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elizah521

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diabetes_v1

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

[PRE] We examined the effect of somatostatin (SRIH) infusion on insulin-mediated glucose disposal (Rd) in normal young subjects (n = 8) to determine the influence of SRIH on insulin action. Paired 3-h euglycemic insulin clamp studies were performed in random order employing insulin alone (25 mU/m2 X min) or insulin with SRIH (250 micrograms/h) and replacement of basal glucagon (0.4 ng/kg X min). Basal plasma glucose, insulin, glucagon (IRG), and GH concentrations, hepatic glucose production, and Rd were similar on each occasion. Steady state (10-180 min) plasma insulin insulin alone, 283 +/- 10 (+/- SEM); insulin, IRG, and SRIH, 284 +/- 10 pmol/L) and glucagon levels (insulin alone, 84 +/- 7; insulin, IRG, and SRIH, 82 +/- 7 ng/L) were similar. Hepatic glucose production (insulin alone, 0.66 +/- 0.12; insulin, IRG, and SRIH, 0.78 +/- 0.48 mg/kg X min) and Rd (insulin alone, 8.16 +/- 0.62; insulin, IRG, and SRIH, 8.17 +/- 0.61 mg/kg X min) were not different at steady state. [HYP] We conclude that SRIH does not impair insulin -mediated glucose disposal in man. OUTPUT:

contradiction

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

[PRE] Pravastatin, irbesartan and captopril are frequently used in the treatment of patients with Type 2 diabetes. These drugs also exert beneficial metabolic effects, causing an improved glucose tolerance in patients, but the precise mechanisms by which this is achieved remain elusive. To this end, we have studied whether these drugs influence insulin secretion in vivo through effects on islet blood perfusion. Captopril (3 mg/kg of body weight), irbesartan (3 mg/kg of body weight) and pravastatin (0.5 mg/kg of body weight) were injected intravenously into anaesthetized female Wistar rats. Blood flow rates were determined by a microsphere technique. Blood glucose concentrations were measured with test reagent strips and serum insulin concentrations were measured by ELISA. Pancreatic blood flow was markedly increased by pravastatin (P<0.001), captopril (P<0.05) and irbesartan (P<0.01). Pancreatic islet blood flow was significantly and preferentially enhanced after the administration of captopril (P<0.01), irbesartan (P<0.01) and pravastatin (P<0.001). Kidney blood flow was enhanced significantly by pravastatin (P<0.01), irbesartan (P<0.05) and captopril (P<0.01). Captopril and pravastatin also enhanced late-phase insulin secretion and positively influenced glycaemia in intraperitoneal glucose tolerance tests. [HYP] In conclusion, the present study suggests that a local pancreatic renin-angiotensin system and pravastatin treatment may be selectively controlling pancreatic islet blood flow, augmenting insulin secretion and thereby improving glucose tolerance. OUTPUT:

entailment

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

[PRE] Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. [HYP] In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves hyperinsulinemia -induced corticosterone . OUTPUT:

contradiction

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

[PRE] Hyperglycemia is known to reduce dehydroepiandrosterone (DHEA) circulating levels; however, the mechanism by which hyperglycemia decreases DHEA is not elucidated. In this study, serum DHEA and DHEA sulfate (DHEA-S) levels were compared in 50 men with non-insulin-dependent diabetes mellitus (NIDDM) and 50 age-matched men with impaired glucose tolerance (IGT) receiving only diet therapy. Serum concentrations of DHEA and DHEA-S in the NIDDM group were significantly lower than in the IGT group (7.8 and 9.7 nmol/l vs 3.4 and 4.9 mumol/l, respectively; p < 0.01) but there was no significant difference in immunoreactive insulin between the two groups. When the results from both groups were combined, HbA1C was significantly inversely related to DHEA (r = -0.243, p < 0.01) and DHEA-S (r = -0.305, p < 0.01). Immunoreactive insulin showed no correlation with DHEA and DHEA-S. [HYP] Multiple regression analysis showed that HbA1C was independently negatively related to both DHEA and DHEA -S. We conclude that hyperglycemia may decrease serum DHEA and DHEA -S in Japanese men with NIDDM, but the depression of DHEA (-S) is independent of serum insulin level. 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] We evaluated the role of melatonin in endotoxemia caused by lipopolysaccharide (LPS) in unanesthetized rats. The expression of inducible isoform of nitric oxide synthase (iNOS) and the increase in the oxidative stress seem to be responsible for the failure of lungs, liver, and kidneys in endotoxemia. Bacterial LPS (10 mg/kg b. w) was i.v. injected 6 h before rats were killed and melatonin (10-60 mg/kg b.w.) was i.p. injected before and/or after LPS. Endotoxemia was associated with a significant rise in the serum levels of aspartate and alanine aminotransferases, gamma-glutamyl-transferase, alkaline phosphatase, creatinine, urea, and uric acid, and hence liver and renal dysfunction. LPS also increased serum levels of cholesterol and triglycerides and reduced glucose levels. Melatonin administration counteracted these organ and metabolic alterations at doses ranging between 20 and 60 mg/kg b. w. Melatonin significantly decreased lung lipid peroxidation and counteracted the LPS-induced NO levels in lungs and liver. Our results also show an inhibition of iNOS activity in rat lungs by melatonin in a dose-dependent manner. Expression of iNOS mRNA in lungs and liver was significantly decreased by melatonin (60 mg/kg b. w., 58-65%). [HYP] We conclude that melatonin promotes NO production mainly by inhibition of iNOS expression. OUTPUT:

contradiction

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

[PRE] Extracellular nucleotides and adenosine regulate endocrine pancreatic functions such as insulin secretion by Langerhans islet β-cells via the activation of specific P2 and P1 receptors. Membrane-bound ectonucleotidases regulate the local concentration of these ligands and consequently control the activation of their receptors. The objective of this study was to identify and localize the major ectonucleotidases, namely NTPDases and ecto-5'-nucleotidase, present in the endocrine pancreas. In addition, the potential implication of ecto-ATPase activity on insulin secretion was investigated in the rat β-cell line INS-1 (832/13). The localization of ectonucleotidase activity and protein was carried out in situ by enzyme histochemistry and immunolocalization in mouse, rat, and human pancreas sections. NTPDase1 was localized in all blood vessels and acini, and NTPDase2 was localized in capillaries of Langerhans islets and in peripheral conjunctive tissue, whereas NTPDase3 was detected in all Langerhans islet cell types. Interestingly, among the mammalian species tested, ecto-5'-nucleotidase was present only in rat Langerhans islet cells, where it was coexpressed with NTPDase3. Notably, the inhibition of NTPDase3 activity by BG0136 and NF279 facilitated insulin release from INS-1 (832/13) cells under conditions of low glycemia, probably by affecting P2 receptor activation. NTPDase3 activity also regulated the inhibitory effect of exogenous ATP in the presence of a high glucose concentration most likely by controlling adenosine production. [HYP] In conclusion, all pancreatic endocrine cells express NTPDase3 that was shown to modulate insulin secretion in rat INS-1 (832/13) β-cells. OUTPUT:

entailment

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

[PRE] Mammalian brain glycogen is adequate to support oxidative metabolism for several minutes. The present studies were done primarily to develop the guinea pig hippocampal slice as a model for studying the function and regulation of that glycogen. Slice glycogen falls to 6 nmol/mg dry wt. during the first hour of incubation at 36 degrees C but during the next 3 h recovers to 20 nmol/mg dry wt., similar to in situ values. Glycogen concentration in the dentate gyrus molecular layer is double its value in the whole hippocampal slice, suggesting its distribution is related to metabolic demand. When both glucose and oxygen are removed from the medium, glycogen and ATP fall to 50% within 6 min. The glycogen fall is unaffected by prolonged calcium depletion or by 3-isobutyl 1-methylxanthine, an adenosine antagonist. It is markedly slowed by preincubating the slice with creatine, which also slows the fall in ATP. [HYP] We conclude that the fall in glycogen in the guinea pig hippocampal slice is a consequence of depletion of ATP . 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 mechanism(s) by which chronic hyperglycemia impairs glucose-stimulated insulin secretion is poorly defined. Here, we compare the "nanomechanics" of single exocytotic events in primary rat pancreatic beta-cells cultured for 48 h at optimal (10 mmol/l) or elevated (30 mmol/l) glucose concentrations. Cargo release was imaged by total internal reflection fluorescence microscopy of lumen-targeted probes (neuropeptide Y [NPY]-pH-insensitive yellow fluorescent protein [NPY-Venus] or NPY-monomeric red fluorescent protein), while the fate of the vesicle membrane was reported simultaneously with phosphatase-on-the-granule-of-insulinoma-enhanced green fluorescent protein. Under all conditions studied, exocytosis proceeded via a "cavity recapture" mechanism in which the vesicle and plasma membranes fused transiently. While essentially complete release of NPY-Venus was observed in 24 +/- 1% of glucose-stimulated exocytotic events in cells maintained at 10 mmol/l glucose, this value was reduced reversibly to 5 +/- 2% of events by culture at 30 mmol/l glucose, in line with decreases in Glut2 and glucokinase gene expression, and attenuated glucose-stimulated increases in NADPH and intracellular [Ca2+]. [HYP] Since vesicle release in response to cell depolarization with KCl was not affected by culture at 30 mmol/l glucose , we conclude that hyperglycemia causes the abnormal termination of individual insulin release events principally by inhibiting glucose signaling. OUTPUT:

entailment

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

[PRE] Glutamate is generated during nutrient stimulation of pancreatic islets and has been proposed to act both as an intra- and extra-cellular messenger molecule. We demonstrate that glutamate is not co-secreted with the hormones from intact islets or purified α- and β-cells. Fractional glutamate release was 5-50 times higher than hormone secretion. Furthermore, various hormone secretagogues did not elicit glutamate efflux. Interestingly, epinephrine even decreased glutamate release while increasing glucagon secretion. Rather than being co-secreted with hormones, we show that glutamate is mainly released via plasma membrane excitatory amino acid transporters (EAAT) by uptake reversal. Transcripts for EAAT1, 2 and 3 were present in both rat α- and β-cells. Inhibition of EAATs by L-trans-pyrrolidine-2,4-dicarboxylate augmented intra-cellular glutamate and α-ketoglutarate contents and potentiated glucose-stimulated insulin secretion from islets and purified β-cells without affecting glucagon secretion from α-cells. [HYP] In conclusion, intra-cellular glutamate-derived metabolite pools are linked to glucose -stimulated insulin but not glucagon secretion. OUTPUT:

entailment

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

[PRE] Urocortin 3 (Ucn 3) is a corticotropin-releasing factor (CRF)-related peptide with high affinity for the type 2 CRF receptor (CRFR2). Central administration of Ucn 3 stimulates the hypothalamic-pituitary-adrenal axis, suppresses feeding, and elevates blood glucose levels, suggesting that activation of brain CRFR2 promotes stress-like responses. Several CRFR2-expressing brain areas, including the ventromedial hypothalamus (VMH) and the posterior amygdala (PA), may be potential sites mediating the effects of Ucn 3. In the present study, Ucn 3 or vehicle was bilaterally injected into the VMH or PA, and food intake and plasma levels of ACTH, corticosterone, glucose, and insulin were determined. Food intake was greatly reduced in rats following Ucn 3 injection into the VMH. Ucn 3 injection into the VMH rapidly elevated plasma levels of glucose and insulin but did not affect ACTH and corticosterone secretion. Injection of Ucn 3 into the PA did not alter any of the parameters measured. We determined that the majority of CRFR2-positive neurons in the VMH were excitatory glutamatergic, and a subset of these neurons project to the arcuate nucleus of the hypothalamus (ARH). Importantly, stimulation of CRFR2 in the VMH increased proopiomelanocortin mRNA expression in the ARH. [HYP] We conclude that Ucn 3 activates CRFR2 neurons in the VMH, which increases proopiomelanocortin mRNA expression in the ARH and suppresses food intake. OUTPUT:

contradiction

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

[PRE] Podocyte injury is an early feature of Fabry nephropathy, but the molecular mechanisms of podocyte injury are poorly understood. Lyso-Gb3 accumulates in serum in Fabry disease and increases extracellular matrix synthesis in podocytes. We explored the contribution of Notch1 signaling, a mediator of podocyte injury, to lyso-Gb3-elicited responses in cultured human podocytes. At clinically relevant concentrations, lyso-Gb3 activates podocyte Notch1 signaling, resulting in increased active Notch1 and HES1, a canonical Notch transcriptional target. A γ-secretase inhibitor or specific Notch1 small interfering RNA (siRNA) inhibited HES1 upregulation in response to lyso-Gb3. Notch1 siRNA or γ-secretase inhibition also prevented the lyso-Gb3-induced upregulation of Notch1, Notch ligand Jagged1 and chemokine (MCP1, RANTES) expression. Notch siRNA prevented the activation of nuclear factor kappa B (NFκB), and NFκB activation contributed to Notch1-mediated inflammatory responses as the NFκB inhibitor, parthenolide, prevented lyso-Gb3-induced chemokine upregulation. Notch1 also mediates fibrogenic responses in podocytes as Notch siRNA prevented lyso-Gb3 upregulation of fibronectin mRNA. Supporting the clinical relevance of cell culture findings, active Notch1, Jagged1 and HES1 were observed in Fabry kidney biopsies. Lyso-Gb3 elicited similar responses in mouse kidney. [HYP] In conclusion, active Notch1 signaling contributes to lyso-Gb3 -elicited responses in podocytes. OUTPUT:

contradiction

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

[PRE] Although the morphological development of the fetal pancreatic B cell has been studied in considerable detail, knowledge about the functional maturation, particularly in early stages of development, is still poor. The present paper describes a method for monolayer culture of fetal rat islet cells which allows a study of the regulation of insulin biosynthesis, release and content during critical stages of embryonic and fetal development. Suspensions of pancreatic cells were prepared from rat fetuses on pregnancy day 16 and cultured for 3 days. During the initial 2 days cultures were performed in the presence of 5 or 15 mmol/l glucose. During this initial period, culture at 5 mmol/l glucose was carried out in the presence or absence of either 10 mmol/l nicotinamide (NA) or 5 or 100 ng/ml nerve growth factor (NGF). After changing the media the cells were further exposed for 24 h to either 5 or 15 mmol/l glucose or 15 mmol/l glucose plus 5 mmol/l theophylline before measuring the insulin concentration in the culture medium. Cells that had initially been cultured for 2 days in 5 mmol/l glucose showed an increased insulin release, when subsequently cultured in 15 mmol/l glucose for 24 h. Theophylline potentiated the response and caused a decrease in cellular insulin content. Cells initially cultured in the presence of 15 mmol/l glucose showed unchanged insulin release during the subsequent 24-hour exposure to 15 mmol/l glucose, irrespective of the presence or absence of theophylline. The presence of NGF (100 ng/ml) during the initial 2-day culture period increased the insulin release in the presence of 15 mmol/l glucose and theophylline during the subsequent 24-hour culture period as compared to cells cultured in the absence of NGF. When cells were first exposed to either NA or NGF followed by exposure to 5 mmol/l glucose alone in the last 24-hour culture period, there was an increased insulin content. Rates of insulin biosynthesis remained unchanged irrespective of the glucose concentration in the culture medium. [HYP] It is concluded that, already in early fetal development, B cells show glucose stimulation of insulin release albeit less pronounced than in the postnatal state. OUTPUT:

entailment

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

[PRE] Both rosiglitazone and metformin increase hepatic insulin sensitivity, but their mechanism of action has not been compared in humans. The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content, hepatic insulin sensitivity, insulin clearance, and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes. A total of 20 drug-naive patients with type 2 diabetes (age 48 +/- 3 years, fasting plasma glucose 152 +/- 9 mg/dl, BMI 30.6 +/- 0.8 kg/m2) were treated in a double-blind randomized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks. Both drugs similarly decreased HbA1c, insulin, and free fatty acid concentrations. Body weight decreased in the metformin (84 +/- 4 vs. 82 +/- 4 kg, P < 0.05) but not the rosiglitazone group. Liver fat (proton spectroscopy) was decreased with rosiglitazone by 51% (15 +/- 3 vs. 7 +/- 1%, 0 vs. 16 weeks, P = 0.003) but not by metformin (13 +/- 3 to 14 +/- 3%, NS). Rosiglitazone (16 +/- 2 vs. 20 +/- 1 ml.kg(-1).min(-1), P = 0.02) but not metformin increased insulin clearance by 20%. Hepatic insulin sensitivity in the basal state increased similarly in both groups. Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin. Serum adiponectin concentrations increased by 123% with rosiglitazone but remained unchanged during metformin treatment. The decrease of serum adiponectin concentrations correlated with the decrease in liver fat (r = -0.74, P < 0.001). Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-gamma, adiponectin, and lipoprotein lipase in adipose tissue. [HYP] In conclusion, rosiglitazone but not metformin decreases liver fat and increases insulin clearance. 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] Oxygen administration to immature neonates suppresses VEGF-A expression in the retina, resulting in the catastrophic vessel loss that initiates retinopathy of prematurity. To investigate the mechanisms responsible for survival of blood vessels in the developing retina, we characterized two VEGF-A receptors, VEGF receptor-1 (VEGFR-1, also known as Flt-1) and VEGF receptor-2 (VEGFR-2, also known as Flk-1). Surprisingly, these two VEGF-A receptors differed markedly during normal retinal development in mice. At 5 days postpartum (P5), VEGFR-1 protein was colocalized with retinal vessels, whereas VEGFR-2 was detected only in the neural retina. Real-time RT-PCR identified a 60-fold induction of VEGFR-1 mRNA in retina from P3 (early vascularization) to P26 (fully vascularized), and no significant change in VEGFR-2 mRNA expression. Placental growth factor-1 (PlGF-1), which exclusively binds VEGFR-1, decreased hyperoxia-induced retinal vaso-obliteration from 22.2% to 5.1%, whereas VEGF-E, which exclusively binds VEGFR-2, had no effect on blood vessel survival. Importantly, under the same conditions, PlGF-1 did not increase vasoproliferation during (a). normal vessel growth, (b). revascularization following hyperoxia-induced ischemia, or (c). the vasoproliferative phase, indicating a selective function supporting blood vessel survival. [HYP] We conclude that VEGFR-1 is critical in maintaining the vasculature of the neonatal retina, and that activation of VEGFR-1 by PlGF-1 is a selective strategy for preventing oxygen-induced retinal ischemia without provoking retinal neovascularization. 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 response to arginine infusion, Zucker fatty rats developed hyperglycemia accompanying hyperglucagonemia and hyperinsulinemia. The hyperglycemia could not be explained by changes in the ratio of glucagon/insulin. However, arginine infusion failed to increase plasma glucose in fatty rats pretreated with anti-glucagon serum, suggesting a hyperglycemic effect of glucagon released by arginine. Kinetic studies of glucose metabolism revealed that the rates of glucose appearance (Ra) and glucose disappearance (Rd) of lean rats rapidly and simultaneously increased to the same extent after the start of arginine infusion. By contrast, in fatty rats, Ra markedly increased immediately after the start of the infusion, but Rd did not significantly increase until hyperglycemia was established. Overall insulin sensitivity of fatty rats was markedly reduced, determined by the steady state plasma glucose method. [HYP] We conclude tht arginine-induced hyperglycemia in fatty rats is caused by enhanced KCl output from the liver due to hyperglucagonemia and/or by decreased KCl utilization due to insulin resistance. OUTPUT:

contradiction

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

[PRE] Chronic intermittent hypoxia (IH) is described as the major detrimental factor leading to cardiovascular morbimortality in obstructive sleep apnea (OSA) patients. OSA patients exhibit increased infarct size after a myocardial event, and previous animal studies have shown that chronic IH could be the main mechanism. Endoplasmic reticulum (ER) stress plays a major role in the pathophysiology of cardiovascular disease. High-intensity training (HIT) exerts beneficial effects on the cardiovascular system. Thus, we hypothesized that HIT could prevent IH-induced ER stress and the increase in infarct size. Male Wistar rats were exposed to 21 days of IH (21-5% fraction of inspired O2, 60-s cycle, 8 h/day) or normoxia. After 1 wk of IH alone, rats were submitted daily to both IH and HIT (2 × 24 min, 15-30m/min). Rat hearts were either rapidly frozen to evaluate ER stress by Western blot analysis or submitted to an ischemia-reperfusion protocol ex vivo (30 min of global ischemia/120 min of reperfusion). IH induced cardiac proapoptotic ER stress, characterized by increased expression of glucose-regulated protein kinase 78, phosphorylated protein kinase-like ER kinase, activating transcription factor 4, and C/EBP homologous protein. IH-induced myocardial apoptosis was confirmed by increased expression of cleaved caspase-3. These IH-associated proapoptotic alterations were associated with a significant increase in infarct size (35.4 ± 3.2% vs. 22.7 ± 1.7% of ventricles in IH + sedenary and normoxia + sedentary groups, respectively, P < 0.05). HIT prevented both the IH-induced proapoptotic ER stress and increased myocardial infarct size (28.8 ± 3.9% and 21.0 ± 5.1% in IH + HIT and normoxia + HIT groups, respectively, P = 0.28). [HYP] In conclusion, these findings suggest that HIT could represent a preventive strategy to limit IH -induced myocardial ischemia-reperfusion damages in OSA patients. 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] Physical activity is known to increase insulin action in skeletal muscle, and data have indicated that 5'-AMP-activated protein kinase (AMPK) is involved in the molecular mechanisms behind this beneficial effect. 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) can be used as a pharmacological tool to repetitively activate AMPK, and the objective of this study was to explore whether the increase in insulin-stimulated glucose uptake after either long-term exercise or chronic AICAR administration was followed by fiber-type-specific changes in insulin signaling and/or changes in GLUT-4 expression. Wistar rats were allocated into three groups: an exercise group trained on treadmill for 5 days, an AICAR group exposed to daily subcutaneous injections of AICAR, and a sedentary control group. AMPK activity, insulin-stimulated glucose transport, insulin signaling, and GLUT-4 expression were determined in muscles characterized by different fiber type compositions. Both exercised and AICAR-injected animals displayed a fiber-type-specific increase in glucose transport with the most marked increase in muscles with a high content of type IIb fibers. This increase was accompanied by a concomitant increase in GLUT-4 expression. Insulin signaling as assessed by phosphatidylinositol 3-kinase and PKB/Akt activity was enhanced only after AICAR administration and in a non-fiber-type-specific manner. [HYP] In conclusion, chronic AICAR administration and long-term exercise both improve insulin -stimulated glucose transport in skeletal muscle in a fiber-type-specific way, and this is associated with an decrease in GLUT-4 content. OUTPUT:

contradiction

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

[PRE] Pregnancy-induced metabolic changes are regulated by signals from an expanded adipose organ. Placental growth factor (PlGF), acting through vascular endothelial growth factor receptor-1, may be among those signals. There is a steep rise in circulating PlGF during normal pregnancy, which is repressed in gravidas who develop preeclampsia. PlGF-deficiency in mice impairs adipose vascularization and development. Here we studied young-adult PlGF-deficient (PlGF(-/-)) and wild-type mice on a high-fat diet in the nongravid state and at embryonic day (E) 13.5 or E18.5 of gestation. Litter size and weight were normal, but E18.5 placentas were smaller in PlGF(-/-) pregnancies. PlGF(-/-) mice showed altered intraadipose dynamics, with the following: 1) less blood vessels and fewer brown, uncoupling protein (UCP)-1-positive, adipocytes in white sc and perigonadal fat compartments and 2) white adipocyte hypertrophy. The mRNA expression of beta(3)-adrenergic receptors, peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and UCP-1 was decreased accordingly. Moreover, PlGF(-/-) mice showed hyperinsulinemia. Pregnancy-associated changes were largely comparable in PlGF(-/-) and wild-type dams. They included expanded sc fat compartments and adipocyte hypertrophy, whereas adipose expression of key angiogenesis/adipogenesis (vascular endothelial growth factor receptor-1, peroxisome proliferator-activated receptor-gamma(2)) and thermogenesis (beta(3)-adrenergic receptors, peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and UCP-1) genes was down-regulated; circulating insulin levels gradually increased during pregnancy. [HYP] In conclusion, reduced adipose vascularization in PlGF(-/-) mice impairs adaptive thermogenesis in favor of energy storage, thereby promoting insulin resistance and hyperinsulinemia . OUTPUT:

entailment

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

[PRE] Leptin levels are elevated in end-stage renal disease, suggesting an impairment of renal leptin degradation. The present study aimed to determine whether leptin levels are also elevated in patients with earlier stages of renal disease, ie, microalbuminuric and macroalbuminuric nephropathy. A total of 60 subjects were assigned to two study groups. Group A contained 10 type 2 diabetics with macroalbuminuria, 10 type 2 diabetics with normoalbuminuria, and 10 healthy control subjects. Group B contained 10 type 2 diabetics with microalbuminuria, 10 type 2 diabetics with normoalbuminuria, and 10 healthy controls. The subgroups of both study groups were matched for sex and body fatness. In group A, macroalbuminuric diabetic patients had higher serum leptin levels than the normoalbuminuric diabetics (11.90 +/- 2.98 v 4.13 +/- 0.92 ng/mL, P < .002) and control subjects (4.78 +/- 1.37 ng/mL, P < .006). In group B, microalbuminuric diabetics had higher serum leptin levels than the normoalbuminuric diabetics (21.16 +/- 5.80 v8.74 +/- 1.89 ng/mL, P < .04) and control subjects (10.06 + 3.00 ng/mL, P < .06). In both groups A and B, creatinine clearance was inversely correlated with the serum leptin level after adjusting for body fat. [HYP] In conclusion, serum leptin levels are elevated in type 10 diabetic patients with microalbuminuria and macroalbuminuria, suggesting that renal leptin degradation is already impaired in the early stages of renal disease. 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 effect of hypoxia on the proliferation and collagen synthesis of cultured rat mesangial cells was examined under normal-glucose (NG, 5 mM) and high-glucose (HG, 25 mM)-media conditions. In addition, a role for osteopontin (OPN) in mediating these processes was assessed. Quiescent cultures were exposed to hypoxia (3% O(2)) and normoxia (18% O(2)) in a serum-free medium with NG or HG, and cell proliferation, collagen synthesis, and OPN expression were assessed. Cells exposed to hypoxia in NG medium resulted in significant increases in [(3)H]thymidine incorporation, cell number, and [(3)H]proline incorporation, respectively. HG incubations also produced significant stimulation of these parameters under normoxic conditions, which were markedly enhanced in cells exposed to hypoxia in HG medium. In addition, hypoxia and HG stimulated the mRNA levels of type IV collagen, and the combination of hypoxia and HG resulted in additive increases in type IV collagen expression. Hypoxia and HG also stimulated OPN mRNA and protein levels in an additive fashion. A neutralizing antibody to OPN or its beta(3)-integrin receptor significantly blocked the effect of hypoxia and HG on proliferation and collagen synthesis. [HYP] In conclusion, these results demonstrate for the first time that collagen synthesis in HG medium produces exaggerated mesangial cell growth and type IV hypoxia . 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 two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are insulinotropic factors released from the small intestine to the blood stream in response to oral glucose ingestion. The insulinotropic effect of GLP-1 is maintained in patients with Type II (non-insulin-dependent) diabetes mellitus, whereas, for unknown reasons, the effect of GIP is diminished or lacking. We defined the exon-intron boundaries of the human GIP receptor, made a mutational analysis of the gene and identified two amino acid substitutions, A207 V and E354Q. In an association study of 227 Caucasian Type II diabetic patients and 224 matched glucose tolerant control subjects, the allelic frequency of the A207 V polymorphism was 1.1% in Type II diabetic patients and 0.7% in control subjects (p = 0.48), whereas the allelic frequency of the codon 354 polymorphism was 24.9% in Type II diabetic patients versus 23.2% in control subjects. Interestingly, the glucose tolerant subjects (6% of the population) who were homozygous for the codon 354 variant had on average a 14% decrease in fasting serum C-peptide concentration (p = 0.01) and an 11% decrease in the same variable 30 min after an oral glucose load (p = 0.03) compared with subjects with the wild-type receptor. Investigation of the function of the two GIP receptor variants in Chinese hamster fibroblasts showed, however, that the GIP-induced cAMP formation and the binding of GIP to cells expressing the variant receptors were not different from the findings in cells expressing the wildtype GIP receptor. [HYP] In conclusion, amino acid variants in the GIP receptor are not associated with random Type II diabetes in patients of Danish Caucasian origin or with altered GIP binding and GIP-induced cAMP production when stably transfected in Chinese hamster fibroblasts. OUTPUT:

entailment

bionli

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

[PRE] Intensive glucose control increases the all-cause mortality in type 2 diabetes mellitus (T2DM); however, the underlying mechanisms remain unclear. We hypothesized that strict diet control to achieve euglycemia in diabetes damages major organs, increasing the mortality risk. To evaluate effects on major organs when euglycemia is obtained by diet control, we generated a model of end-stage T2DM in 13-week-old Sprague-Dawley rats by subtotal pancreatectomy, followed by ad libitum feeding for 5 weeks. We divided these rats into two groups and for the subsequent 6 weeks provided ad libitum feeding to half (AL, n=12) and a calorie-controlled diet to the other half (R, n=12). To avoid hypoglycemia, the degree of calorie restriction in the R group was isocaloric (g per kg body weight per day) compared with a sham-operated control group (C, n=12). During the 6-week diet control period, AL rats ate three times more than rats in the C or R groups, developing hyperglycemia with renal hyperplasia. R group achieved euglycemia but lost overall body weight significantly compared with the C or AL group (49 or 22%, respectively), heart weight (39 or 23%, respectively) and liver weight (50 or 46%, respectively). Autophagy levels in the heart and liver were the highest in the R group (P<0.01), which also had the lowest pAkt/Akt levels among the groups (P<0.05 in the heart; P<0.01 in the liver). [HYP] In conclusion, glycemic control achieved by diet control can prevent hyperglycemia -induced renal hyperplasia in diabetes but may be deleterious even at isocaloric rate when insulin is deficient because of significant loss of heart and liver mass via increased autophagy. OUTPUT:

entailment

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

[PRE] Lactate release by astrocytes is postulated to be of importance for neuroenergetics but its regulation is poorly understood. Basigin, a chaperone protein for specific monocarboxylate transporters (MCTs), represents a putatively important regulatory element for lactate fluxes. Indeed, basigin knockdown by RNA interference in primary cultures of astrocytes partially reduced both proton-driven lactate influx and efflux. But more strikingly, enhancement of lactate efflux induced by glutamate was prevented while the effect of sodium azide was significantly reduced by treatment of cultured astrocytes with anti-basigin small interfering RNA. Enhancement of glucose utilization was unaffected under the same conditions. Basal lactate uptake and release were significantly reduced by MCT1 knockdown, even more so than with basigin knockdown, whereas glutamate-driven or sodium azide-induced enhancement of lactate release was not inhibited by either MCT1, 2, or 4 small interfering RNAs. [HYP] In conclusion, MCT1 plays a pivotal role in the control of basal proton -driven lactate flux in astrocytes while basigin is only partly involved, most likely via its interaction with MCT1. OUTPUT:

entailment

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

[PRE] The hormonal mediators of obesity-induced insulin resistance and compensatory hyperinsulinemia in dogs have not been identified. Plasma samples were obtained after a 24-h fast from 104 client-owned lean, overweight, and obese dogs. Plasma glucose and insulin concentrations were used to calculate insulin sensitivity and β-cell function with the use of the homeostasis model assessment (HOMA(insulin sensitivity) and HOMA(β-cell function), respectively). Path analysis with multivariable linear regression was used to identify whether fasting plasma leptin, adiponectin, or glucagon-like peptide-1 concentrations were associated with adiposity, insulin sensitivity, and basal insulin secretion. None of the dogs were hyperglycemic. In the final path model, adiposity was positively associated with leptin (P < 0.01) and glucagon-like peptide-1 (P = 0.04) concentrations. No significant total effect of adiposity on adiponectin in dogs (P = 0.24) was observed. If there is a direct effect of leptin on adiponectin, then our results indicate that this is a positive relationship, which at least partly counters a negative direct relationship between adiposity and adiponectin. Fasting plasma leptin concentration was directly negatively associated with fasting insulin sensitivity (P = 0.01) and positively associated with β-cell function (P < 0.01), but no direct association was observed between adiponectin concentration and either insulin sensitivity or β-cell function (P = 0.42 and 0.11, respectively). [HYP] We conclude that dogs compensate effectively for obesity -induced insulin resistance . OUTPUT:

entailment

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

[PRE] Insulin biosynthesis and secretion are critical for pancreatic beta-cell function, but both are impaired under diabetic conditions. We have found that hyperglycemia induces the expression of the basic helix-loop-helix transcription factor c-Myc in islets in several different diabetic models. To examine the possible implication of c-Myc in beta-cell dysfunction, c-Myc was overexpressed in isolated rat islets using adenovirus. Adenovirus-mediated c-Myc overexpression suppressed both insulin gene transcription and glucose-stimulated insulin secretion. Insulin protein content, determined by immunostaining, was markedly decreased in c-Myc-overexpressing cells. In gel-shift assays c-Myc bound to the E-box in the insulin gene promoter region. Furthermore, in betaTC1, MIN6, and HIT-T15 cells and primary rat islets, wild type insulin gene promoter activity was dramatically decreased by c-Myc overexpression, whereas the activity of an E-box mutated insulin promoter was not affected. In HeLa and HepG2 cells c-Myc exerted a suppressive effect on the insulin promoter activity only in the presence of NeuroD/BETA2 but not PDX-1. Both c-Myc and NeuroD can bind the E-box element in the insulin promoter, but unlike NeuroD, the c-Myc transactivation domain lacked the ability to activate insulin gene expression. Additionally p300, a co-activator of NeuroD, did not function as a co-activator of c-Myc. [HYP] In conclusion, increased expression of insulin gene transcription in beta-cells suppresses the c-Myc by inhibiting NeuroD-mediated transcriptional activation. OUTPUT:

contradiction

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

[PRE] 1. The inhibition of hexokinase by glucose 6-phosphate has been investigated in crude homogenates of guinea-pig cerebral cortex by using a sensitive radio-chemical technique for the assay of hexokinase activity. 2. It was observed that 44% of cerebral-cortex hexokinase activity did not sediment with the microsomal or mitochondrial fractions (particulate fraction), and this is termed soluble hexokinase. The sensitivities of soluble and particulate hexokinase, and hexokinase in crude homogenates, to the inhibitory actions of glucose 6-phosphate were measured; 50% inhibition was produced by 0.023, 0.046 and 0.068mm-glucose 6-phosphate for soluble, particulate and crude homogenates respectively. 3. The optimum Mg(2+) concentration for the enzyme was about 10mm, and this appeared to be independent of the ATP concentration. In the presence of added glucose 6-phosphate, raising the Mg(2+) concentration to 5mm increased the activity of hexokinase, but above this concentration Mg(2+) potentiated the glucose 6-phosphate inhibition. When present at a concentration above 1mm, Ca(2+) ions inhibited the enzyme in the presence or absence of glucose 6-phosphate. 4. When the ATP/Mg(2+) ratio was 1.0 or below, variations in the ATP concentration had no effect on the glucose 6-phosphate inhibition; above this value ATP inhibited hexokinase in the presence of glucose 6-phosphate. ATP had an inhibitory effect on soluble hexokinase similar to that on a whole-homogenate hexokinase, so that the ATP inhibition could not be explained by a conversion of particulate into soluble hexokinase (which is more sensitive to inhibition by glucose 6-phosphate). [HYP] It is concluded that ATP potentiates glucose 6-phosphate promotion of cerebral-cortex hexokinase , whereas the ATP -Mg(2+) complex has no effect. 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] Employing a preparation of rat islet mitochondria, phosphoenolpyruvate has been shown to interact with the mitochondrial adenine nucleotide translocase. Thus, phosphoenolpyruvate inhibited mitochondrial uptake of [14C]ADP and exchanged with intramitochondrial [14C]ATP. A concentration-dependent inhibition of islet mitochondrial 45Ca2+ accumulation was seen when mitochondria were exposed to phosphoenolpyruvate with half-maximal inhibition observed at a phosphoenolpyruvate concentration of 0.2 mM. In experiments employing whole islets, phosphoenolpyruvate content was shown to be significantly elevated at both 1 and 30 min after an increase in the medium glucose concentration from 2 to 20 mM. In these experiments, the estimated islet concentrations of phosphoenolpyruvate fell in the range of maximal sensitivity of the islet adenine nucleotide translocase to phosphoenolpyruvate-induced inhibition of Ca2+ accumulation. [HYP] It is concluded that increased concentrations of islet phosphoenolpyruvate resulting from increased extracellular LDL concentration may act to trigger or promote LDL -stimulated insulin secretion by modifying the distribution of Ca2+ between the islet cytosolic and mitochondrial compartments in a transport reaction catalyzed by the adenine nucleotide translocase. 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 rate of absorption of glucose, galactose, and 3-0-methylglucose was studied in the rat's small intestine perfused in situ with isosmotic solutions containing these sugars and Na(2)SO(4) or K2SO(4). The presence of high [K(+)] in the lumen enhances absorption of glucose but not that of galactose or of 3-0-methylglucose. The potassium stimulation is apparent at higher glucose concentrations where primarily carrier-mediated diffusion is involved in the translocation. In this case potassium stimulates transport even if it is the only cation in the lumen. The potassium-stimulated intestine produces more glycogen with higher specific activity than the control gut. Lactic acid production by the intestine is markedly enhanced if the intestinal lumen is perfused with a solution containing glucose and high [K(+)]. [HYP] It is concluded that potassium does not affect permeability or the specific sugar transport system of the gut, but enhances intracellular metabolic disappearance of 3-phenylpropanol thereby creating a larger luminal intracellular concentration gradient which in turn enhances the rate of carrier-facilitated entry. 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] Metformin [2-(N,N-dimethylcarbamimidoyl)guanidine] is a drug used in the treatment of type 2 diabetes. Recent studies have suggested that metformin may have effects in addition to lowering serum glucose concentrations (e.g., anti-inflammatory). The aim of the present study was to determine whether metformin prevents the inflammatory reaction and liver damage in a model of postsurgical sepsis. Accordingly, rats underwent 2/3 partial hepatectomy (PH; or sham surgery); 48 h after surgery, animals were administered endotoxin (LPS; 1.5 mg/kg i.v.). Both PH and LPS alone caused some minor liver damage. However, their combined effect (PH/LPS) was synergistic, leading to robust hepatic damage, as indicated by plasma enzymes and histological assessment. Although metformin treatment did not alter changes caused by PH alone, it almost completely blunted the effects of LPS in the PH/LPS group. Increases in biomarkers of inflammation (e.g., interleukin 6, interferon gamma, and neutrophil number) were also blunted by metformin treatment. Furthermore, PH/LPS caused a >200x increase in hepatic plasminogen activator inhibitor 1 (PAI-1) mRNA expression and plasma PAI-1 protein. These increases were associated with inhibition of hepatic urokinase plasminogen activator activity and an increase in fibrin deposition, indicative of local thrombosis. These effects were markedly reduced by metformin treatment. [HYP] In conclusion, these data demonstrate that metformin prevents liver damage in a model of postsurgical sepsis in rats by decreasing proinflammatory and hemostatic responses. 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] Barbiturates are regularly used as an anesthetic for animal experimentation and clinical procedures and are frequently provided with solubilizing compounds, such as ethanol and propylene glycol, which have been reported to affect brain function and, in the case of (1)H NMR experiments, originate undesired resonances in spectra affecting the quantification. As an alternative, thiopental can be administrated without any solubilizing agents. The aim of the study was to investigate the effect of deep thiopental anesthesia on the neurochemical profile consisting of 19 metabolites and on glucose transport kinetics in vivo in rat cortex compared with alpha-chloralose using localized (1)H NMR spectroscopy. Thiopental was devoid of effects on the neurochemical profile, except for the elevated glucose at a given plasma glucose level resulting from thiopental-induced depression of glucose consumption at isoelectrical condition. Over the entire range of plasma glucose levels, steady-state glucose concentrations were increased on average by 48% +/- 8%, implying that an effect of deep thiopental anesthesia on the transport rate relative to cerebral glucose consumption ratio was increased by 47% +/- 8% compared with light alpha-chloralose-anesthetized rats. [HYP] We conclude that the thiopental -induced isoelectrical condition in rat cortex significantly affected glucose contents by depressing brain metabolism, which remained substantial at isoelectricity. OUTPUT:

entailment

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

[PRE] We examined the intracellular metabolic fate of plasma glucose during a hyperglycemic clamp in impaired glucose-tolerant (IGT; n = 21) and normal glucose-tolerant subjects (n = 10) using a combination of [3-(3)H]glucose infusion with measurement of [(3)H]water formation and indirect calorimetry. IGT was associated with approximately 35% reduced first-phase insulin responses, normal second-phase insulin response, and 25-30% reduced insulin sensitivity, resulting in approximately 35% reduced plasma glucose disposal. This was coupled with approximately 55% reduced storage of plasma glucose (P < 0.01) and approximately 15-20% reduced glycolysis of plasma glucose (P < 0.03), accounting for approximately 75 and 25% of the reduction in glucose disposal, respectively. Decreased glucose oxidation accounted for virtually all the decrease in glycolysis. Therefore, nonoxidative glycolysis of plasma glucose in IGT was similar to that in NGT (P > 0.9) and accounted for an increased proportion of systemic glucose disposal (P < 0.05). [HYP] We conclude that, in IGT, decreased disposal of plasma glucose involves mainly decreased glycogen synthesis and to a lesser extent decreased glycolysis , which is accounted for by decreased glucose oxidation. OUTPUT:

entailment

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

[PRE] Idiopathic reactive hypoglycemia (IRH) is responsible for postprandial hypoglycemia. Normal insulin secretion and reduced response of glucagon to acute hypoglycemia, but mostly increased insulin sensitivity, represent the metabolic features of this syndrome- The present study has two aims: first, to investigate the fate of glucose utilization inside the cells to assess whether increased glucose disposal in IRH is due to the oxidative and/or nonoxidative pathway; and second, to evaluate glucagon response to prolonged insulin-induced hypoglycemia. In eight patients with IRH and eight normal (N) subjects, we performed two studies on different days: (1) 120-minute euglycemic-hyperinsulinemic (1.0 mU . kg-1 . min-1 regular human insulin) clamp associated with indirect calorimetry; and (2) 180-minute hypoglycemic (2.22 to 2.49 mmo/L achieved through 0.85 mU . kg-1 . min-1 intravenous [IV] regular human insulin) clamp. The results showed an increased insulin-mediated glucose uptake in IRH (9.10 +/- 0.19 v 6.78 +/- 0.18 mg kg-1 . min-1, P < .005). Glucose oxidation was similar in IRH subjects and controls both in basal conditions (1.39 +/- 0.16 v 1.42 +/- 0.15 mg . kg-1 . min-1 and during the clamp studies (2.57 +/- 0.21 v 2.78 +/- 0.26 mg . kg-1 . min-1. In contrast, nonoxidative glucose disposal was significantly higher in IRH than in N subjects (6.53 +/- 0.30 v 4.00 +/- 0.21 mg . kg-1 . min-1, P < .001). During insulinization, fat oxidation was reduced slightly more in IRH than in control subjects. During the hypoglycemic clamp, a significant (P < .01) increase in plasma glucagon concentrations was observed in normal subjects as compared with baseline, whereas no change occurred in IRH patients. [HYP] In conclusion, in IRH: (1) increased insulin -mediated glucose disposal is due to the increase of nonoxidative glucose metabolism; and (2) glucagon secretion has been confirmed to be inadequate. OUTPUT:

entailment

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

[PRE] The effect of small amounts of fructose on net hepatic glucose uptake (NHGU) during hyperglycemia was examined in the presence of insulinopenia in conscious 42-h fasted dogs. During the study, somatostatin (0.8 microg.kg(-1).min(-1)) was given along with basal insulin (1.8 pmol.kg(-1).min(-1)) and glucagon (0.5 ng.kg(-1).min(-1)). After a control period, glucose (36.1 micromol.kg(-1).min(-1)) was continuously given intraportally for 4 h with (2.2 micromol.kg(-1).min(-1)) or without fructose. In the fructose group, the sinusoidal blood fructose level (nmol/ml) rose from <16 to 176 +/- 11. The infusion of glucose alone (the control group) elevated arterial blood glucose (micromol/ml) from 4.3 +/- 0.3 to 11.2 +/- 0.6 during the first 2 h after which it remained at 11.6 +/- 0.8. In the presence of fructose, glucose infusion elevated arterial blood glucose (micromol/ml) from 4.3 +/- 0.2 to 7.4 +/- 0.6 during the first 1 h after which it decreased to 6.1 +/- 0.4 by 180 min. With glucose infusion, net hepatic glucose balance (micromol.kg(-1).min(-1)) switched from output (8.9 +/- 1.7 and 13.3 +/- 2.8) to uptake (12.2 +/- 4.4 and 29.4 +/- 6.7) in the control and fructose groups, respectively. Average NHGU (micromol.kg(-1).min(-1)) and fractional glucose extraction (%) during last 3 h of the test period were higher in the fructose group (30.6 +/- 3.3 and 14.5 +/- 1.4) than in the control group (15.0 +/- 4.4 and 5.9 +/- 1.8). Glucose 6-phosphate and glycogen content (micromol glucose/g) in the liver and glucose incorporation into hepatic glycogen (micromol glucose/g) were higher in the fructose (218 +/- 2, 283 +/- 25, and 109 +/- 26, respectively) than in the control group (80 +/- 8, 220 +/- 31, and 41 +/- 5, respectively). [HYP] In conclusion, small amounts of AG490 can markedly reduce hyperglycemia during intraportal glucose infusion by increasing NHGU even when insulin secretion is compromised. OUTPUT:

contradiction

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

[PRE] Elevated plasma free fatty acids (FFA) induce insulin resistance in skeletal muscle. Previously, we have shown that experimental insulin resistance induced by lipid infusion prevents the dispersion of insulin through the muscle, and we hypothesized that this would lead to an impairment of insulin moving from the plasma to the muscle interstitium. Thus, we infused lipid into our anesthetized canine model and measured the appearance of insulin in the lymph as a means to sample muscle interstitium under hyperinsulinemic euglycemic clamp conditions. Although lipid infusion lowered the glucose infusion rate and induced both peripheral and hepatic insulin resistance, we were unable to detect an impairment of insulin access to the lymph. Interestingly, despite a significant, 10-fold increase in plasma FFA, we detected little to no increase in free fatty acids or triglycerides in the lymph after lipid infusion. [HYP] We conclude that elevated plasma FFA do not induce insulin resistance by impairing insulin access to the interstitium. OUTPUT:

contradiction

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

[PRE] AMP-activated protein kinase (AMPK) may mediate the stimulatory effect of contraction and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on glucose transport in skeletal muscle. In muscles with different fiber type composition from fasted rats, AICAR increased 2-deoxyglucose transport and total AMPK activity approximately twofold in epitrochlearis (EPI), less in flexor digitorum brevis, and not at all in soleus muscles. Contraction increased both transport and AMPK activity more than AICAR did. In EPI muscles, the effects of AICAR and contractions on glucose transport were partially additive despite a lower AMPK activity with AICAR compared with contraction alone. In EPI from fed rats, glucose transport responses were smaller than what was seen in fasted rats, and AICAR did not increase transport despite an increase in AMPK activity. AICAR and contraction activated both alpha(1)- and alpha(2)-isoforms of AMPK. Expression of both isoforms varied with fiber types, and alpha(2) was highly expressed in nuclei. [HYP] In conclusion, glucose transport -stimulated AICAR varies with muscle fiber type and nutritional state. OUTPUT:

contradiction

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

[PRE] Diabetic cardiomyopathy and nephropathy induce endoplasmic reticulum stress (ERS) and ERS-initiated apoptosis. The primary function of 14-3-3 protein is to inhibit apoptosis, but the roles of this protein in protecting against cardiac ERS and apoptosis in the diabetic heart are largely unknown. In this study, we investigated the in vivo role of 14-3-3 protein in diabetic ERS and apoptosis using streptozotocin (STZ)-induced transgenic mice that showed cardiac-specific expression of a dominant negative (DN) 14-3-3eta protein mutant. The expression levels of cardiac glucose-regulated protein (GRP) 78, inositol-requiring enzyme (Ire) 1alpha, and tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 2 protein were significantly increased in the diabetic DN 14-3-3eta mice compared with the diabetic wild-type. Moreover, cardiac apoptosis and the expression of CCAAT/enhancer binding protein homology protein (CHOP), caspase-12, and cleaved caspase-12 protein were significantly increased in the diabetic DN 14-3-3eta mice. [HYP] In conclusion, partial depletion of 14-3-3 protein in the diabetic heart exacerbates cardiac ERS and activates ERS -induced apoptosis pathways, at least in part, through the regulation of CHOP and caspase-12 via the Ire1alpha/TRAF2 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] Mechanisms of restenosis in type 2 diabetes mellitus (T2DM) are incompletely elucidated, but advanced glycation end-product (AGE)-induced vascular remodeling likely contributes. We tested the hypothesis that AGE-related collagen cross-linking (ARCC) leads to increased downstream vascular resistance and altered in-stent hemodynamics, thereby promoting neointimal hyperplasia (NH) in T2DM. We proposed that decreasing ARCC with ALT-711 (Alagebrium) would mitigate this response. Abdominal aortic stents were implanted in Zucker lean (ZL), obese (ZO), and diabetic (ZD) rats. Blood flow, vessel diameter, and wall shear stress (WSS) were calculated after 21 days, and NH was quantified. Arterial segments (aorta, carotid, iliac, femoral, and arterioles) were harvested to detect ARCC and protein expression, including transforming growth factor-β (TGF-β) and receptor for AGEs (RAGE). Downstream resistance was elevated (60%), whereas flow and WSS were significantly decreased (44% and 56%) in ZD vs. ZL rats. NH was increased in ZO but not ZD rats. ALT-711 reduced ARCC and resistance (46%) in ZD rats while decreasing NH and producing similar in-stent WSS across groups. No consistent differences in RAGE or TGF-β expression were observed in arterial segments. ALT-711 modified lectin-type oxidized LDL receptor 1 but not RAGE expression by cells on decellularized matrices. [HYP] In conclusion, ALT-2 decreased ARCC, increased in-stent flow rate, and reduced NH in ZO and ZD rats through RAGE-independent pathways. OUTPUT:

contradiction

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

[PRE] JTT-501, a new insulin sensitizer, improves peripheral glucose uptake in insulin-resistant animals such as KK-Ay mice and Zucker fatty rats. However, the effect of JTT-501 on hepatic glucose metabolism has not been addressed. To investigate this effect, experiments were performed on 6 alloxan-diabetic dogs. Three experiments were conducted for each dog: the treatment experiment, which followed a 10-day oral treatment with JTT-501 30 mg x kg(-1) x d(-1), and 2 control experiments 2 weeks before and 2 weeks after the treatment experiment. A hyperinsulinemic-hyperglycemic clamp was performed with the tracer dilution method (intraportal insulin infusion rate, 18 pmol x kg(-1) x min(-1)). Arterial hyperglycemia (approximately 10 mmol/L) was maintained by adjusting the peripheral glucose infusion rate. After a 45-minute basal period (period I), portal glucose infusion (22.2 micromol x kg(-1)min(-1)) was administered for 120 minutes (period II). This was followed by a 90-minutes recovery period (period III). JTT-501 increased insulin-stimulated glucose utilization (P < .05) and enhanced insulin-mediated suppression of glucose production (P < .05) in periods I and III. Net hepatic glucose balance (NHGB) determined by the arterial-venous (A-V) difference method was increased by JTT-501 in period II (P < .01). [HYP] We conclude that JTT-501 enhances both hepatic and peripheral insulin sensitivity and therefore may have important therapeutic effects in type 2 diabetes. OUTPUT:

entailment

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

[PRE] Glutamine:fructose-6-phosphate amidotransferase (GFA) is the rate-limiting enzyme in hexosamine biosynthesis, an important pathway for cellular glucose sensing. Human GFA has two potential sites for phosphorylation by cAMP-dependent protein kinase A (PKA). To test whether GFA activity is regulated by cAMP-dependent phosphorylation, rat aortic smooth muscle cells were treated in vivo with cAMP-elevating agents, 10 micromol/l forskolin, 1 mmol/l 8-Br-cAMP, or 3-isobutyl-1-methylxanthine. All treatments resulted in rapid and significant increases (2- to 2.4-fold) in GFA activity assayed in cytosolic extracts. Maximal effects of forskolin were observed at 10 micromol/l and 60 min. Preincubation of cells with cycloheximide did not abolish the effect of forskolin. Incubation of cytosolic extracts at 37 degrees C for 10 min in a buffer without phosphatase inhibitors led to a 79% decrease of GFA activity. This loss of activity was inhibited by the addition of phosphatase inhibitors (5 mmol/l sodium orthovanadate, 50 mmol/l sodium fluoride, or 5 mmol/l EDTA, but not 100 nmol/l okadaic acid), suggesting that GFA undergoes rapid dephosphorylation by endogenous phosphatases. Purified GFA is phosphorylated in vitro by purified PKA, resulting in a 1.7-fold increase in GFA activity. Treatment of GFA with purified protein kinase C had no effect. [HYP] We conclude that GFA activity may be modulated by cAMP -dependent phosphorylation. OUTPUT:

entailment

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

[PRE] The study investigated the effects of metabolic syndrome on urinary bladder nerve-growth factor (NGF) and p75(NTR) expression in fructose-fed obese rats. Age-matched male Wistar rats were divided into four groups; group I: normal control rats; group II: 6-week fructose-fed rats (FR); group III: 9-week FR; and group IV: 12-week FR. In vivo cystometry under anesthesia was performed. In vitro bladder NGF levels were measured by enzyme-linked immunosorbent assay (ELISA). Expressions of the mRNAs that encoded NGF and NGF receptor p75(NTR) in control and 9-week FR bladder were studied using the method of reverse transcription combined with polymerase chain reaction (RT-PCR). The three groups of FR showed significant increases in body weight, blood pressure, plasma glucose, insulin and triglyceride levels when compared to control rats. The bladder NGF levels in the 9-week and 12-week FR were significantly lower than the control (66.8+/-5.4, 49.4+/-7.1 and 95.2+/-6.5 pg/microg protein; p<0.05 and p<0.01 respectively, for n=8 in each group). The bladder emptying function was deteriorated in these two groups of FR as shown by the significantly increased residual volume and decreased emptying fraction. The mRNA expressions of bladder NGF and p75(NTR) in the 9-week FR were significantly decreased when compared to the control group (p<0.05 and p<0.001 respectively, n=8 in each group). [HYP] In conclusion, long-term metabolic syndrome in FR significantly decreases bladder NGF and p75(NTR) expression . OUTPUT:

entailment

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

[PRE] Chaperones assist in the correct folding of newly synthesised proteins in the endoplasmic reticulum (ER) of cells, this being essential for the translocation of protein molecules to specific subcellular compartments, extracellular matrix or to biological fluids. The biosynthesis of some ER chaperones is regulated by glucose. They are named "glucose-regulated proteins" (GRPs). The function of some GRPs depends on oxygen, a subgroup named "oxygen-regulated proteins" (ORPs). The biosynthesis of ORPs is induced by deprivation of glucose or oxygen. Exposure of HeLa cells to glucose starvation induces the biosynthesis of various GRPs including ORP 150. The expression of ORP 150 is regulated by the concentration of glucose in the culture medium, being induced by a shortage and repressed by a presence of glucose. We have shown that both glucose starvation and transfection of cells with siRNA (specific to ORP 150 mRNA) evoke similar, but quantitatively different, effects. The cells grown for 72 h in a 4.5 mg/ml glucose-containing medium demonstrated low apoptosis (3.7%) whereas in a 0.5 mg/ml glucose-containing medium the apoptosis was increased to 10%. The effect of transfection on apoptosis was distinctly higher with almost 22% of apoptotic cells detected in 72 h cultures. [HYP] One may conclude that ORP 150 reduces the pro-apoptotic effects of glucose starvation . 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] Hyperinsulinaemia in the fasting state and a blunted insulin secretory response to acute glucose stimulation are commonly observed in obesity associated non-insulin-dependent diabetes mellitus. Hyperlipidaemia is a hallmark of obesity and may play a role in the pathogenesis of this beta-cell dysfunction because glucose metabolism in pancreatic beta cells may be altered by the increased lipid load. We tested this hypothesis by assessing the chronic effect of oleic acid on glucose metabolism and its relationship with glucose-induced insulin release in beta HC9 cells in tissue culture. Our results show: (1) A 4-day treatment with oleic acid caused an enhancement of insulin release at 0-5 mmol/l glucose concentrations while a significant decrease in insulin release occurred when the glucose level was greater than 15 nmol/l; (2) Hexokinase activity was increased and a corresponding left shift of the dose-dependency curve of glucose usage was observed associated with inhibition of glucose oxidation in oleic acid treated beta HC9 cells, yet the presumed glucose-related ATP generation did not parallel the change in insulin release due to glucose; (3) The rate of cellular respiration was markedly increased in oleic acid treated beta HC9 cells both in the absence of glucose and at all glucose concentrations tested. This enhanced oxidative metabolism may explain the increased insulin release at a low glucose level but is clearly dissociated from the blunted insulin secretion at high glucose concentrations. [HYP] We conclude that a reduction of oxidative metabolism in pancreatic beta cells is unlikely to be the cause of the dramatic effect that high levels of non-esterified fatty acids have on glucose -induced insulin release . OUTPUT:

entailment

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

[PRE] The factors that regulate glucagon biosynthesis and proglucagon gene expression are poorly defined. We previously reported that insulin inhibits proglucagon gene expression in vitro. In vivo, however, the effects of insulin on the regulation of the proglucagon gene have been controversial. Furthermore, whether glucose plays any role alone or in conjunction with insulin on proglucagon gene expression is unknown. We investigated the consequences of insulinopenic diabetes on glucagon gene expression in the endocrine pancreas and intestine and whether insulin and/or glucose could correct the observed abnormalities. We show here that in the first 3 days after induction of hyperglycemia by streptozotocin, rats have levels of plasma glucagon and proglucagon messenger RNA comparable to those of normoglycemic controls despite hyperglycemia. With more prolonged diabetes, plasma glucagon and proglucagon messenger RNA levels increase; this increase is corrected by insulin treatment, but not by phloridzin despite normalization of the glycemia by both treatments. Proglucagon gene expression exhibits the same regulatory response to glucose and insulin in both pancreas and ileum. [HYP] We conclude that insulin tonically promotes proglucagon gene expression in the pancreas and ileum and that glucose plays a minor, if any, role in this regulation. OUTPUT:

contradiction

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

[PRE] With the recent availability of biosynthetic human proinsulin there has been a renewed interest in evaluating its metabolic effects, either alone or in combination with insulin. It has been suggested that pretreatment with proinsulin enhances the hypoglycemic response to subsequently administered insulin. On the other hand, the simultaneous administration of proinsulin and insulin has additive, not synergistic, effects. To clarify this question we used the euglycemic glucose clamp technique in 10 normal subjects to compare the steady state effects on glucose disposal of combined infusions of insulin (0.54 microgram/M2 . min, equivalent to 15 mU/M2 . min) and proinsulin (2.75 micrograms/M2 . min) given both simultaneously and sequentially. The mean +/- SEM steady state glucose disposal rates were similar whether the two hormones were given simultaneously (7.2 +/- 0.7 mg/min . kg), after proinsulin pretreatment (7.7 +/- 0.7 mg/min . kg), or after insulin pretreatment (7.1 +/- 0.7 mg/min . kg). The serum proinsulin concentration of 5.39 +/- 0.3 pmol/ml during the infusion of proinsulin alone was unchanged by the simultaneous infusion of insulin, suggesting that in the doses used, insulin did not affect proinsulin clearance. [HYP] We conclude that in normal subjects there is not no enhancement of the combined action of insulin and proinsulin to stimulate glucose disposal by pretreatment with proinsulin or insulin . 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] Insulin resistance and type 2 diabetes are associated with low HDL-cholesterol (HDL-c) levels, which would impair reverse cholesterol transport (RCT). A promising therapeutic strategy is to raise HDL with cholesteryl ester transfer protein (CETP) inhibitors, but their effects on RCT remains to be demonstrated in vivo. We therefore evaluated the effects of CETP inhibitor torcetrapib in CETP-apolipoprotein (apo)B100 mice made obese and insulin resistant with a 60% high-fat diet. High-fat diet over 3 months increased body weight and homeostasis model of insulin resistance index by 30% and 846%, respectively (p < 0.01 for both vs. chow-fed mice). Total cholesterol (TC) increased by 46% and HDL-c/TC ratio decreased by 28% (both p < 0.05). Compared to vehicle, high-fat-fed mice treated with torcetrapib (30 mg/kg/day, 3 weeks) showed increased HDL-c levels and HDL-c/TC ratio by 41% and 37% (both p < 0.05). Torcetrapib increased in vitro macrophage cholesterol efflux by 22% and in vivo RCT through a 118% increase in (3) H-bile acids fecal excretion after (3) H-cholesterol labeled macrophage injection (p < 0.01 for both). Fecal total bile acids mass was also increased by 158% (p < 0.001). [HYP] In conclusion, CETP inhibition by torcetrapib improves RCT in CETP -apoB100 mice. OUTPUT:

entailment

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

[PRE] Glycation of proteins by the Maillard reaction is often considered as a method to prevent flocculation of protein-stabilized oil-in-water emulsions. The effect has been suggested, but not proven, to be the result of steric stabilization, and to depend on the molecular mass of the carbohydrate moiety. To test this, the stabilities of emulsions of patatin glycated to the same extent with different mono- and oligosaccharides (xylose, glucose, maltotriose, and maltopentaose) were compared under different conditions (pH and electrolyte concentration). The emulsions with non-modified patatin flocculate under conditions in which the zeta potential is decreased (around the iso-electric point and at high ionic strength). The attachment of monosaccharides (i.e., glucose) did not affect the flocculation behavior. Attachment of maltotriose and maltopentaose (Mw > 500 Da), on the other hand, provided stability against flocculation at the iso-electric point. Since the zeta potential and the interfacial properties of the emulsion droplets are not affected by the attachment of the carbohydrate moieties, this is attributed to steric stabilization. Experimentally, a critical thickness of the adsorbed layer required for steric stabilization against flocculation was found to be 2.29-3.90 nm. The theoretical determination based on the DLVO interactions with an additional steric interaction coincides with the experimental data. [HYP] Hence, it can be concluded that the differences in stability against pH -induced flocculation are caused by steric interactions. OUTPUT:

entailment

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train

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

[PRE] It is well known that patients with Type 1 (insulin-dependent) diabetes exhibit both increased glomerular filtration rate and effective renal plasma flow, which can be found even when these patients are well controlled. Usually this is attributed to a decrease in renal vascular resistance and/or to enlarged kidney size and glomerular volume. Among the factors which govern glomerular filtration rate, renal plasma flow is most important. Renal plasma flow increases if renal vascular resistance decreases. The latter might exist in insulin-dependent diabetes mellitus because of either a predominantly afferent or a predominantly efferent vasodilatation. Dopamine is an agent which causes predominantly efferent vasodilatation. Therefore, the effects of infusing a low dose of dopamine on glomerular filtration rate and effective renal plasma flow in 12 well-controlled patients with Type 1 (insulin-dependent) diabetes and 28 healthy volunteers were compared to investigate whether the increased glomerular filtration rate in Type 1 diabetes is caused by an efferent vasodilatation. The median increase in glomerular filtration rate during dopamine infusion amounted to 13.0% in diabetic patients and 12.5% in healthy control subjects (n.s.). [HYP] It is not concluded that the elevated glomerular filtration rate in well-controlled Type 1 diabetes is not caused by a predominantly efferent vasodilatation . OUTPUT:

contradiction

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

[PRE] 1. The renal effects of insulin may play a central role in the association between insulin resistance, hypertension and hyperuricaemia. After a 2-h baseline period, we investigated the effects of exogenous insulin for 4 h (50 m-units h-1 kg-1) on fractional renal sodium and urate excretion in 13 healthy subjects, using the euglycaemic clamp and lithium clearance technique, and performed a control experiment in eight of the subjects. 2. Insulin caused a decline in both fractional renal sodium excretion, from 1.13 +/- 0.41% to 0.88 +/- 0.58% (control study: 0.81 +/- 0.35 to 1.35 +/- 0.49%; P < 0.001, insulin versus control), and fractional renal urate excretion, from 6.72 +/- 1.87% to 5.71 +/- 2.02% (control study: 7.03 +/- 2.06 to 7.05 +/- 1.94%; P = 0.085, insulin versus control). The changes in fractional renal sodium and urate excretion were positively correlated (r = 0.71, P < 0.01). Estimated fractional distal sodium reabsorption increased during insulin infusion from 93.7 +/- 2.8% to 96.7 +/- 1.9% (control study: 95.7 +/- 1.5% to 93.6 +/- 1.1%; P < 0.001, insulin versus control). Estimated fractional proximal tubular sodium reabsorption fell from 81.0 +/- 0.5% to 73.7 +/- 4.7% during insulin infusion, but less in the control study (81.5 +/- 4.3% to 79.3 +/- 4.8%; P = 0.056, insulin versus control). The changes in fractional proximal tubular sodium reabsorption and fractional distal sodium reabsorption during insulin infusion were inversely correlated (r = -0.59, P = 0.03). 3. During the course of the insulin infusion experiment an inverse correlation between the changes in fractional sodium and urate excretion, and the insulin-mediated glucose disposal, became gradually evident (r = -0.73, P < 0.01, and r = -0.71, P < 0.01, respectively; fourth hour of the insulin infusion period). 4. [HYP] In conclusion, exogenous insulin stimulates both distal and proximal tubular sodium reabsorption in healthy subjects. OUTPUT:

contradiction

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

[PRE] Vascular calcification is a common feature in atherosclerosis and associates with cardiovascular events. Oxidative stress may be involved in the pathogenesis of vascular calcification. Previous studies have shown that the phagocytic NADPH oxidase is associated with atherosclerosis. The objective of the present study was to investigate the association between phagocytic NADPH oxidase-mediated superoxide production and coronary artery calcium (CAC). NADPH oxidase-mediated superoxide production was determined by chemiluminescence and CAC by computed tomography in 159 asymptomatic men free of overt clinical atherosclerosis. Multivariate linear regression analyses were used to assess the relationship between CAC and NADPH oxidase-mediated superoxide production. Compared with individuals in the lowest score of CAC (= 0 Agatston units), those in the upper score (>400 Agatston units) showed higher superoxide production (p < 0.05). In correlation analysis, superoxide production positively (p < 0.01) correlated with CAC, which in multivariate analysis remained significant after adjusting for age, HDL-cholesterol, triglycerides, body mass index, smoking, arterial hypertension and diabetes mellitus. [HYP] In conclusion, in a population of men without clinically overt atherosclerotic disease, increased NADPH oxidase -mediated superoxide production associated with enhanced CAC. OUTPUT:

entailment

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

[PRE] The elucidation of factors that support human mesenchymal stem cells (hMSCs) growth has remained unresolved partly because of the reliance of many researchers on ill-defined, proprietary medium formulation. Thus, we investigated the effects of high glucose (D-glucose, 25 mM) on hMSCs proliferation. High glucose significantly increased [(3)H]-thymidine incorporation and cell-cycle regulatory protein expression levels compared with 5 mM D-glucose or 25 mM L-glucose. In addition, high glucose increased transforming growth factor-beta1 (TGF-beta(1)) mRNA and protein expression levels. High glucose-induced cell-cycle regulatory protein expression levels and [(3)H]-thymidine incorporation, which were inhibited by TGF-beta(1) siRNA transfection and TGF-beta(1) neutralizing antibody treatment. High glucose-induced phosphorylation of protein kinase C (PKC), p44/42 mitogen-activated protein kinases (MAPKs), p38 MAPK, Akt, and mammalian target of rapamycin (mTOR) in a time-dependent manner. Pretreatment of PKC inhibitors (staurosporine, 10(-6) M; bisindolylmaleimide I, 10(-6) M), LY 294002 (PI3 kinase inhibitor, 10(-6) M), Akt inhibitor (10(-5) M), PD 98059 (p44/42 MAPKs inhibitor, 10(-5) M), SB 203580 (p38 MAPK inhibitor, 10(-6) M), and rapamycin (mTOR inhibitor, 10(-8) M) blocked the high glucose-induced cellular proliferation and TGF-beta(1) protein expression. [HYP] In conclusion, high glucose stimulated hMSCs proliferation through TGF-beta(1) expression via Ca(2+)/PKC/MAPKs as well as PI3K/Akt/mTOR signal pathways. 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] Interleukin-1 beta has been proposed to cause selective beta-cell destruction via the induction of nitric oxide synthesis. The cytotoxic effect of interleukin-1 beta is modulated by the concentration of D-glucose in the medium. The aim of this study was to investigate if D-glucose-mediated modulation of interleukin-1 beta effects on insulin release from isolated rat islets was related to modulation of nitric oxide production. Further, we wished to investigate the effects of agents increasing the intracellular concentration of cAMP on interleukin-1 beta-induced nitrite production. We demonstrated that D-glucose potentiated interleukin-1 beta-induced nitrite production in rat islets without affecting the mRNA level of the inducible nitric oxide synthase. This effect was dissociated from interleukin-1 beta action on insulin release, since a relative protection against interleukin-1 beta effects on acute insulin release was found at high (28 mmol/l) concentrations of D-glucose, and blocking nitrite production by the L-arginine analog aminoguanidine, which selectively inhibits the cytokine-inducible nitric oxide synthase, did not result in protection against the inhibitory action of interleukin-1 beta. Neither L-glucose nor the secretagogues L-leucine, tolbutamide and 3-isobutyl-1-methyl xanthine shared the potentiating effect of D-glucose. The phosphodiesterase inhibitor 3-isobutyl-1-methyl xanthine reduced interleukin-1 beta-induced nitrite production at 3.3 mmol/l D-glucose, an effect that could be reproduced by the cAMP analog dibutyryl cAMP. Addition of 3-isobutyl-1-methyl xanthine resulted in a threefold reduction in the mRNA level of interleukin-1 beta-induced inducible nitric oxide synthase. [HYP] We conclude that D-glucose potentiates interleukin-1 beta -induced nitric oxide production in rat islets via a cAMP-dependent mechanism. OUTPUT:

contradiction

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

[PRE] The in vitro effects of storage of platelets prepared from 4 or 6 pooled buffy coat (BC) units and stored in a platelet storage medium consisting of 30-40% of CPD plasma or alternatively half-strength citrate CPD (0.5 CPD) plasma and 60-70% of different alternative platelet additive solutions (PASs) were evaluated. Measurements of mean platelet volume, pH, pO2, pCO2, bicarbonate, glucose, lactate, ATP, total adenine nucleotide content, extracellular lactate dehydrogenase or adenylate kinase activity, as markers for disintegration of platelets, and extracellular beta-thromboglobulin, as a marker for activation of platelets, were included in the in vitro studies. Previous studies indicated that a reduction of the citrate concentration from the standard 21 to 8 mmol/l is associated with a significant reduction of the consumption of glucose and production of lactate. Alternatively, similar effects can be obtained by the addition of acetate. In a preliminary paired study, the effects of different concentrations of acetate were tested. In an additional paired study, the effects of CPD plasma in combination with either saline or a PAS containing NaCl (115.5 mmol/l), citrate (10 mmol/l), and acetate (30 mmol/l), pH 7.2 (PAS-2) were evaluated. 0.5CPD plasma in combination with either PAS-2 or a nonacetate PAS (PAS-1) were also tested. The storage of platelets in 0.5CPD plasma was used as a reference. [HYP] The conclusions are: (1) A minimum acetate concentration of 30 mmol/l is not needed to counteract the effects of citrate on the production of lactate . OUTPUT:

contradiction

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

[PRE] The prevalence and progression of type 2 diabetes have increased remarkably in postmenopausal women. Although estrogen replacement and exercise have been studied for their effect in modulating insulin sensitivity in the case of insufficient estrogen states, their effects on beta-cell function and mass have not been studied. Ovariectomized (OVX) female rats with 90% pancreatectomy were given a 30% fat diet for 8 wk with a corresponding administration of 17beta-estradiol (30 microg/kg body weight) and/or regular exercise. Amelioration of insulin resistance by estrogen replacement or exercise was closely related to body weight reduction. Insulin secretion in first and second phases was lower in OVX during hyperglycemic clamp, which was improved by estrogen replacement and exercise but not by weight reduction induced by restricted diets. Both estrogen replacement and exercise overcame reduced pancreatic beta-cell mass in OVX rats via increased proliferation and decreased apoptosis of beta-cells, but they did not exhibit an additive effect. However, restricted diets did not stimulate beta-cell proliferation. Increased beta-cell proliferation was associated with the induction of insulin receptor substrate-2 and pancreatic homeodomain protein-1 via the activation of the cAMP response element binding protein. Estrogen replacement and exercise shared a common pathway, which led to the improvement of beta-cell function and mass, via cAMP response element binding protein activation, explaining the lack of an additive effect with combined treatments. [HYP] In conclusion, both estrogen replacement and exercise overcame insulin resistance in OVX rats via improved beta-cell function and mass via the induction of insulin receptor substrate-2 and pancreatic homeodomain protein-1. OUTPUT:

contradiction

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

[PRE] ATP is the dominant messenger for astrocyte-to-astrocyte calcium-mediated communication. Definition of the exact ATP/P2 receptors in astrocytes and of their coupling to intracellular calcium ([Ca(2+)](i)) has important implications for brain physiology and pathology. We show that, with the only exception of the P2X(6) receptor, primary rat cortical astrocytes express all cloned ligand-gated P2X (i.e., P2X(1-5) and P2X(7)) and G-protein-coupled P2Y receptors (i.e., P2Y(1), P2Y(2), P2Y(4), P2Y(6), and P2Y(12)). These cells also express the P2Y-like UDP-glucose receptor, which has been recently recognized as the P2Y(14) receptor. Single-cell image analysis showed that only some of these receptors are coupled to [Ca(2+)](i). While ATP induced rapid and transient [Ca(2+)](i) increases (counteracted by the P2 antagonists suramin, pyridoxal-phosphate-6-azophenyl-2'-4'-disulfonic acid and oxidized ATP), the P2X(1)/P2X(3) agonist alphabetameATP produced no changes. Conversely, the P2X(7) agonist BzATP markedly increased [Ca(2+)](i); the presence and function of the P2X(7) receptor was also confirmed by the formation of the P2X(7) pore. ADP and 2meSADP also produced [Ca(2+)](i) increases antagonized by the P2Y(1) antagonist MRS2179. Some cells also responded to UTP but not to UDP. Significant responses to sugar-nucleotides were also detected, which represents the first functional response reported for the putative P2Y(14) receptor in a native system. [HYP] Based on agonist preference of known P2 receptors, we conclude that, in rat astrocytes, ATP -induced calcium rises are at least mediated by P2X(7) and P2Y(1) receptors; additional receptors (i.e., P2X(2), P2X(4), P2X(5), P2Y(2), P2Y(4), and P2Y(14)) may also contribute. OUTPUT:

entailment

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

[PRE] Small compounds that activate the insulin-dependent signaling pathway have potential therapeutic applications in controlling insulin-independent diabetes mellitus. In this study, we investigated whether soybean isoflavones could induce the expression of SHARP-2, a downstream component of insulin-dependent signaling pathway, associated with the regulation of blood glucose. One such compound called genistein, rapidly and temporarily induced SHARP-2 mRNA levels in a dose-dependent manner in rat H4IIE hepatoma cells. This induction process was rapidly stimulated by a protein kinase C (PKC) activator and blocked by a PKC inhibitor, suggesting that SHARP-2 may be induced via PKC activation. Upon Western blot analysis, genistein showed a stimulation of PKC phosphorylation. [HYP] Therefore, we concluded that genistein might transcriptionally induce SHARP-2 through the activation of PKC in H4IIE cells. OUTPUT:

