulin content and gene expression. OUTPUT:

entailment

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] Exposure of cardiomyocytes to high glucose concentrations (HG) stimulates reactive oxygen species (ROS) production by NADPH oxidase (NOX2). NOX2 activation is triggered by enhanced glucose transport through a sodium-glucose cotransporter (SGLT) but not by a stimulation of glucose metabolism. The aim of this work was to identify potential therapeutic approaches to counteract this glucotoxicity. In cultured adult rat cardiomyocytes incubated with 21 mM glucose (HG), AMP-activated protein kinase (AMPK) activation by A769662 or phenformin nearly suppressed ROS production. Interestingly, glucagon-like peptide 1 (GLP-1), a new antidiabetic drug, concomitantly induced AMPK activation and prevented the HG-mediated ROS production (maximal effect at 100 nM). α2-AMPK, the major isoform expressed in cardiomyocytes (but not α1-AMPK), was activated in response to GLP-1. Anti-ROS properties of AMPK activators were not related to changes in glucose uptake or glycolysis. Using in situ proximity ligation assay, we demonstrated that AMPK activation prevented the HG-induced p47phox translocation to caveolae, whatever the AMPK activators used. NOX2 activation by either α-methyl-d-glucopyranoside, a glucose analog transported through SGLT, or angiotensin II was also counteracted by GLP-1. The crucial role of AMPK in limiting HG-mediated NOX2 activation was demonstrated by overexpressing a constitutively active form of α2-AMPK using adenoviral infection. This overexpression prevented NOX2 activation in response to HG, whereas GLP-1 lost its protective action in α2-AMPK-deficient mouse cardiomyocytes. Under HG, the GLP-1/AMPK pathway inhibited PKC-β2 phosphorylation, a key element mediating p47phox translocation. [HYP] In conclusion, GLP-47 induces α2-AMPK activation and blocks HG -induced p47phox translocation to the plasma membrane, thereby preventing glucotoxicity. OUTPUT:

contradiction

bionli

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] The present study examined the effect of 5-hydroxytraptamine (5-HT) on the feeding behavior of transgenic mice with neuropeptide Y (NPY) overexpression. Solution of 5-HT (1, 2.5 or 5 mg/kg) was administered intraperitoneally into (1) NPY-overexpressing mice, and (2) wild-type mice with 2-deoxy-d-glucose (2-DG) induced hyperphagia. The NPY-overexpressing mice were further divided into five groups: (1) control mice, (2) mice treated with 5-HT (5 mg/kg), (3) mice treated with 5-HT (5 mg/kg) and ketanserin (0.5 or 1 mg/kg), a 5-HT2A receptor antagonist, (4) mice treated with insulin (1 IU/kg), and (5) mice treated with insulin (1 IU/kg) and 5-HT (5 mg/kg). Food intake and plasma glucose levels were measured. The results showed that 5-HT reduced hyperphagia in both NPY-overexpressing mice and 2-DG-treated mice in dose-dependent manner. Hyperglycemia was induced by 5-HT administration. Ketanserin antagonized the 5-HT induced hypophagia and hyperglycemia. Insulin, on the other hand, prevented 5-HT induced hyperglycemia but not the hypophagic effect. [HYP] In conclusion, 5-HT reduces hyperphagia in the NPY-overexpressing rat through action on 5-HT 2A receptors and this hypophagic effect of 5-HT does not depend on the hyperglycemia. OUTPUT:

entailment

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] Insulin regulates the activity of key enzymes of glucose metabolism in skeletal muscle by altering transcription or translation or by producing activity-altering modifications of preexisting enzyme molecules. Because of the small size of percutaneous muscle biopsies, these phenomena have been difficult to study in humans. This study was performed to determine how physiological hyperinsulinemia regulates the activities of hexokinase (HK), glycogen synthase (GS), and GLUT-4 in human skeletal muscle in vivo. We determined mRNA abundance, protein content, and activities for these proteins in muscle biopsies before and after a hyperinsulinemic clamp in normal subjects. HK I, HK II, GS, and GLUT-4 were expressed in muscle. HK II accounted for 80% of total HK activity and was increased by insulin from a basal value of 2.11 +/- 0.26 to 3.35 +/- 0.47 pmol.min-1.mg protein-1 (P < 0.05); HK I activity was unaffected. Insulin increased GS activity from 3.85 +/- 0.82 to 6.06 +/- 0.49 nmol.min-1.mg-1 (P < 0.01). HK II mRNA was increased 3.3 +/- 1.3-fold (P < 0.05) by insulin infusion. HK I, GS, and GLUT-4 mRNA and protein were unaffected. [HYP] Because insulin infusion increased HK II but not GS mRNA, we conclude that HK II and GS may be regulated by insulin by different mechanisms in human skeletal muscle. OUTPUT:

entailment

bionli

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] Pathways previously proposed for sensory transduction in chemotaxis to oxygen (aerotaxis) involved either (i) cytochrome o, the electron transport system, and proton motive force or (ii) enzyme IIGlucose and the phosphoenolpyruvate:carbohydrate phosphotransferase system for active transport. This investigation distinguished between these possibilities. Aerotaxis was absent in a cyo cyd strain of Escherichia coli that lacked both cytochrome o and cytochrome d, which are the terminal oxidases for the branched electron transport system in E. coli. Aerotaxis, measured by either a spatial or temporal assay, was normal in E. coli strains that had a cyo+ or cyd+ gene or both. The membrane potential of all oxidase-positive strains was approximately -170 mV in aerated medium at pH 7.5. Behavioral responses to changes in oxygen concentration correlated with changes in proton motive force. Aerotaxis was normal in ptsG and ptsI strains that lack enzyme IIGlucose and enzyme I, respectively, and are deficient in the phosphotransferase system. A cya strain that is deficient in adenylate cyclase also had normal aerotaxis. [HYP] We conclude that aerotaxis is mediated by proton motive force generated by the branched electron transport system. OUTPUT:

contradiction

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] We have previously demonstrated that parathyroid hormone (PTH) infusion decreases glucose disappearance rate (Kg) in vivo. Because in the rodent model used it was not possible to determine whether the PTH itself, the induced hypercalcemia, or both contributed to the glucose intolerance, we examined the effect of vitamin D infusion on insulin-mediated glucose disposal. In this model also hypercalcemia is induced but PTH levels are suppressed. Thirty male Sprague Dawley rats were continuously infused with vit D for 5 days using an Alzet miniosmotic pump, at a rate of 9.7 pmol/hour. Thirty controls were infused with the vehicle alone. On the 5th day, glucose 700 mg/kg and insulin 0.35 U/kg were given as a bolus through the left femoral vein and blood samples were obtained from the right femoral vein just prior to and at 2, 5, 10, and 20 minutes post-glucose/insulin infusion. At the end of 5 days, plasma calcium levels were higher in the vit D-infused rats than in the control rats (12.8 +/- 0.1 versus 10.0 +/- 0.1 mg/dL, P < 0.01) and rat PTH levels were suppressed (2.1 +/- 0.1 versus 62 +/- 12 pg/ml, P < 0. 01). Glucose levels were higher in the vit D animals only at 5 minutes following glucose/insulin bolus (375 +/- 7 versus 350 +/- 6 mg/dL, P < 0.01) but at no other time. There were no differences between serum insulin levels at any time. Unlike previous findings in PTH-infused rats, Kg (measured from 2 to 20 minutes following glucose/insulin bolus) was not different between groups (4.5 +/- 0.3 versus 4.7 +/- 0.2, P = 0.92.) A positive correlation between serum calcium and serum glucose was found only at 5 minutes (r = 0.55, P < 0.01) and only in the vit D animals. The areas under the glucose curves approached statistically significant differences (vit D-infused 5258 +/- 142 mg/dL/18 minutes versus control 4947 +/- 127, P = 0.06.) Analysis of serum glucose data by two-factor analysis of variance (ANOVA) suggests that the two groups differ slightly in glucose values (P = 0.03) but have parallel Kg. In order to define whether different effects of PTH (1-34) and vit D on intracellular calcium [Ca2+]i levels could partly explain the different effects of PTH and vit D infusion on glucose disposal, we investigated the effect of PTH and vit D infusions on basal and concanavalin A (con A)-stimulated changes in mononuclear [Ca+2]i levels. Following 5 days of PTH, vit D, or control infusion, peripheral mononuclear cells were incubated with 50 microgram/ml con A. Changes in [Ca+2]i over 5 minutes were calculated by flow cytometric measurement of the calcium sensitive fluo-3 AM dye. Despite achieving significant and comparable degrees of hypercalcemia in the PTH and vit D infused animals, there were no differences in basal or con A-stimulated [Ca+2]i levels from control. [HYP] Consequently, we conclude that vit D-induced PTH associated with suppressed hypercalcemia levels has mild affects on glucose homeostasis but does not affect glucose disappearance rate in vivo (Kg) as does PTH induced by hypercalcemia infusion, and that neither chronic hypercalcemia infusion nor chronic vit D infusion are associated with long-standing changes in [Ca2+]i levels. OUTPUT:

contradiction

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] To determine if increased secretion of amylin can be implicated in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) in vitro and in vivo, we studied its relationships to insulin in insulin-resistant rats with and without NIDDM. In obesity-associated and dexamethasone-induced insulin resistance without diabetes, basal and stimulated secretion of amylin and insulin by isolated pancreata were proportionately elevated, leaving the amylin-to-insulin ratio (A/I) unchanged. By contrast, whenever diabetes occurred in dexamethasone-treated rats or in spontaneously diabetic obese insulin-resistant ZDF-drt male rats, a doubling of A/I was invariably observed due to an increase in amylin without a proportional increase in insulin secretion. Correction of dexamethasone-induced hyperglycemia with the glucocorticord receptor antagonist RU-486 was accompanied by a decline in A/I. Longitudinal in vivo studies demonstrated in both spontaneous and dexamethasone-induced models of NIDDM an increase in plasma A/I at the onset of hyperglycemia. In dexamethasone-induced diabetes, the increased A/I was associated with a high proamylin mRNA relative to proinsulin mRNA. [HYP] We conclude that amylin and insulin expression and secretion rise in concert in compensated insulin-resistant states, but when hyperglycemia is present the increase in amylin exceeds that of insulin. OUTPUT:

entailment

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] Qing-Hua Granule (QHG), the modified formulation of a classical Chinese prescription named Gegen Qinlian Decoction, was clinically employed to treat type 2 diabetes mellitus (T2DM) through regulation of glucagon-like peptide-1 (GLP-1). However, the potential mechanism is unknown. We investigate whether QHG induces GLP-1 secretion via activation of bitter taste receptor (TAS2R) pathway in the gastrointestinal tract of db/db mice. The db/db mice were intragastrically (i.g.) administered QHG (low/medium/high dose) once daily for 8 weeks. GLP-1 secretion was evaluated. The bitter receptor signaling pathway, which regulates GLP-1 secretion, including TAS2R5 (a subtype of TAS2R), α-gustducin (Gαgust), 1-phosphatidylinositol-4, 5-bisphosphate phosphodiesterase beta-2 (PLCβ2), transient receptor potential cation channel subfamily M member 5 (TRPM5), was assessed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot and immunohistochemistry (IHC). The biochemical observations of ileum and pancreas tissue were detected histopathologically. Acquity Ultra Performance LCTM - Micromass ZQ 2000 (UPLC-MS) was used for the phytochemical analysis. QHG exhibited significant and dose-dependent effect on GLP-1 secretion in db/db mice, along with significant up-regulation of TAS2R5 mRNA level and activation of TAS2R pathway (p<0.05). In addition, QHG improved the histopathological structure of ileum and pancreatic tissue. Seventeen compounds were identified in QHG. [HYP] In conclusion, QHG induces GLP-1 secretion in db/db mice, most likely through the bitter taste receptor pathway. OUTPUT:

entailment

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Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] Recently, we reported that C-reactive protein (CRP) elicits inflammatory and procoagulant responses in humans. In addition, CRP has been associated with the development of type 2 diabetes mellitus. To further explore interactions between CRP and glucose handling, we evaluated the effects of CRP infusion on glucose metabolism in humans. Seven healthy white male volunteers (age, 39.3 +/- 16.9 years) received a single bolus infusion of 1.25 mg/kg purified recombinant human (rh) CRP or CRP-free diluent in a crossover design. C-reactive protein infusion induced an inflammatory response, which was followed by increased plasma concentrations of norepinephrine (3 hours) and cortisol (4 hours). Concomitantly, plasma concentrations of insulin and C-peptide decreased transiently. These metabolic changes increased plasma glucose concentrations from 8 hours after CRP infusion, which was preceded by an increased rate of glucose appearance that was a direct consequence of increased gluconeogenesis. [HYP] In conclusion, CRP infusion induces an inflammatory response followed by increased norepinephrine and cortisol levels, which results in increased gluconeogenesis. OUTPUT:

entailment

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] In this paper we investigate the effects of a grape seed procyanidin extract (GSPE) on the metabolic fate of glucose in adipocytes. Differentiated 3T3-L1 cells were treated with 140 mg/L GSPE or 100 nM insulin for a short period (1 h, acute treatment) or for a long period (15 h, chronic treatment). 2-Deoxy-[1-(3)H]glucose uptake and [1-(14)C]glucose incorporation into cells, glycogen, and lipid were measured. We found that GSPE mimicked the anabolic effects of insulin but there were several important differences. GSPE stimulated glycogen synthesis less than insulin. After chronic exposure, GSPE induced a higher incorporation of glucose into lipid, mainly due to the increase in glucose directed to glycerol synthesis. [HYP] Our main conclusions, therefore, are that GSPE has insulinomimetic properties and activates glycogen and lipid synthesis. OUTPUT:

entailment

bionli

train

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] To determine the effects of an increase in lipolysis on the glycogenolytic effect of epinephrine (EPI), the catecholamine was infused portally into 18-h-fasted conscious dogs maintained on a pancreatic clamp in the presence [portal (Po)-EPI+FFA, n = 6] and absence (Po-EPI+SAL, n = 6) of peripheral Intralipid infusion. Control groups with high glucose (70% increase) and free fatty acid (FFA; 200% increase; HG+FFA, n = 6) and high glucose alone (HG+SAL, n = 6) were also included. Hepatic sinusoidal EPI levels were elevated (Delta 568 +/- 77 and Delta 527 +/- 37 pg/ml, respectively) in Po-EPI+SAL and EPI+FFA but remained basal in HG+FFA and HG+SAL. Arterial plasma FFA increased from 613 +/- 73 to 1,633 +/- 101 and 746 +/- 112 to 1,898 +/- 237 micromol/l in Po-EPI+FFA and HG+FFA but did not change in EPI+SAL or HG+SAL. Net hepatic glycogenolysis increased from 1.5 +/- 0.3 to 3.1 +/- 0.4 mg x kg(-1) x min(-1) (P < 0.05) by 30 min in response to portal EPI but did not rise (1.8 +/- 0.2 to 2.1 +/- 0.3 mg x kg(-1) x min(-1)) in response to Po-EPI+FFA. Net hepatic glycogenolysis decreased from 1.7 +/- 0.2 to 0.9 +/- 0.2 and 1.6 +/- 0.2 to 0.7 +/- 0.2 mg x kg(-1) x min(-1) by 30 min in HG+FFA and HG+SAL. Hepatic gluconeogenic flux to glucose 6-phosphate increased from 0.6 +/- 0.1 to 1.2 +/- 0.1 mg x kg(-1) x min(-1) (P < 0.05; by 3 h) and 0.7 +/- 0.1 to 1.6 +/- 0.1 mg x kg(-1) x min(-1) (P < 0.05; at 90 min) in HG+FFA and Po-EPI+FFA. The gluconeogenic parameters remained unchanged in the Po-EPI+SAL and HG+SAL groups. [HYP] In conclusion, increased FFA markedly changed the mechanism by which EPI stimulated hepatic epinephrine production, suggesting that its overall lipolytic effect may be important in determining its effect on the liver. OUTPUT:

contradiction

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] The induction of nitric oxide (NO) synthase in astrocytes by endotoxin and/or cytokine treatment is associated with increased glucose consumption and glycolysis, but the mechanism whereby this phenomenon occurs remains obscure. In this work, we have addressed this issue and found that incubation of cultured rat astrocytes with lipopolysaccharide (LPS; 1 microg/mL) for 24 h increased the level of constitutively expressed GLUT1 glucose transporter mRNA, and triggered GLUT3 mRNA expression, which was absent in normal astrocytes. The occurrence of GLUT3 protein after LPS treatment was corroborated by western blotting and immunocytochemistry. A 4-h incubation of astrocytes in the absence of glucose, or under an oxygen-poor (3%) atmosphere also resulted in GLUT3 mRNA overexpression. Experiments performed with 2-deoxy-D-[U-14C]glucose (at 0.1 mM of D-glucose) confirmed that LPS (0.1-10 microg/mL) dose-dependently increased the rate of glucose uptake (by a factor of 1.6 at 1 microg/mL of LPS), which was paralleled with the increase in NO synthesis. Furthermore, blockade of NO synthase with 2-amino-5,6-dihydro-6-methyl-(4H)-1,3-thiazine (AMT; 50 microM) partially (by 45%) prevented the LPS-mediated increase in glucose uptake. Finally, incubation of astrocytes with the NO donor 1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA; 100 microM) increased by a factor of 1.4 the rate of glucose uptake. [HYP] We conclude that the decrease in GLUT3 -driven glucose uptake in astrocytes would have a neuroprotective role under conditions in which NO formation is combined with hypoglycaemia, such as in brain ischemia. OUTPUT:

contradiction

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Classify the relationship between the premise and the hypothesis into one of three categories: entailment, contradiction, or neutral.

[PRE] The alpha-glucose anomer produces a greater insulin release than beta-glucose in various animal models. These glucose anomers were dissolved rapidly and administered intravenously to human volunteers at a high dose (0.5 g/kg) over a 3-min period or a low dose (3.5 g) over a 20-s period. Blood samples were obtained at frequent time intervals for measurement of whole blood glucose (ferricyanide), plasma glucose (beta-glucose oxidase) and serum immunoreactive insulin. The high-dose infusion test showed no differences between the anomers of either blood glucose or serum insulin levels. However, at the lower dose, the alpha-glucose anomer stimulated a significantly greater insulin release than did beta-glucose. [HYP] It is concluded that the alpha-glucose anomer stimulates a greater insulin release than the beta-glucose anomer in human subjects at low but not at high doses intravenously and that this response is not apparently related to approximations of the degree of mutarotation. OUTPUT:

entailment

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Given a premise and a hypothesis, determine their relationship: entailment, contradiction, or neutral.

[PRE] Arginase has been reported to reduce nitric oxide bioavailability in cardiovascular disease. However, its specific role in retinopathy has not been studied. In this study, we assessed the role of arginase in a mouse model of endotoxin-induced uveitis induced by lipopolysaccharide (LPS) treatment. Measurement of arginase expression and activity in the retina revealed a significant increase in arginase activity that was associated with increases in both mRNA and protein levels of arginase (Arg)1 but not Arg2. Immunofluorescence and flow cytometry confirmed this increase in Arg1, which was localized to glia and microglia. Arg1 expression and activity were also increased in cultured Muller cells and microglia treated with LPS. To test whether arginase has a role in the development of retinal inflammation, experiments were performed in mice deficient in one copy of the Arg1 gene and both copies of the Arg2 gene or in mice treated with a selective arginase inhibitor. These studies showed that LPS-induced increases in inflammatory protein production, leukostasis, retinal damage, signs of anterior uveitis, and uncoupling of nitric oxide synthase were blocked by either knockdown or inhibition of arginase. Furthermore, the LPS-induced increase in Arg1 expression was abrogated by blocking NADPH oxidase. [HYP] In conclusion, these studies suggest that LPS-induced retinal inflammation in endotoxin -induced uveitis is mediated by NADPH oxidase-dependent increases in arginase activity. OUTPUT:

entailment

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Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] Using the euglycemic clamp technique, we investigated the effects of high ketone body levels on basal and insulin-stimulated glucose utilization in normal subjects. Infusion of sodium acetoacetate in the postabsorptive state raised ketone body levels from 150 +/- 20 (+/- SE) mumol/liter to more than 1 mmol/liter. Endogenous glucose production declined from 2.71 +/- 0.20 mg kg-1 min-1 to 1.75 + 0.26 (P less than 0.01) and glucose utilization from 2.71 +/- 0.20 to 1.98 +/- 0.17 mg kg-1 min-1 (P less than 0.01), while blood glucose was maintained at the initial level by the infusion of glucose. There were no changes in plasma glucagon, insulin, or C-peptide. Plasma nonesterified fatty acids (P less than 0.01) and blood glycerol (P less than 0.01) and alanine (P less than 0.05) decreased, while blood lactate increased (P less than 0.01). Infusion of sodium bicarbonate had no effect on glucose kinetics. The decreases in glucose utilization and endogenous glucose production during the infusion of acetoacetate were not modified when the fall of plasma nonesterified fatty acids was prevented by iv heparin injection. During control euglycemic hyperinsulinemic clamps (1 and 10 mU kg-1 min-1 insulin infusion), endogenous glucose production was suppressed at the lowest insulin infusion rate; glucose utilization increased first to 7.32 +/- 0.96 mg kg-1 min-1 and then to 16.5 +/- 1.27 mg kg-1 min-1. During euglycemic hyperinsulinemic clamps with simultaneous sodium acetoacetate infusion, similar insulin levels were attained; endogenous glucose production was also suppressed at the lowest insulin infusion rate, and insulin-stimulated glucose utilization rates (7.93 +/- 1.70 and 15.80 +/- 1.30 mg kg-1 min-1) were not modified. [HYP] In conclusion, acetoacetate infusion decreased basal, but not insulin-stimulated, glucose utilization. OUTPUT:

entailment

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] Adipose tissue is a complex endocrine organ which coordinates several crucial biological functions including fatty acid metabolism, glucose metabolism, energy homeostasis, and immune function. Brown adipose tissue (BAT) is most abundant in young infants during the brain growth spurt when demands for omega-3 docosahexaenoic acid (DHA, 22:6n-3) is greatest for brain structure. Our aim was to characterize relative biosynthesis of omega-3 long chain polyunsaturated fatty acids (LCPUFA) from precursors in cultured white (WAT) and brown (BAT) cells and study relevant gene expression. Mouse WAT and BAT cells were grown in regular DMEM media to confluence, and differentiation was induced. At days 0 and 8 cells were treated with albumin bound d5-18:3n-3 (d5-ALA) and analyzed 24h later. d5-ALA increased cellular eicosapentaenoic acid (EPA, 20:5n-3) and docosapentaenoic acid (DPA, 22:5n-3) in undifferentiated BAT cells, whereas differentiated BAT cells accumulated 20:4n-3, EPA and DPA. DHA as a fraction of total omega-3 LCPUFA was greatest in differentiated BAT cells compared to undifferentiated cells. Undifferentiated WAT cells accumulated EPA, whereas differentiated cells accumulated DPA. WAT accumulated trace newly synthesized DHA. Zic1 a classical brown marker and Prdm16 a key driver of brown fat cell fate are expressed only in BAT cells. Ppargc1a is 15 fold higher in differentiated BAT cells. [HYP] We conclude that in differentiated adipose cells accumulating fat, BAT cells but not WAT cells synthesize DHA , supporting the hypothesis that BAT is a net producer of DHA . OUTPUT:

entailment

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] Prolactin is best known for its involvement in lactation, where it regulates mechanisms that supply nutrients for milk production. In individuals with pathological hyperprolactinemia, glucose and fat homeostasis have been reported to be negatively influenced. It is not previously known, however, whether prolactin regulates lipogenesis in human adipose tissue. The aim of this study was to investigate the effect of prolactin on lipogenesis in human adipose tissue in vitro. Prolactin decreased the concentration of malonyl-CoA, the product of the first committed step in lipogenesis, to 77+/-6% compared to control 100+/-5% (p=0.022) in cultured human adipose tissue. In addition, prolactin was found to decrease glucose transporter 4 ( GLUT4) mRNA expression, which may cause decreased glucose uptake. [HYP] In conclusion, we propose that prolactin decreases lipogenesis in human adipose tissue as a consequence of suppressed malonyl-CoA concentration in parallel with decreased GLUT-4 expression. OUTPUT:

entailment

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] Hyperglycemia, which occurs under the diabetic condition, is widely recognized as the causal link between diabetes and its serious complications. Diabetic neuropathies, which are among the most frequent complications of diabetes, affect sensory, motor, and autonomic nerves. The exact molecular mechanisms of high glucose-induced toxicity on neuronal cells, is still unclear. We previously reported that high glucose can induce apoptosis in PC12 cells, as evidenced by DNA fragmentation and high Bax/Bcl-2 ratio. The present study examined the involvement of caspase-3, the executioner, and two initiators of apoptosis, caspase-8 and caspase-9, during high glucose-induced apoptosis in PC12 cells, a neuronal cell line. Cells were exposed to high glucose with or without z-VAD-fmk, a pan-caspase inhibitor. Cell viability was measured by MTT assay. Caspase activity was determined spectrophotometrically using enzyme specific substrates. To correlate and confirm the caspase activity with changes in protein expression, procaspase-8, -9, and -3 were evaluated by Western blot analysis. The DNA-fragmentation was determined by DNA ladder using gel electrophoresis. The PC12 cell viability on high glucose exposure was decreased compared to controls, which was reversed by z-VAD-fmk. The activities of caspase-8, -9, and -3 were significantly increased in treated cells compared to controls. Moreover, high glucose exposure induced a significant decrease in protein levels of procaspases, indicating conversion of pro-form into the mature caspases. Finally, DNA fragmentation (Ladder) was shown in treated cells by high glucose. [HYP] Based on the current data, it could be concluded that high glucose -induced apoptosis in PC12 cells is mediated, in part, by activation of caspase-8, -9, and -3 dependent pathways. OUTPUT:

entailment

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] We previously reported that endoplasmic reticulum (ER) stress-mediated apoptosis participated in vascular calcification. Importantly, a novel paracrine/autocrine peptide intermedin1-53 (IMD1-53) in the vasculature inhibited vascular calcification in rats. But the mechanisms needed to be fully elucidated. Vascular smooth muscle cells (VSMCs) calcification was induced by CaCl2 and β-glycerophosphate. Tunicamycin (Tm) or dithiothreitol (DTT) was used to induce ER stress. We found that IMD1-53 (10(-7)mol/L) treatment significantly alleviated the protein expression of ER stress hallmarks activating transcription factor 4 (ATF4), ATF6, glucose-regulated protein 78 (GRP78) and GRP94 induced by Tm or DTT. ER stress occurred in early and late calcification of VSMCs but was inhibited by IMD1-53. These inhibitory effects of IMD1-53 were abolished by treatment with the protein kinase A (PKA) inhibitor H89. Pretreatment with IMD1-53 decreased the number of apoptotic VSMCs and downregulated protein expression of cleaved caspase 12 and C/EBP homologous protein (CHOP) in calcified VSMCs. Concurrently, IMD1-53 restored the loss of VSMC lineage markers and ameliorated calcium deposition and alkaline phosphatase activity in calcified VSMCs as well. The observation was further verified by Alizarin Red S staining, which showed that IMD1-53 reduced positive red nodules among calcified VSMCs. [HYP] In conclusion, ER stress attenuated VSMC calcification by inhibiting IMD1-53 through cAMP/PKA signalling. OUTPUT:

contradiction

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] Mammalian and yeast hexokinases were reported to be reversibly inhibited by fructose 2,6-bisphosphate in the presence of cytosolic proteins (H. Niemeyer, C. Cerpa, and E. Rabajille (1987) Arch. Biochem. Biophys. 257, 17-26). Reinvestigation of this finding using a radioassay with [14C]glucose as substrate showed no effect of fructose 2,6-bisphosphate on hexokinase activity of rat liver cytosols. Detailed reexamination of the spectrophotometric assay resulted in the observation that the fructose 2,6-bisphosphate-dependent inhibition was a function of the cytosolic phosphoglucose isomerase and phosphofructokinase activities compared to the amount of glucose-6-phosphate dehydrogenase used as auxiliary enzyme. The diminution or loss of the fructose 2,6-bisphosphate-dependent inhibition produced in aged cytosols was restored by addition of crystalline muscle phosphofructokinase, as well as by decreasing the amount of glucose-6-phosphate dehydrogenase in the assay. When phosphoglucose isomerase, phosphofructokinase, and hexokinase activities were separated by DEAE-chromatography of liver cytosol, no fructose 2,6-bisphosphate-dependent inhibition of hexokinase was found in any single fraction of the chromatogram. However, combination of fractions containing both phosphoglucose isomerase and phosphofructokinase displayed the fructose 2,6-bisphosphate-dependent inhibition on either endogenous hexokinase or added yeast hexokinase. [HYP] It is concluded that cytosolic phosphofructokinase mediates the fructose 2,6-bisphosphate -dependent inhibition of hexokinase. OUTPUT:

contradiction

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] Receptor-specific agonists of the extracellular calcium-sensing receptor (CaSR) potentiate glucose-induced insulin secretion, an effect similar to that of glucagon-like peptide-1 (GLP-1). We have sequenced the full open reading frame of the CaSR from rat insulinoma (INS-1) cells and find that the predicted amino acid sequence of the receptor is identical with that of the receptor from the parathyroid gland. This receptor couples to both Gq/11 and Gi/o, and this dual coupling may partly explain the varying effects of nonspecific agonists on secretion reported previously. L-Histidine (L-His) increases the sensitivity of the CaSR to extracellular Ca2+ and potentiates glucose-dependent insulin secretion from INS-1 cells. This potentiation is partially inhibited at low extracellular [Ca2+] where the CaSR is ineffective. Coexpression of the CaSR and GLP-1 receptor (GLP-1R) produces a pertussis toxin-sensitive inhibition of GLP-1-induced cAMP production in response to elevated extracellular [Ca2+]. However, l-His potentiates cAMP response element reporter activity in INS-1 cells and in human embryonic kidney-293 cells expressing either the GLP-1R alone or the CaSR and GLP-1R. INS-1 cells express the RNA for the CaSR at a lower level than that for the GLP-1R. This difference in expression level of the receptors may explain the potentiation of insulin secretion by L-His despite coupling of the CaSR to Gi/o. [HYP] In conclusion, L-His can potentiate both GLP-1R- and CaSR-activated signaling pathways, and these effects may play a role in the potentiation of insulin secretion -induced glucose in response to meals containing protein in addition to carbohydrates and fat. OUTPUT:

contradiction

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] Previously, we demonstrated that maternal diabetes reduced the excitability and increased small-conductance Ca(2+)-activated K(+) (SK) currents of parasympathetic cardiac motoneurons (PCMNs) in the nucleus ambiguus (NA). In addition, blockade of SK channels with apamin completely abolished this reduction. In the present study, we examined whether maternal diabetes affects large-conductance Ca(2+)-activated K(+) (BK) channels and whether BK channels contribute to the attenuation of PCMN excitability observed in neonates of diabetic mothers. Neonatal mice from OVE26 diabetic mothers (NMDM) and normal FVB mothers (control) were used. The pericardial sac of neonatal mice at postnatal days 7-9 was injected with the tracer X-rhodamine-5 (and 6)-isothiocyanate 2 days prior to the experiment to retrogradely label PCMNs in the NA. Whole cell current- and voltage-clamps were used to measure spike frequency, action potential (AP) repolarization (half-width), afterhyperpolarization potential (AHP), transient outward currents, and afterhyperpolarization currents (I(AHP)). In whole cell voltage clamp mode, we confirmed that maternal diabetes increased transient outward currents and I(AHP) compared with normal cells. Using BK channel blockers charybdotoxin (CTx) and paxilline, we found that maternal diabetes increased CTx- and paxilline-sensitive transient outward currents but did not change CTx- and paxilline-sensitive I(AHP). In whole cell current-clamp mode, we confirmed that maternal diabetes increased AP half-width and AHP, and reduced excitability of PCMNs. Furthermore, we found that after blockade of BK channels with CTx or paxilline, maternal diabetes induced a greater increase of AP half-width but similarly decreased fast AHP without affecting medium AHP. Finally, blockade of BK channels decreased spike frequency in response to current injection in both control and NMDM without reducing the difference of spike frequency between the two groups. [HYP] Therefore, we conclude that although PCMN transient outward currents, which may alter AP repolarization, are increased in NMDM, PCMN channels do not directly contribute to maternal diabetes-induced attenuation of BK excitability. OUTPUT:

contradiction

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] Dehydration hastens the decline in cerebral blood flow (CBF) during incremental exercise, whereas the cerebral metabolic rate for O2 (CMRO2 ) is preserved. It remains unknown whether CMRO2 is also maintained during prolonged exercise in the heat and whether an eventual decline in CBF is coupled to fatigue. Two studies were undertaken. In study 1, 10 male cyclists cycled in the heat for ∼2 h with (control) and without fluid replacement (dehydration) while internal and external carotid artery blood flow and core and blood temperature were obtained. Arterial and internal jugular venous blood samples were assessed with dehydration to evaluate CMRO2 . In study 2, in 8 male subjects, middle cerebral artery blood velocity was measured during prolonged exercise to exhaustion in both dehydrated and euhydrated states. After a rise at the onset of exercise, internal carotid artery flow declined to baseline with progressive dehydration (P < 0.05). However, cerebral metabolism remained stable through enhanced O2 and glucose extraction (P < 0.05). External carotid artery flow increased for 1 h but declined before exhaustion. Fluid ingestion maintained cerebral and extracranial perfusion throughout nonfatiguing exercise. During exhaustive exercise, however, euhydration delayed but did not prevent the decline in cerebral perfusion. [HYP] In conclusion, during prolonged exercise in the heat, CBF accelerates the decline in dehydration without affecting CMRO2 and also restricts extracranial perfusion. OUTPUT:

contradiction

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] Diabetic nephropathy is characterised by an increase in glomerular and tubular fibrosis that compromises kidney function. The transforming growth factor-betas (TGF-betas) have been shown to play a major role in fibrosis and we have shown that TGF-beta2, in particular, increases co-ordinately with fibrogenesis in the diabetic kidney. The aim of this study was to investigate the changes in expression of extracellular matrix molecules in the diabetic kidney, with and without systemic administration of a recombinant human monoclonal antibody to TGF-beta2. Streptozotocin-induced diabetic rats were split into two groups. The first were treated with 5 mg/kg irrelevant control IgG4 (placebo) and the second treated with 5 mg/kg isoform-specific recombinant monoclonal anti-TGF-beta2 IgG4 (termed CAT-152) systemically every second day for 14 days. A further group of six non-diabetic rats was also used as a control. Various biological parameters were measured daily throughout the experimental period, and on termination of the experiment at 14 days Western blotting was performed on kidney cortices for procollagen-I C-propeptide, which is an indicator of the rate of collagen-I synthesis within the kidney. In the placebo-treated diabetic rats, blood glucose, food consumption, urinary albumin excretion (UAE) and kidney weights were all significantly higher than in the non-diabetic group (P<0.05, n=24, by ANOVA). In the anti-TGF-beta2-treated diabetic rats, kidney weights and UAE levels were decreased when compared with those in placebo-treated diabetics. Western blotting for the procollagen-I C-propeptide in kidney cortices showed a significant increase in levels in placebo-treated diabetic rats compared with non-diabetic controls over the 14 day diabetic period, indicating initiation of fibrogenesis. By contrast, in anti-TGF-beta2-treated diabetic rats, levels of the propeptide remained at non-diabetic levels. In summary, a significant suppression of kidney fibrosis was seen in anti-TGF-beta2-treated diabetic rats, compared with placebo-treated diabetic rats. [HYP] We conclude that systemic delivery of CAT-152 , a neutralising anti-TGF-beta2 antibody, during the acute stages of diabetic nephropathy reduces the rate of pathogenic fibrosis in the kidney. OUTPUT:

entailment

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] The effect of glibenclamide treatment on insulin action in isolated fat cells was studied in eight moderately obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Insulin receptor binding and the effect of insulin on glucose transport and lipogenesis were determined before and after 3 months of glibenclamide therapy. At the end of the treatment period, mean daytime plasma glucose concentrations were reduced (10.8 +/- 0.4 versus 7.0 +/- 0.3 mmol/L, p less than 0.001) whereas mean daytime plasma insulin level was increased (40 +/- 12 versus 71 +/- 9 mU/L, p less than 0.001). Adipocyte insulin receptor binding as well as basal glucose transport and metabolism were unaffected by drug treatment. In contrast, insulin-stimulated glucose transport and lipogenesis were both significantly enhanced (p less than 0.05). These findings are comparable to those of another study involving seven moderately obese subjects with NIDDM who had biopsies of the lateral vastus muscle taken for measurement of insulin receptor function and glycogen synthase activity before and during 2 months of gliclazide treatment. In that study insulin receptors purified with wheatgerm agglutinin showed unchanged insulin binding and receptor kinase activity. Moreover, gliclazide had no impact on maximal glycogen synthase activity. However, under physiologic hyperinsulinemic conditions gliclazide therapy was associated with an increased sensitivity of glycogen synthase for its allosteric activation by glucose-6-phosphatase (p less than 0.04). [HYP] In conclusion, sulfonylurea treatment of NIDDM enhances insulin -stimulated peripheral glucose utilization in part through a potentiation of insulin action on adipose tissue glucose transport and lipogenesis and skeletal muscle glycogen synthase. OUTPUT:

entailment

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] Regulation of calcium balance is important in the secretory function of pancreatic islets. Ca2+-adenosine triphosphatase (ATPase) is altered in tissues of non-insulin-dependent diabetes mellitus (NIDDM) rats, and they have an impaired response to glucose, "glucose blindness." We propose that the glucose blindness of the diabetic islet is the result of defective cellular calcium metabolism. Since Ca2+-ATPase activity is important in the regulation of calcium balance, we investigated the effect of glucose and/or calcium on Ca2+-ATPase activity in pancreatic islets in vitro and compared it with the effect in freshly isolated islets from controls and from rats with NIDDM induced by streptozotocin neonatally. Islets were isolated using collagenase and were stored fresh or cultured up to 2 days in RPMI 1640 in the presence of different concentrations of glucose and calcium. Membrane Ca2+-ATPase activity, insulin secretion, and insulin content were determined. Ca2+-ATPase activity was 1.30 +/- 0.20 micromol/L Pi/microg membrane protein in normal noncultured islets and 1.02 +/- 0.15 in islets cultured in 5.6 mmol/L glucose. Ca2+-ATPase activity progressively decreased to 0.56 +/- 0.10 and 0.34 +/- 0.14 micromol/L Pi/microg membrane protein when glucose was increased in the culture media to 16.6 and 27.7 mmol/L, respectively. Decreasing glucose to 2.8 mmol/L did not alter Ca2+-ATPase activity. Increasing or decreasing the Ca2+ content of the media did not significantly change Ca2+-ATPase activity. Islets isolated from NIDDM rats had lower basal Ca2+-ATPase activity and insulin content compared with normal controls. Incubation of islets from diabetic rats in high glucose further decreased the Ca2+-ATPase content, but incubation in low glucose did not reverse it. Insulin secretion was responsive to glucose and calcium in normal islets, but was suppressed in islets from diabetic animals. [HYP] From these studies, we conclude that high Ca2 , but not calcium, decreases glucose +-ATPase activity in islets from normal rats. OUTPUT:

contradiction

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Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] Glucose and palmitate synergistically stimulate insulin secretion, but chronically elevated they induce apoptotic β-cell death. The glucotoxic effect has been attributed, at least partly, to the upregulation of the oxidative stress marker thioredoxin interacting protein (TXNIP). Palmitate downregulates TXNIP expression, the functional significance of which is still under debate. This study examines the mechanism and consequence of palmitate-mediated TXNIP regulation in insulin secreting cells. Palmitate (600 μM) reduced TXNIP mRNA levels in isolated human and mouse islets independently of FFAR1/GPR40. Similar effects of palmitate were observed in INS-1E cells and mimicked by other long chain fatty acids. The lowering of TXNIP mRNA was significant already 1 h after addition of palmitate, persisted for 24 h and was directly translated to changes in TXNIP protein. The pharmacological inhibition of palmitate-induced phosphorylation of AMPK, ERK1/2, JNK and PKCα/β by BML-275, PD98059, SP600125 and Gö6976, respectively, did not abolish palmitate-mediated TXNIP downregulation. The effect of palmitate was superimposed by a time-dependent (8 h and 24 h) decline of TXNIP mRNA and protein. This decline correlated with accumulation of secreted insulin into the medium. Accordingly, exogenously added insulin reduced TXNIP mRNA and protein levels, an effect counteracted by the insulin/IGF-1 receptor antagonist linsitinib. The inhibition of PI3K and Akt/PKB increased TXNIP mRNA levels. The histone deacetylase (HDAC1/2/3) inhibitor MS-275 completely abrogated the time-dependent, insulin-mediated reduction of TXNIP, leaving the effect of palmitate unaltered. Acute stimulation of insulin secretion and chronic accentuation of cell death by palmitate occurred independently of TXNIP regulation. On the contrary, palmitate antagonized glucose-augmented ROS production. [HYP] In conclusion, glucose -induced TXNIP expression is efficiently antagonized by two independent mechanisms, namely via an autocrine activation of insulin/IGF-1 receptors involving HDAC and by palmitate attenuating oxidative stress of β-cells. OUTPUT:

entailment

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] Pomegranate peel is an agro-industrial residue obtained after fruit processing with high total polyphenol (TP) content, making it an attractive by-product for its reuse. Pomegranate peel extract (PPE) and its bioactive compounds have shown positive effects on obesity models. Effects on favouring mitochondrial biogenesis and function have also been described. However, once phenolic compounds are extracted, their stability can be affected by diverse factors. Microencapsulation could improve PPE stability, allowing its incorporation into functional foods. Nevertheless, studies on the potential biological effects of PPE microparticles (MPPE) in obesity models are lacking. This study aims to evaluate the effect of MPPE on brown adipose tissue (BAT) mitochondrial structure and function and metabolic alterations related to obesity in mice fed a high-fat diet (HFD). PPE was microencapsulated by spray drying using inulin (IN) as a wall material and physically-chemically characterised. Eight-week-old male C57BL/6J mice (n 40) were randomly distributed into five groups: control diet (CD), HFD, HFD + IN, HFD + PPE (50 mg/kg per d TP) and HFD + MPPE (50 mg/kg per d TP), for 14 weeks. A glucose tolerance test and indirect calorimetry were conducted. Blood and adipose tissue samples were obtained. MPPE supplementation prevented HFD-induced body weight gain (P < 0·001), fasting glycaemia (P = 0·007) and total cholesterol rise (P = 0·001). MPPE resulted in higher BAT mitochondrial complex IV activity (P = 0·03) and prevented HFD-induced mitochondrial cristae alteration (P = 0·02). [HYP] In conclusion, body weight prevented HFD-induced excessive MPPE gain and associated metabolic disturbances, potentially by activating complex IV activity and preserving mitochondrial cristae structure in BAT in mice fed with a HFD. OUTPUT:

contradiction

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] We tested retinyl palmitate for in vivo effects in man and in vitro effects on the IM-9 lymphocyte insulin receptor. Intravenous glucose tolerance tests (IVGTT) with 25 g glucose were performed on 10 healthy subjects before and after two intramuscular injections of retinyl palmitate (25,000 IU) 18 hours apart. In 9 of 10 subjects, glucose disposition was impaired after treatment with retinyl palmitate. In vitro, retinyl palmitate 10(-4) - 10(-6) M did not affect the binding or displacement of insulin 125I from lymphocyte receptors. [HYP] We conclude that retinyl palmitate decreases glucose tolerance without demonstrable effects on insulin release or insulin binding to receptors. OUTPUT:

entailment

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Classify the relationship between the premise and the hypothesis into one of three categories: entailment, contradiction, or neutral.

[PRE] Neurite plasticity is a critical aspect of brain functional recovery after stroke. Emerging data suggest that Ras-related C3 botulinum toxin substrate 1 (Rac1) plays a central role in axonal regeneration in the injured brain, specifically by stimulating neuronal intrinsic growth and counteracting the growth inhibitory signaling that leads to growth cone collapse. Therefore, we investigated the functional role of Rac1 in axonal regeneration after stroke.Delayed treatment with a specific Rac1 inhibitor, NSC 23766, worsened functional recovery, which was assessed by the pellet reaching test from day 14 to day 28 after stroke. It additionally reduced axonal density in the peri-infarct zone, assessed 28 days after stroke, with no effect on brain cavity size or on the number of newly formed cells. Accordingly, Rac1 overexpression using lentivirus promoted axonal regeneration and functional recovery after stroke from day 14 to day 28. Rac1 inhibition led to inactivation of pro-regenerative molecules, including mitogen-activated protein kinase kinase (p-MEK)1/2, LIM domain kinase (LIMK)1, and extracellular signal-regulated kinase (p-ERK)1/2 at 14 days after stroke. Inhibition of Rac1 reduced axonal length and number in cultured primary mouse cortical neurons using microfluidic chambers after oxygen-glucose deprivation (OGD) without affecting cell viability. [HYP] In conclusion, Rac1 inhibition promoted axonal regeneration and functional recovery after stroke. OUTPUT:

contradiction

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] Two isoforms of sphingosine kinase, SK1 and SK2, catalyze the formation of the bioactive lipid sphingosine 1-phosphate (S1P) in mammalian cells. We have previously shown that treatment of androgen-sensitive LNCaP prostate cancer cells with a non-selective SK isoform inhibitor, 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SKi), induces the proteasomal degradation of SK1. This is concomitant with a significant increase in C22:0-ceramide and sphingosine levels and a reduction in S1P levels, resulting in the apoptosis of LNCaP cells. In contrast, we show here that a SK2-selective inhibitor, (R)-FTY720 methyl ether (ROME), increases sphingosine and decreases S1P levels but has no effect on ceramide levels and does not induce apoptosis in LNCaP cells. We also show that several glycolytic metabolites and (R)-S-lactoylglutathione are increased upon treatment of LNCaP cells with SKi, which induces the proteasomal degradation of c-Myc. These changes reflect an indirect antagonism of the Warburg effect. LNCaP cells also respond to SKi by diverting glucose 6-phosphate into the pentose phosphate pathway to provide NADPH, which serves as an antioxidant to counter an oxidative stress response. SKi also promotes the formation of a novel pro-apoptotic molecule called diadenosine 5',5'''-P(1),P(3)-triphosphate (Ap3A), which binds to the tumor suppressor fragile histidine triad protein (FHIT). In contrast, the SK2-selective inhibitor, ROME, induces a reduction in some glycolytic metabolites and does not affect oxidative stress. [HYP] We conclude that c-Myc functions to increase the stability of SK1 and suppresses Ap3A formation, which might maintain the Warburg effect and cell survival, while SK2 exhibits a non-overlapping function. OUTPUT:

contradiction

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] The macrovascular complications of non-insulin-dependent diabetes mellitus (NIDDM) are related to the features of insulin resistance (IR). High Factor VII:C (FVII:C) levels are associated with increased cardiovascular risk and relate to a base change in the FVII gene detected by Msp I endonuclease, and also to an insertion polymorphism in the promoter region. To examine the association between FVII:C levels, genotype and features of IR, 95 NIDDM patients were studied. Genotype was related to FVII:C levels (M1M1 137%, n = 75; M1M2 and M2M2 114%, n = 20, p < 0.005; AA 136%, n = 71; Aa 119%, n = 21, p < 0.05), which is consistent with previous studies in healthy populations. FVII:C correlated with cholesterol (r = 0.51, p < 0.0005), insulin (r = 0.36, p = 0.002), triglycerides (r = 0.34, p = 0.001), age (r = 0.23, p < 0.005) and body mass index (r = 0.23, p < 0.05). When analysed by Msp I genotype, the stronger predictor of FVII:C levels, these correlations remained, with no difference in regression slopes. In a multiple regression model, genotype, cholesterol, insulin, and gender remained as independent predictors of FVII:C levels. [HYP] In conclusion, FVII:C concentrations are elevated in NIDDM in relation to both FVII genotypes and features of IR. OUTPUT:

entailment

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] Protein kinase C (PKC) is implicated in the pathogenesis of diabetic nephropathy. This study was designed to identify the expression of diacylglycerol (DAG)-sensitive PKC-alpha, -betaII, -delta, and -epsilon isoforms in normal and diabetic rat glomerular cells and to determine the effects of high glucose and insulin on PKC isoform cellular compartmentalization and PKC activity. Diabetic rats treated with or without insulin and normal rats were examined 2 and 4 weeks after streptozotocin/vehicle injection. Renal cortical tissue immunogold-labeled with anti-PKC-alpha, -betaII, -delta, or -epsilon antibody was visualized by electron microscopy. From isolated glomeruli, total cell lysate and cytosol and membrane fractions were immunoblotted with the same anti-PKC isoform antibodies. PKC activity in isolated glomeruli was measured by 32P-phosphorylation of the epidermal growth factor (EGF)-receptor substrate. Immunogold labeling revealed expression of the four PKC isoforms by glomerular visceral epithelial, endothelial, and mesangial cells of both normal and diabetic rats. Immunoblot analysis of the diabetic rat glomeruli at 2 weeks demonstrated a significant increase in membrane-associated PKC-alpha, -delta, and -epsilon and a significant decrease in membrane PKC-betaII content compared with normal, which were similar at 4 weeks. Insulin treatment normalized membrane PKC isoform contents and caused a significant decrease in the cytosol content of PKC-alpha, -betaII, and -delta and total cellular PKC-alpha compared with normal. Although PKC activity in the cells of diabetic rat glomeruli was increased by 20% compared with normal, the difference did not reach statistical significance. In insulin-treated diabetic rat glomeruli, PKC activity was significantly decreased compared with non-insulin-treated diabetic rat glomeruli. [HYP] In conclusion, DAG-sensitive PKC-alpha, -betaII, -delta, and -epsilon isoforms are all found in the three major glomerular cell types in rats, and the expression, compartmentalization, and activity are modulated independently by high glucose and insulin . OUTPUT:

entailment

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] High circulating fasting and prandial triglyceride levels are associated with both insulin resistance and the development of cardiovascular disease. The aim of this investigation was to study the effects of NO-1886, a novel lipoprotein lipase (LPL) activator, on triglyceride levels, fat oxidation, and glucose tolerance in fructose-fed rats, a hypertriglyceridemic model of insulin resistance. Adult male Wistar rats were fed for 4 weeks with a high-starch diet or a high-fructose diet without and with NO-1886 (50 mg x kg[-1] x d[-1] orally). Fructose feeding increased plasma triglyceride levels, an effect that was ameliorated by NO-1886 treatment (week 1/week 4: starch-fed, 2.4 +/- 0.1/2.8 +/- 0.2 mmol/L; fructose-fed, 3.6 +/- 0.5/5.5 +/- 0.5; fructose + NO-1886, 2.7 +/- 0.2/3.6 +/- 0.3). The mean 24-hour respiratory quotient (RQ) was significantly lower in the fructose + NO-1886 group compared with fructose-fed rats, indicating increased oxidation of fat. Fructose feeding elevated liver triglyceride levels by 74% (P < .01), an effect not altered by NO-1886. Red and white quadriceps hindlimb muscle triglyceride levels were not different between groups. Glucose tolerance (intravenous test in long-term cannulated rats) was mildly deteriorated and fasting insulin and glucose levels were elevated in fructose-fed rats, effects which were ameliorated by NO-1886. [HYP] In conclusion, in the fructose-fed rat model of hypertriglyceridemia and insulin resistance, addition of a LPL activator reduced circulating glucose levels without causing increased muscle glucose accumulation or deterioration in triglyceride tolerance. OUTPUT:

contradiction

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Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] Adipose tissue leptin mRNA levels are decreased by food deprivation or induction of insulin-deficient diabetes. To determine whether plasma leptin concentrations are similarly affected, whether treatment of diabetes with insulin restores plasma leptin, and whether this requires restoration of body weight (lost as a result of diabetes) and/or normalization of glycemia, we measured plasma leptin concentrations in control, untreated streptozotocin (STZ)-diabetic, and insulin-treated STZ-diabetic rats. Plasma leptin was markedly reduced in untreated STZ-diabetic rats. Insulin treatment for 4 to 17 days increased plasma leptin approximately twofold above control levels. However, despite the hyperleptinemia, insulin-treated diabetic rats gained weight at a rate equal to that of sham-treated controls. Epididymal adipose tissue leptin mRNA levels in 17-day insulin-treated diabetic rats were equal to but did not exceed sham-control levels, unlike plasma leptin. Plasma glucose concentrations in insulin-treated STZ-diabetic rats were lower than in sham controls. Therefore, to determine whether hypoglycemia may be important in increasing plasma leptin, we measured plasma leptin levels in diabetic rats infused with insulin for 3 hours along with a variable-rate glucose infusion targeting glycemia to 200 or 40 mg/100 mL. Plasma leptin rapidly increased in these rats irrespective of target glycemia. Plasma leptin also increased rapidly in normal rats infused with insulin and glucose (target glycemia, 200 mg/100 mL). [HYP] We conclude that both insulin treatment and normalization of glycemia increase plasma leptin . OUTPUT:

contradiction

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] Platelets obtained from some diabetic patients show enhanced in vitro platelet aggregation. These studies were designed to determine if platelets obtained from diabetic subjects manifest increased metabolism of arachidonic acid to labile aggregating substances, such as thromboxane A2 (TXA2), and if they play a role in the enhanced platelet aggregation. Arachidonic acid stimulated TXA2 synthesis, as determined via radioimmunoassay of its stable metabolite TXB2, was significantly greater (p less than 0.01, n = 12) in platelet-rich plasma obtained from diabetic compared to matched controls. Arachidonic acid stimulated TXB2 synthesis in the diabetic platelet-rich plasma was positively correlated with the ambient fasting plasma glucose (r = 0.61, p less than 0.02, n = 15). Platelet aggregation induced by arachidonic acid (0.4-0.8 mM) was inhibited significantly less by 13-azaprostanoic acid (p less than 0.04, n = 14), an antagonist of the actions of prostaglandin H2 or TXA2 on platelets, compared to matched controls. [HYP] We conclude that platelets obtained from some diabetic subjects manifest increased metabolism of arachidonic acid to labile aggregating substances which may contribute to the enhanced platelet aggregation . OUTPUT:

entailment

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] Glycogen synthase kinase 3beta (GSK3beta) is increased by high glucose in mesangial cells. Thus, we studied the role of GSK3beta in advanced glycation end-product (AGE)-induced effects in the proximal tubule-like LLC-PK1 cells. We found that AGE (100 microg/ml) time-dependently (8-48 h) increased phospho-GSK3beta-Tyr216 (active GSK3beta) and time-dependently (4-24 h) decreased phospho-GSK3beta-Ser21/9 (inactive GSK3beta) protein expression. Meanwhile, AGE (100 microg/ml) activated GSK3beta kinase at 8-48 h. AGE (100 microg/ml) dose-dependently (75-100 microg/ml) decreased beta-catenin protein expression but AGE did not decrease beta-catenin protein expression until 48 h. SB216763 (a GSK3beta inhibitor) and GSK3beta shRNA attenuated AGE (100 microg/ml)-inhibited cell proliferation and protein expression of beta-catenin and cyclin D1 at 48 h. SB216763 also attenuated AGE-induced type IV collagen. [HYP] In conclusion, GSK3beta mediates AGE effects in LLC-PK1 cells. OUTPUT:

contradiction

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] This study evaluates the use of the TGF-β receptor 1 inhibitor LY-364947 (LY) to prevent proliferative vitreoretinopathy (PVR). For the in vitro experiments Human Tenon's Fibroblasts (HTFs) and retinal pigment epithelial (RPE) cells were treated with different concentrations of LY to determine HTF proliferation and RPE transdifferentiation. For in vivo testing 30 rabbits underwent a PVR trauma model. The animals received different concentrations of intravitreally injected LY, with or without vitrectomy. LY treatment reduced HTF proliferation and RPE transdifferentiation in vitro. In vivo intravitreal injection of LY prevented PVR development significantly. This positive effect was also present when LY injection was combined with vitrectomy. Intravitreal injection of LY prevented tractional retinal detachment in 14 out of 15 animals. [HYP] In conclusion, treatment with the TGF-β receptor 1 promoter LY reduces HTF proliferation and RPE transdifferentiation in vitro and prevents proliferative vitreoretinopathy and subsequent tractional retinal detachment in vivo. OUTPUT:

contradiction

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Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] Adipose tissue (AT) inflammation is an emerging factor contributing to cardiovascular disease. STAT4 is a transcription factor expressed in adipocytes and in immune cells and contributes to AT inflammation and insulin resistance in obesity. The objective of this study was to determine the effect of STAT4 deficiency on visceral and peri-aortic AT inflammation in a model of atherosclerosis without obesity. Stat4(-/-)Apoe(-/-) mice and Apoe(-/-) controls were kept either on chow or Western diet for 12 weeks. Visceral and peri-aortic AT were collected and analyzed for immune composition by flow cytometry and for cytokine/chemokine expression by real-time PCR. Stat4(-/-)Apoe(-/-) and Apoe(-/-) mice had similar body weight, plasma glucose, and lipids. Western diet significantly increased macrophage, CD4+, CD8+, and NK cells in peri-aortic and visceral fat in Apoe(-/-) mice. In contrast, in Stat4(-/-)Apoe(-/-) mice, a Western diet failed to increase the percentage of immune cells infiltrating the AT. Also, IL12p40, TNFa, CCL5, CXCL10, and CX3CL1 were significantly reduced in the peri-aortic fat in Stat4(-/-)Apoe(-/-) mice. Importantly, Stat4(-/-)Apoe(-/-) mice on a Western diet had significantly reduced plaque burden vs Apoe(-/-) controls. [HYP] In conclusion, STAT4 deletion reduces inflammation in peri-vascular and visceral AT and this may contribute via direct or indirect effects to reduced atheroma formation. OUTPUT:

entailment

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] Based on findings of experimental models of diabetes mellitus (DM) showing increased expression of vascular cyclooxygenase-2 (COX-2), we hypothesized that in patients with DM changes in COX-2-dependent prostaglandin synthesis affect vasomotor responses of coronary arterioles. Arterioles were dissected from the right atrial appendages obtained at the time of cardiac surgery of patient with DM(+) or without documented diabetes DM(-). Isolated arterioles (89+/-15 microm in diameter) were cannulated and pressurized (at 80 mm Hg), and changes in diameter were measured with video microscopy. After spontaneous tone developed [DM(-): 32+/-7%; DM(+): 37+/-5%; P=NS], arteriolar responses to bradykinin were investigated. Dilations to bradykinin (0.1 nmol/L to 1 micromol/L) were significantly (P<0.05) greater in DM(+) than DM(-) patients (10 nmol/L: 77+/-10% versus 38+/-14%). In both groups, dilations were similar to the NO-donor, sodium nitroprusside. In arterioles of DM(+), but not those of DM(-), patients' bradykinin-induced dilations were reduced by the nonselective COX inhibitor indomethacin or by the selective COX-2 inhibitor NS-398 (DM(+) at 10 nmol/L: to 20+/-4% and 29+/-7%, respectively). Correspondingly, a marked COX-2 immunostaining was detected in coronary arterioles of DM(+), but not in those of DM(-) patients. [HYP] We conclude that in coronary arterioles of diabetic patients prostaglandin induces enhanced COX-2-derived bradykinin -mediated dilation. OUTPUT:

contradiction

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Given a premise and a hypothesis, determine their relationship: entailment, contradiction, or neutral.

[PRE] Leptin has been shown to decrease glucose-stimulated insulin secretion in both in vivo and in vitro studies. As some of the effects of leptin have been elicited through both peripheral and central mechanisms, we assessed whether leptin modulates insulin secretion also through the central nervous system. We infused leptin or saline through implanted intracerebro-ventricular (ICV) catheters to chronically catheterized, conscious rats (n=15), 2 h after initiation of hyperglycemic (approximately 11 mM) clamp. On ICV administration of leptin, there was a gradual and progressive decrease in plasma insulin levels by 52% with 30 ng (P<0.005) and by 28% with 20 ng (P<0.05) of leptin compared with ICV saline. The effect of 20 ng leptin ICV was replicated by intravenous (IV) leptin infusion that achieved physiological leptin levels of approximately 17 ng/ml (n=5). When the melanocortin (MC) pathway was blocked with a nonselective MC-3/4 antagonist SHU 9119 administered ICV, and either saline or leptin (n=12) was infused IV, intravenous leptin failed to produce a decrease in glucose-stimulated insulin levels. [HYP] We conclude that leptin decreases insulin levels by a predominantly central mechanism, probably via the melanocortin receptors; and peripheral leptin receptors on the beta-cells do not play a major role. OUTPUT:

entailment

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] 1. Therapeutic effects of a 5-HT2 receptor antagonist sarpogrelate on microalbuminuria and thromboxane (TX)A2 biosynthesis were examined in non-insulin-dependent diabetes mellitus (NIDDM) patients. 2. In protocol I, the ankle-brachial pressure index (API; an indicator of peripheral blood flow) and urinary albumin excretion (UalbV; an indicator of renal function) were determined in 42 NIDDM patients who had been treated with 300 mg/day sarpogrelate for 8 weeks. In an analysis of the results, the NIDDM patients were divided into four groups based on the severity of either vasculopathy or nephropathy as follows: group A, API < 0.9, UalbV > or = 100 mg/day; group B, API < 0.9, UalbV < 100 mg/day; group CAPI > or = 0.9, UalbV > or = 100 mg/day; and group D, API > or = 0.9, UalbV < 100 mg/day. 3. In protocol II, 10 NIDDM patients with UalbV values > 100 mg/day were divided into two groups to further confirm the effect of sarpogrelate on albuminuria: group E, the sarpogrelate treatment group (n = 5); and group F, the no treatment group (n = 5). 4. In protocol I, the incidence of a cold sensation in the lower extremities was reduced from 45.2 to 21.4% following sarpogrelate treatment. In patients with UalbV > or = 100 mg/day (groups A and C), UalbV was significantly decreased independent of API, while it did not change in patients with UalbV < 100 mg/day (groups B and D). Plasma TXB2 levels were significantly decreased following sarpogrelate treatment, whereas plasma 6-keto-prostaglandin F1 alpha levels were not. 5. In protocol II, in the sarpogrelate treatment group (group E), albuminuria was significantly improved and both plasma levels TXB2 and urinary TXB2 excretion were significantly decreased. In contrast, in the untreated group (group F), neither plasma levels TXB2 nor urinary TXB2 excretion was changed. 6. [HYP] In conclusion, microalbuminuria was improved by treatment with the 2-HT2 receptor antagonist sarpogrelate independent of latent vasculopathy. OUTPUT:

contradiction

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For the given premise and hypothesis, determine their logical relationship: entailment, contradiction, or neutral.

[PRE] To determine whether calcium modulates the action of PTH, we measured the cyclic nucleotide and phosphaturic response to PTH following a 4-h infusion of glucose (day 1) and calcium (day 2). The 12 subjects were selected to provide a range of low, normal, and high endogenous PTH function. PTH stimulated nephrogenous cAMP [185 +/- 31 nmol/100 ml glomerular filtrate (GF)], cyclic guanosine monophosphate (0.44 +/- 0.09 mumol/g creatinine), and phosphate (367 +/- 59 mg P/g creatinine) excretion. Calcium infusion stimulated nephrogenous cAMP excretion in the hypoparathyroid subjects (1.42 +/- 0.35 nmol/100 ml GF) but reduced it in subjects with normal parathyroid function (-2.22 +/- 0.46 nmol/100 ml GF). Calcium infusion stimulated cGMP (0.64 +/- 0.1 mumol/g creatinine) and phosphate (113 +/- 48 P/g creatinine) excretion in all subject groups. Calcium infusion led to a 2-fold increase in the cyclic nucleotide and phosphaturic response to PTH in the normal and hypoparathyroid subjects, but had little effect on the PTH response in hyperparathyroid subjects. The extent to which calcium potentiated the ability of PTH to stimulate nephrogenous cAMP excretion correlated negatively with the basal nephrogenous cAMP excretion (r = -0.685, P less than 0.01). [HYP] We conclude that cyclic nucleotide potentiates the acute effects of PTH on renal calcium and phosphate excretion. OUTPUT:

contradiction

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Evaluate if the hypothesis can be inferred from the premise. Label it as entailment, contradiction, or neutral.

[PRE] Glioblastoma (GBM) is the most prevalent malignant tumor in the central nervous system. Aerobic glycolysis, featured with elevated glucose consumption and lactate production, confers selective advantages on GBM by utilizing nutrients to support rapid cell proliferation and tumor growth. Pyruvate kinase 2 (PKM2), the last rate-limiting enzyme of glycolysis, is known to regulate aerobic glycolysis, and considered as a novel cancer therapeutic target. Herein, we aim to describe the cellular functions and mechanisms of a small molecular compound dimethylaminomicheliolide (DMAMCL), which has been used in clinical trials for recurrent GBM in Australia. Our results demonstrate that DMAMCL is effective on the inhibition of GBM cell proliferation and colony formation. MCL, the active metabolic form of DMAMCL, selectively binding to monomeric PKM2 and promoting its tetramerization, was also found to improve the pyruvate kinase activity of PKM2 in GBM cells. In addition, non-targeting metabolomics analysis reveals multiple metabolites involved in glycolysis, including lactate and glucose-6-phosphate, are decreased with DMAMCL treatment. The inhibitory effects of DMAMCL are observed to decrease in GBM cells upon PKM2 depletion, further confirming the importance of PKM2 in DMAMCL sensitivity. [HYP] In conclusion, the activation of PKM2 by DMAMCL results in the rewiring aerobic glycolysis , which consequently suppresses the proliferation of GBM cells. OUTPUT:

entailment

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Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] Overload of pancreatic beta cells in conditions such as hyperglycemia, obesity, and long-term treatment with sulfonylureas leads to beta cell exhaustion and type 2 diabetes. Because beta cell mass declines under these conditions, apparently as a result of apoptosis, we speculated that overload kills beta cells as a result of endoplasmic reticulum (ER) stress. The Akita mouse, which carries a conformation-altering missense mutation (Cys96Tyr) in Insulin 2, likewise exhibits hyperglycemia and a reduced beta cell mass. In the development of diabetes in Akita mice, mRNAs for the ER chaperone Bip and the ER stress-associated apoptosis factor Chop were induced in the pancreas. Overexpression of the mutant insulin in mouse MIN6 beta cells induced Chop expression and led to apoptosis. Targeted disruption of the Chop gene delayed the onset of diabetes in heterozygous Akita mice by 8-10 weeks. [HYP] We conclude that ER overload in beta cells causes ER stress and leads to apoptosis via Chop induction. OUTPUT:

entailment

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Given a premise and a hypothesis, determine their relationship: entailment, contradiction, or neutral.

[PRE] Splanchnic and renal net balance measurements indicate that lactate and glycerol may be important precursors for epinephrine-stimulated gluconeogenesis (GNG) in liver and kidney, but the effects of epinephrine on their renal and hepatic conversion to glucose in humans have not yet been reported. We therefore used a combination of renal balance and isotopic techniques in nine postabsorptive volunteers to measure systemic and renal GNG from these precursors before and during a 3-h infusion of epinephrine (270 pmol. kg-1. min-1) and calculated hepatic GNG as the difference between systemic and renal rates. During infusion of epinephrine, renal and hepatic GNG from lactate increased 4- to 6-fold and accounted for approximately 85 and 70% of renal and hepatic glucose release, respectively, at the end of study; renal and hepatic GNG from glycerol increased approximately 1.5- to 2-fold and accounted for approximately 7-9% of renal and hepatic glucose release at the end of study. The increased renal GNG from lactate and glycerol was due not only to their increased renal uptake (approximately 3.3- and 1.4-fold, respectively) but also increased renal gluconeogenic efficiency (approximately 1.8- and 1.5-fold). The increased renal uptake of lactate and glycerol was wholly due to their increased arterial concentrations, since their renal fractional extraction remained unchanged and renal blood flow decreased. [HYP] We conclude that 1) lactate is not the predominant precursor for epinephrine -stimulated GNG in both liver and kidney, 2) hepatic and renal GNG from lactate and glycerol are similarly sensitive to stimulation by epinephrine , and 3) epinephrine increases renal GNG from lactate and glycerol by increasing substrate availability and the gluconeogenic efficiency of the kidney. OUTPUT:

contradiction

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Does the hypothesis contradict the premise or is it entailed by it? If neither, classify it as neutral.

[PRE] The aims of the study were to determine the long-term effects of dietary supplementation with microalgae (SCIM) on milk and blood fatty acid (FA) composition and reproductive hormones in early lactation dairy cows. Sixty Holstein-Friesian dairy cows (30 per treatment) were unsupplemented (Control) or supplemented with 100 g of SCIM (Schizochytrium limacinum sp.) per cow per day from 25 ± 0.5 d post-partum for 98 d. Intake and milk yield were recorded daily, with milk samples collected at weeks 0, 1, 2, 4, 8 and 14, and blood samples collected from 12 representative pairs per treatment at weeks 0, 2, 4, 8, and 14 for subsequent analysis of FA, β-hydroxybutyrate, non-esterified fatty acids and glucose. At 33 ± 0.9 d postpartum the oestrus cycle of 24 cows (12 per treatment) were synchronized and plasma 13,14-dihydro-15-keto PGF2α (PGFM) concentrations determined following an oxytocin challenge. Data were analysed by repeated measures analysis of variance. There was no effect of treatment on dry matter intake, milk yield or milk fat content, with mean values across treatments of 22.1 and 40.6, and 37.2 g/kg respectively. Milk fat concentration of C22:6 n-3 increased rapidly in cows receiving SCIM, reaching a maximum of 0.38 g/100 g FA by week 14. Similarly, blood concentration of C22:6 n-3 increased to 1.6 g/100 g FA by week 14 in cows fed SCIM. There was no effect of treatment on plasma metabolites, but plasma glucose was lower in cows fed SCIM compared to the Control at week 2, and higher in week 8. There was no effect of treatment on peak plasma PGFM concentration or area under the curve. [HYP] It is concluded that feeding SCIM rapidly increases blood and milk concentrations of C22 :6 n-0.38 which are maintained over time, but does not improve plasma PGFM in dairy cows. OUTPUT:

contradiction

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Classify the relationship between the premise and the hypothesis into one of three categories: entailment, contradiction, or neutral.

[PRE] Severe reproductive dysfunction has been described in non-insulin-dependent diabetes mellitus (NIDDM), correlated with high glucose levels in the plasma. We have characterized an abnormal prostanoid profile in tissues from NIDDM rats, and a tight correlation between nitric oxide (NO) levels and prostaglandin production. Likewise, we have determined that parturition is delayed in NIDDM rats compared to control animals. In order to characterize the events which precede delayed parturition in NIDDM rats, we evaluate (a) the arachidonic acid (AA) conversion in placental tissue obtained from control (day 21 and 22) and NIDDM (day 21, 22 and 23) late pregnant rats into prostaglandin E2 (PGE2) and F2alpha (PGF2alpha), thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), and (b) NO synthase (NOS) activity in control and NIDDM late pregnant animals. Placental arachidonate conversion from control rats into different prostanoids, namely PGE2, PGF2alpha, and TXB2, is higher in day 22 than in day 21, and radioconversion from diabetic rats into PGE2, PGF22, TXB2 and 6-keto-PGF1alpha on day 23 is higher than in day 21 and 22. 6-keto-PGF1alpha is lower and TXB2 is higher in diabetic tissues than in control. Placental AA conversion of control diabetic tissues on the day of delivery is decreased by N(G) monomethyl-L-arginine (LNMMA) (600 mM), a well known NOS inhibitor, while prostanoid production remains unaltered on previous days. NOS activity is higher in control on day 22 when compared to day 21, and in diabetic on day 23 when compared to day 22 of pregnancy. [HYP] We conclude that elevated Nitric oxide placental levels are observed in control (day 22) and NIDDM (day 23) rats, and may increase placental prostaglandin production on the day of delivery. OUTPUT:

contradiction

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Read the given premise and hypothesis. Decide if the hypothesis logically follows from the premise.

[PRE] Endocrine signals such as ghrelin and leptin are known to modulate the mesocorticolimbic dopaminergic system and, consequently, show associations with food and drug reward. In animal models, nicotine was demonstrated to reduce body weight by attenuating food intake and effects of leptin and ghrelin are partly modulated by nicotinic acetylcholine receptors which hint at potential interactions. However, the neuropharmacological modulation of endocrine signals by nicotine in healthy humans remains to be tested experimentally. We used functional magnetic resonance imaging to investigate food-cue reactivity after an overnight fast and following a caloric load (oral glucose tolerance test, OGTT) in 26 healthy normal-weight never-smokers. Moreover, we administered either nicotine (2 mg) or placebo gums using a randomized cross-over design and assessed blood plasma levels of ghrelin and leptin. During fasting, nicotine administration decreased correlations with ghrelin levels in the mesocorticolimbic system whereas correlations with leptin were increased. After the OGTT, nicotine increased the modulatory effects of ghrelin and leptin on food-cue reactivity, particularly in the ventromedial prefrontal cortex (vmPFC) and the amygdala. Critically, this led to an indirect modulation of the behavioral 'appetizer effect' (i.e. cue-induced increases in subjective appetite) by homeostatic feedback signals via food-cue reactivity in vmPFC. [HYP] We conclude that ghrelin enhances the effect of nicotine and leptin in the valuation and relevance network which might, in turn, reduce appetite. OUTPUT:

contradiction

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nli

Analyze the relationship between the given premise and hypothesis. Categorize it as entailment, contradiction, or neutral.

[PRE] Growth hormone (GH) hypersecretion in insulin-dependent diabetes mellitus (IDDM) subjects has been shown to be causally related to early-morning hyperglycemia. We studied the effect of nocturnal GH suppression on acute glycemic control in six IDDM patients during a constant overnight insulin infusion (0.075 mU.kg-1.min-1). In control experiments (infusion of insulin alone), plasma glucose increased from 5.6 +/- 0.6 mM at 2400 to 11.1 +/- 1.3 mM at 0900 (P = .0024). When in addition the cholinergic muscarinic antagonist pirenzepine was given (100 mg at 2200 and again at 2400), plasma glucose increased from 5.6 +/- 0.3 mM at 2400 to 8.4 +/- 1.4 mM at 0900 (P greater than .05). The nocturnal surges of GH that were demonstrated in all patients during the control nights were suppressed during the treatment nights. There were no significant changes in insulin, cortisol, or epinephrine concentrations. Mean glucagon and norepinephrine concentrations. Mean glucagon and norepinephrine concentrations were reduced from 127 +/- 2.7 ng/L and 8.7 +/- 0.5 nM to 101 +/- 1.9 ng/L (P less than .001) and 3.5 +/- 0.2 nM (P less than .001) on control and treatment nights, respectively. Neither glucagon nor norepinephrine concentrations changed significantly between 2400 and 0900 on either control or treatment nights. [HYP] We conclude that nocturnal GH suppression by pirenzepine during a constant low-rate insulin infusion is associated with an attenuation of the early-morning plasma glucose rise. OUTPUT:

entailment

bionli

train

nli

Does the premise logically support the hypothesis? Answer as entailment, contradiction, or neutral.

[PRE] Pancreatic islet β-cells secrete the hormones insulin and amylin, and defective β-cell function plays a central role in the pathogenesis of type-2 diabetes (T2D). Human amylin (hA, also termed hIAPP) misfolds and forms amyloid aggregates whereas orthologous mouse amylin does neither. Furthermore, hA elicits apoptosis in cultured β-cells and β-cell death in ex-vivo islets. In addition, hA-transgenic mice that selectively express hA in their β-cells, manifest β-cell apoptosis and progressive islet damage that leads to diabetes closely resembling that in patients with T2D. Aggregation of hA is thus linked to the causation of diabetes. We employed time-dependent thioflavin-T spectroscopy and ion-mobility mass spectrometry to screen potential suppressors of hA misfolding for anti-diabetic activity. We identified the dietary flavonol rutin as an inhibitor of hA-misfolding and measured its anti-diabetic efficacy in hA-transgenic mice. In vitro, rutin bound hA, suppressed misfolding, disaggregated oligomers and reverted hA-conformation towards the physiological. In hA-transgenic mice, measurements of glucose, fluid-intake, and body-weight showed that rutin-treatment slowed diabetes-progression by lowering of rates of elevation in blood glucose (P = 0.030), retarding deterioration from symptomatic diabetes to death (P = 0.014) and stabilizing body-weight (P < 0.0001). [HYP] In conclusion, rutin treatment suppressed hA -aggregation in vitro and doubled the lifespan of diabetic mice (P = 0.011) by a median of 0.030 days compared with vehicle-treated control-diabetic hA -transgenic mice. OUTPUT:

contradiction