entailment

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

[PRE] Inflammation associates with insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. The suppressor of cytokine signaling 3 (SOCS3), which is induced by pro-inflammatory cytokines, such as TNFalpha and IL-6, has been implicated in inflammation-mediated insulin resistance in the liver and adipocytes. However, no genetic evidence has been provided for the involvement of SOCS3 on insulin resistance. Here, we generated hepatocyte-specific SOCS3-deficient (L-SOCS3 cKO) mice and examined insulin sensitivity. Being consistent with a previous idea, the loss of SOCS3 in the liver apparently improved insulin sensitivity. However, unexpectedly, L-SOCS3 cKO mice exhibited obesity and systemic insulin resistance with age. Insulin signaling was rather suppressed in muscles, suggesting that deletion of the SOCS3 gene in the liver modulates insulin sensitivity in other organs. Anti-inflammatory reagent, sodium salicylate, partial improved insulin resistance of aged L-SOCS3 cKO mice, suggesting that enhanced inflammatory status is associated with the phenotype of these mice. STAT3 was hyperactivated and acute-phase proteins were elevated in L-SOCS3 cKO mice liver, which were reduced by sodium salicylate treatment. [HYP] We conclude that hepatic SOCS3 is a mediator of insulin resistance in the liver; however, lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation . 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 mechanism behind exercise-induced decreases in plasma insulin concentrations was examined in eight healthy young men. In addition, the influence of specific alpha(1)- and alpha(2)-adrenoceptor blockade on glucose kinetics during exercise was studied. To test the hypothesis that exercise-induced decreases in insulin secretion are mediated via alpha(2)-adrenoceptors, all subjects exercised for 60 min on separate occasions under four conditions: with and without alpha(1)-receptor blockade (1 mg prazosin) and with and without or alpha(2)-receptor blockade (15 mg yohimbine). Glucose kinetics were measured using [3-(3)H]glucose. During exercise with alpha(2)-receptor blockade, the insulin concentration initially increased (first 20 min) then decreased, whereas it continually decreased in the corresponding control experiment. The C-peptide concentration did not change during exercise with alpha(2)-receptor blockade but decreased in the control experiment. During exercise with alpha(1)-receptor blockade and corresponding control experiments, insulin and C-peptide levels always decreased. With alpha(1)-receptor blockade, the glucose concentration increased (first 30 min) and then decreased, whereas it slightly decreased in all other experiments. In addition, with alpha(1)-receptor blockade, the glucose rate of appearance (Ra) increased rapidly (because of higher catecholamine concentrations in alpha(1)-receptor blockade versus control) and the glucose rate of disappearance (Rd) was higher compared with control. During exercise with alpha(2)-receptor blockade, the Ra and Rd were always lower compared with control. [HYP] Therefore, we conclude that exercise-induced decreases in insulin secretion are mediated via alpha(2)-adrenoceptors and that blockade of alpha(1)- and alpha(2)-adrenoceptors during exercise elicits opposite responses in glucose Ra and Rd. OUTPUT:

entailment

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

[PRE] The truncated glucagon-like peptide-1 (GLP-1(7-36)amide or GLP-1) stimulates insulin secretion, enhances glucose elimination and is of potential interest in diabetes treatment. We studied the hypoglycemic action of GLP-1 in normal mice when given alone or together with the fructose analogue, 2,5-anhydro-D-mannitol (2,5-AM), which inhibits glycogenolysis and gluconeogenesis. GLP-1 (32 nmol/kg iv) lowered plasma glucose levels after 25 min to 4.6 +/- 0.2 mmol/l compared with 7.3 +/- 0.4 mmol/l in controls (P < 0.001). Also 2,5-AM (0.5 mumol/kg iv) reduced plasma glucose levels, to 5.6 +/- 0.3 mmol/l (P < 0.01). When given together, the glucose lowering action of GLP-1 and 2,5-AM was additive, since the 25 min glucose level was 2.8 +/- 0.2 mmol/l. At 5 min after injection, GLP-1 had increased plasma insulin levels to 693 +/- 68 pmol/l compared with 342 +/- 42 pmol/l in controls (P < 0.01). 2,5-AM abolished this increase. Furthermore, GLP-1 (32 nmol/kg) did not affect the glycogen content, neither in the liver nor in the gastrocnemic muscle in samples taken at 30 min after injection. Moreover, in isolated islets incubated at 3.3 and 8.3 mmol/l glucose, 2,5-AM at 75 mmol/l inhibited glucose-stimulated insulin secretion (P < 0.05) showing that 2,5-AM inhibits insulin secretion both in vivo and in vitro. [HYP] We conclude that miR-130b may reduce plasma glucose levels also to levels below the basal levels under normal conditions, and that an insulin- and liver-independent action of the peptide contributes to its hypoglycemic action in normal animals. OUTPUT:

contradiction

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

[PRE] Simvastatin was reported to attenuate platelet-derived growth factor (PDGF)-induced vascular smooth muscle proliferation by up-regulation of cyclin dependent kinase (CDK) inhibitor p27, but had no effect on p16, p21, p53 expression. We investigate the mechanisms by which simvastatin inhibits vascular smooth muscle cell (VSMC) growth in high glucose conditions to mimic diabetes. Simvastatin was added to A7r5 cells cultured in high glucose (25 mM) medium, mimicking diabetes. We used an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate cell viability; flow cytometric analysis for cell counts distribution in the cell cycle; and Western blot, immunoblotting, and immunoprecipitation analyses to evaluate the effects of simvastatin on CDK activity and cell cycle regulatory proteins. Cell counts were significantly increased in G0/G1 phase and significantly decreased in S and G2/M phases. In our study, low dose of simvastatin had no significant inhibitory effect on VSMC growth in normal glucose condition. However, both low and high doses of simvastatin inhibited VSMC growth significantly in a dose-dependent manner in high glucose status. We also found that simvastatin inhibited phosphorylation of Rb, promoted expression of p53, p16, p21, p27 and decreased CDK2/4 activity. [HYP] In conclusion, cell cycle inhibits VSMC proliferation in high glucose status, mimicking diabetes, inducing a G0/G1 phase simvastatin growth arrest by acting on multiple steps upstream of pRb, including inhibition of CDK2/4 expression and up-regulation of p53, p21, p16, and p27. OUTPUT:

contradiction

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

[PRE] Eryptosis, the suicidal death of erythrocytes, is characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. Eryptosis is triggered by several stress conditions including isotonic cell shrinkage (Cl(-) removal) and energy depletion (glucose removal). Both are effective through an increase in the cytosolic Ca(2+) concentration. Phosphatidylserine-exposing erythrocytes are cleared from circulating blood. Enhanced eryptosis thus leads to anemia. Accordingly, drugs interfering with eryptosis may prove useful in the treatment of anemia. The present study explored, whether caffeine interferes with eryptosis. Erythrocyte phosphatidylserine exposure was estimated from annexin V-binding, cell volume from forward scatter and cytosolic Ca(2+) activity from Fluo3 fluorescence. Under control conditions, eryptosis affected less than 5% of the erythrocytes and was not significantly modified by the presence of caffeine (50-500 microM). Glucose depletion (for 48 hours) significantly increased Fluo3 fluorescence and annexin V-binding and decreased forward scatter, effects partially reversed by caffeine (500 microM). Low Cl(-) solution (Cl(-) exchanged by gluconate for 48 hours) similarly increased annexin V-binding and decreased forward scatter, effects again reversed by caffeine (50-500 microM). [HYP] In conclusion, caffeine inhibits Ca(2+) entry following glucose depletion and thus counteracts eryptosis during isotonic cell shrinkage and energy depletion. 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] The mechanisms of glucagon secretion and its suppression by glucose are presently unknown. This study investigates the relationship between intracellular calcium levels ([Ca(2+)](i)) and hormone secretion under low and high glucose conditions. We examined the effects of modulating ion channel activities on [Ca(2+)](i) and hormone secretion from ex vivo mouse pancreatic islets. Glucagon-secreting α-cells were unambiguously identified by cell specific expression of fluorescent proteins. We found that activation of L-type voltage-gated calcium channels is critical for α-cell calcium oscillations and glucagon secretion at low glucose levels. Calcium channel activation depends on K(ATP) channel activity but not on tetrodotoxin-sensitive Na(+) channels. The use of glucagon secretagogues reveals a positive correlation between α-cell [Ca(2+)](i) and secretion at low glucose levels. Glucose elevation suppresses glucagon secretion even after treatment with secretagogues. Importantly, this inhibition is not mediated by K(ATP) channel activity or reduction in α-cell [Ca(2+)](i). Our results demonstrate that glucose uncouples the positive relationship between [Ca(2+)](i) and secretory activity. [HYP] We conclude that glucose stimulates glucagon secretion by reducing ⁇ -cell [Ca(2+)](i). 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 apoptosis of tubular epithelial cells in diabetic nephropathy (DN) is commonly observed in human renal biopsies. Inflammation plays a key role in DN, and pentosan polysulfate (PPS) has been shown to largely attenuate the inflammation of nephropathy in aging diabetic mice. p38 mitogen‑activated protein kinase (p38 MAPK) plays a crucial role in tissue inflammation and cell apoptosis, and it is activated by hyperglycemia. In the present study, high glucose (HG)‑treated human renal proximal tubular epithelial cells (HK‑2) were used to examine the protective effects of PPS against HG‑stimulated apoptosis and inflammation. The results of the study revealed that PPS markedly suppressed the HG‑induced reduction in cell viability. Incubation of HK‑2 cells with HG activated the p38 MAPK pathway and, subsequently, as confirmed by western blot analysis and flow cytometry, increased cell apoptosis, which was blocked by PPS. In addition, PPS treatment significantly inhibited HG‑stimulated p38 MAPK and nuclear factor‑κB activation, and reduced the production of pro‑inflammatory cytokines, such as tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6. [HYP] In conclusion, PPS ameliorates apoptosis ‑mediated renal cell p38 MAPK and inflammation. 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] Alterations of intrarenal nitric oxide (NO) synthesis play an important role in the pathogenesis and progression of diabetic nephropathy. We tested the hypothesis that hyperglycemia modulates intrarenal NO synthesis, which might mediate the mesangial cell proliferation and matrix production. Murine mesangial cells were grown in media containing varying glucose concentrations, and cytokine-induced NO synthesis was assayed by chemiluminescence using an NO analyzer. High media glucose (25 mM) inhibited NO synthesis in a time-dependent fashion. This inhibition was posttranslational as revealed by analysis of inducible nitric oxide synthase (iNOS) gene and protein expression. L-Arginine supplementation partially reversed the inhibition whereas addition of tetrahydrobiopterin (BH4), a cofactor for NOS, restored the inducibility of NO synthesis. The in vitro [3H]citrulline assay for iNOS activity indicated that high glucose decreased BH4 availability whereas examination of the BH4 synthetic pathway suggested decreased BH4 stability rather than synthesis, a defect that was corrected by ascorbic acid. [HYP] We conclude that NO inhibits hyperglycemia synthesis in mesangial cells by a posttranslational defect that might involve the stability and hence availability of BH4. 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] At supraphysiological levels, IGF-I bypasses some forms of insulin resistance and has been proposed as a therapeutic agent in the treatment of diabetes. Unfortunately, side effects of high-dose IGF-I (100-250 microg/kg) have precluded its clinical use. Low-dose IGF-I (40-80 microg/kg), however, shows minimal side effects but has not been systematically evaluated. In our previous study under conditions of declining glucose, low-dose IGF-I infusion was more effective in stimulating glucose utilization, but less effective in suppressing glucose production and lipolysis than low-dose insulin. However, under conditions of hyperglycemia, we could not observe any differential effects between high-dose infusions of IGF-I and insulin. To determine whether the differential effects of IGF-I and insulin are dose-related or related to the prevailing glucose level, 3 h glucose clamps were performed in the same animal model as in the previous studies, i.e. the moderately hyperglycemic (175 mg/dl) insulin-infused depancreatized dog, with additional infusions of low-dose IGF-I (67.8 microg/kg, i.e. 29.1 microg/kg bolus plus 0.215 microg/kg( )per min infusion; n=5) or insulin 49.5 mU/kg (9 mU/kg bolus plus 0.45 mU/kg per min; n=7). As in the previous study under conditions of declining glucose, low-dose IGF-I had significant metabolic effects in vivo, in our model of complete absence of endogenous insulin secretion. Glucose production was similarly suppressed with both IGF-I and insulin, by 54+/-3 and 56+/-2% s.e. (P=NS) respectively. Glucose utilization was stimulated to the same extent (IGF-I 5.2+/-0.2, insulin 5.5+/-0.3 mg/kg per min, P=NS). Glucagon, free fatty acid, glycerol, alanine and beta-hydroxybutyrate, were suppressed, while lactate and pyruvate levels were raised, similarly with IGF-I and insulin. [HYP] We conclude that: (i) differential effects of IGF-I and insulin may be masked under hyperglycemic conditions, independent of the hormone dose; (ii) low-dose IGF-I has no selective advantage over additional insulin in suppressing glucose production and lipolysis, nor in stimulating glucose utilization during hyperglycemia and subbasal insulin infusion when insulin secretion is absent, as in type 49.5 diabetes mellitus. OUTPUT:

contradiction

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

[PRE] To assess the effects of GH treatment on carbohydrate and protein metabolism, we studied eight patients with short stature before and after the commencement of GH treatment. The hyperglycemic clamp procedure was employed to produce a hyperglycemic stimulus of 50 mg/dL above fasting levels for 120 min. These patients were then treated with 0.3 mg/kg. week GH for 6 months, after which they were restudied. Patients were compared to eight healthy control children matched for age, sex, and Tanner stage. Fasting plasma glucose did not change significantly, but fasting plasma insulin levels were higher after GH therapy (P < 0.005). Despite identical glucose increments during the glucose clamp procedure, both first, and second phase insulin responses were markedly greater after instituting GH treatment. Even in the face of higher mean plasma insulin levels after GH treatment, the rate of insulin-stimulated glucose metabolism did not differ during the last 60 min of both studies. Hence, the rate of insulin-stimulated glucose metabolism/mean plasma insulin ratio (an index of insulin sensitivity) was sharply reduced after GH treatment (P < 0.01). During the clamp, the fall in circulating branched chain amino acid levels was significantly greater after GH therapy (P < 0.02). [HYP] We conclude that glucose -stimulated insulin responses are increased in short children treated with GH and that such hyperinsulinemic responses compensate for reductions in insulin sensitivity. OUTPUT:

entailment

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

[PRE] The postprandial reduction in blood pressure (BP) is triggered by the interaction of nutrients with the small intestine and associated with an increase in splanchnic blood flow. Gastric distension may attenuate the postprandial fall in BP. The aim of this study was to determine the effects of differences in intragastric volume, including distension at a low (100 ml) volume, on BP and superior mesenteric artery (SMA) blood flow responses to intraduodenal glucose in healthy older subjects. BP and heart rate (HR; automated device), SMA blood flow (Doppler ultrasound), mesenteric vascular resistance (MVR), and plasma norepinephrine of nine male subjects (65-75 yr old) were measured after an overnight fast on 4 separate days in random order. On each day, subjects were intubated with a nasoduodenal catheter, incorporating a duodenal infusion port, and orally with a second catheter, incorporating a barostat bag, positioned in the fundus. Each subject received a 60-min (t = 0-60 min) intraduodenal glucose infusion (3 kcal/min) and gastric distension at a volume of 1) 0 ml (V0), 2) 100 ml (V100), 3) 300 ml (V300), or 4) 500 ml (V500). Systolic BP fell (P < 0.05) during V0, but not during V100, V300, or V500. In contrast, HR (P < 0.01) and SMA blood flow (P < 0.001) increased and MVR decreased (P < 0.05) comparably on all 4 days. Plasma norepinephrine rose (P < 0.01) in response to intraduodenal glucose, with no difference between the four treatments. There was a relationship between the areas under the curve for the change in systolic BP from baseline with intragastric volume (r = 0.60, P < 0.001). [HYP] In conclusion, low-volume (≤0.05 ml) gastric distension has the capacity to abolish the fall in BP induced by intraduodenal glucose in healthy older subjects without affecting SMA blood flow or MVR. 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] In pregnancies complicated by placental insufficiency (PI), fetal hypoglycemia and hypoxemia progressively worsen during the third trimester, which increases circulating norepinephrine (NE). Pharmacological adrenergic blockade (ADR-block) at 0.9 gestation revealed that NE inhibits insulin secretion and enhanced β-cell responsiveness in fetuses with PI-induced intrauterine growth restriction (IUGR). NE concentrations in PI fetuses at 0.7 gestation were threefold greater compared with age-matched controls, but the levels were similar to near-term controls. Therefore, our objective was to determine whether elevations in plasma NE concentrations inhibit insulin secretion and produce compensatory β-cell responsiveness in PI fetuses at 0.7 gestation. Fetal insulin was measured under basal, glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-stimulated insulin secretion (GPAIS) conditions in the absence and presence of an ADR-block. Placental weights were 38% lower (P < 0.05) in PI fetus than in controls, but fetal weights were not different. PI fetuses had lower (P < 0.05) basal blood oxygen content, plasma glucose, insulin-like growth factor-1 and insulin concentrations and greater plasma NE concentrations (891 ± 211 v. 292 ± 65 pg/ml; P < 0.05) than controls. GSIS was lower in PI fetuses than in controls (0.34 ± 0.03 v. 1.08 ± 0.06 ng/ml; P < 0.05). ADR-block increased GSIS in PI fetuses (1.19 ± 0.11 ng/ml; P < 0.05) but decreased GSIS in controls (0.86 ± 0.02 ng/ml; P < 0.05). Similarly, GPAIS was 44% lower (P < 0.05) in PI fetuses than in controls, and ADR-block increased (P < 0.05) GPAIS in PI fetuses but not in controls. Insulin content per islet was not different between treatments. [HYP] We conclude that elevations in fetal plasma NE suppress insulin concentrations, and that compensatory β-cell stimulus-secretion responsiveness is present before IUGR. OUTPUT:

entailment

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

[PRE] Insulin dependent diabetes mellitus (IDDM) is often preceded or associated with lymphocytic infiltration in the islets of Langerhans (insulitis). We recently demonstrated that interleukin-1 (IL-1) produced by activated macrophages exerts a bimodal effect on insulin release and biosynthesis in isolated rat islets. In the present study we have further analysed the effect of recombinant human interleukin-1 beta (rIL-1) on the biosynthesis and conversion of proinsulin 1 and 2 in rat islets. By RP-HPLC-analysis of islets labelled with [3H]leucine we found that exposure to 6 ng/ml of IL-1 for 24 h reduced the insulin biosynthesis to 6.1 +/- 2.7% (n = 4). During the 3 h labelling period the labelled proinsulin content compared to insulin was increased from 9.0 +/- 1.3% (control) to 26.6 +/- 6.4% in the IL-1 exposed islets, and the ratio between labelled insulin 1 to 2 was increased from 2.0 +/- 0.1 to 3.4 +/- 0.4, respectively. Pulse-chase experiments with [3H]leucine and [35S]methionine indicated a more marked reduction in the conversion rate of proinsulin-2 compared to that of proinsulin-1. [HYP] In conclusion these experiments demonstrate that IL-1 promotes insulin biosynthesis by preferential attenuation of the rate of conversion of proinsulin 2. OUTPUT:

contradiction

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

[PRE] SIRT1 is a NAD+-dependent deacetylase thought to regulate cellular metabolic pathways in response to alterations in nutrient flux. In the current study we investigated whether acute changes in SIRT1 expression affect markers of muscle mitochondrial content and also determined whether SIRT1 influenced muscle insulin resistance induced by acute glucose oversupply. In male Wistar rats either SIRT1 or a deacetylase inactive mutant form (H363Y) was electroprated into the tibialis cranialis (TC) muscle. The other leg was electroporated with an empty control vector. One week later, glucose was infused and hyperglycaemia was maintained at ~11mM. After 5 hours, 11mM glucose induced significant insulin resistance in skeletal muscle. Interestingly, overexpression of either SIRT1 or SIRT1 (H363Y) for 1 week did not change markers of mitochondrial content or function. SIRT1 or SIRT1 (H363Y) overexpression had no effect on the reduction in glucose uptake and glycogen synthesis in muscle in response to hyperglycemia. [HYP] Therefore we conclude that acute increases in SIRT1 protein have little impact on mitochondrial content and that overexpressing SIRT1 does not prevent the development of insulin resistance during hyperglycaemia. OUTPUT:

entailment

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

[PRE] Obesity and insulin resistance are associated with altered brain glucose metabolism. Here, we studied brain glucose metabolism in 22 morbidly obese patients before and 6 months after bariatric surgery. Seven healthy subjects served as control subjects. Brain glucose metabolism was measured twice per imaging session: with and without insulin stimulation (hyperinsulinemic-euglycemic clamp) using [18F]fluorodeoxyglucose scanning. We found that during fasting, brain glucose metabolism was not different between groups. However, the hyperinsulinemic clamp increased brain glucose metabolism in a widespread manner in the obese but not control subjects, and brain glucose metabolism was significantly higher during clamp in obese than in control subjects. After follow-up, 6 months postoperatively, the increase in glucose metabolism was no longer observed, and this attenuation was coupled with improved peripheral insulin sensitivity after weight loss. [HYP] We conclude that obesity is associated with increased insulin -stimulated glucose metabolism in the brain and that this abnormality can be reversed by bariatric surgery. 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] To examine the impact of diabetes and its treatment on plasma free-fatty acid (FFA) and oxidative fuel metabolism during hypoglycemia, we combined indirect calorimetry with [3-3H]glucose during a 4-h low-dose insulin infusion (plasma insulin approximately 2-fold above basal) in six poorly controlled and nine well-controlled insulin-dependent diabetes mellitus (IDDM) patients and in six healthy subjects. Diabetic subjects received insulin overnight to maintain euglycemia before study. Although free-insulin levels and counterregulatory hormone responses were similar, the plasma glucose fall was more pronounced in well-controlled diabetic subjects. In well-controlled diabetic and healthy subjects, the small increment in insulin rapidly suppressed plasma FFA and fat oxidation by approximately 50% and stimulated carbohydrate oxidation by approximately 80%. In contrast, plasma FFA levels did not fall in poorly controlled diabetic subjects, and glucose oxidation was not stimulated. To determine whether this resistance to the antilipolytic effect of insulin occurs in the absence of hypoglycemic counterregulation, we used a sequential low-dose euglycemic insulin clamp (0.2, 0.3, and 0.5 mU.kg-1.min-1). In healthy subjects, plasma FFA was nearly maximally suppressed at the lowest insulin dose. In contrast, plasma FFA remained persistently elevated in poorly controlled diabetic subjects at each insulin dose. However, the insulin dose-response curve for suppression of plasma FFA was near normal in well-controlled subjects. [HYP] We conclude that poorly controlled IDDM diabetic patients are resistant to the antilipolytic effects of insulin and show impaired stimulation of glucose oxidation during insulin -induced hypoglycemia . OUTPUT:

entailment

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

[PRE] Plasma acutephase protein pentraxin 3 (PTX3) concentration is dysregulated in human obesity and metabolic syndrome. Here, we explore its relationship with insulin secretion and sensitivity, obesity markers, and adipose tissue PTX3 gene expression. Plasma PTX3 protein levels were analyzed in a cohort composed of 27 lean [body mass index (BMI) ≤ 25 kg/m(2)] and 48 overweight (BMI 25-30 kg/m(2)) men (cohort 1). In this cohort, plasma PTX3 was negatively correlated with fasting triglyceride levels and insulin secretion after intravenous and oral glucose administration. Plasma PTX3 protein and PTX3 gene expression in visceral (VAT) and subcutaneous (SAT) whole adipose tissue and adipocyte and stromovascular fractions were analyzed in cohort 2, which was composed of 19 lean, 28 overweight, and 15 obese subjects (BMI >30 kg/m(2)). An inverse association with body weight and waist/hip ratio was observed in cohort 2. In VAT depots, PTX3 mRNA levels were higher in subjects with BMI >25 kg/m(2) than in lean subjects, positively correlated with IL-1β mRNA levels, and higher in the adipocyte than stromovascular fraction. Human preadipocyte SGBS cell line was used to study PTX3 production in response to factors that obesity entails. In SGBS adipocytes, PTX3 gene expression was enhanced by IL-1β and TNFα but not IL-6 or insulin. [HYP] In conclusion, the negative correlation between PTX3 and insulin secretion -stimulated glucose suggests a role for PTX3 in metabolic control. OUTPUT:

contradiction

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

[PRE] The effect of portal glucose infusion on serum thyroid hormone levels was studied in five anaesthetized pigs during 48 h observation in an intensive care unit following standardized high energy trauma. At 10-18 h post-trauma, and again at 28-36 h, 100 g glucose was infused into the portal circulation via a splenic vein. In six animals, otherwise treated in the same way, the glucose infusions were given via a peripheral venous catheter. During portal glucose infusion at 28-36 h post-trauma, serum T3 rose significantly above the level in the controls. After termination of the portal glucose infusion, the serum concentration again fell. At 48 h the rT3 concentration was significantly lower in the pigs given portal glucose than in the control pigs. [HYP] It was concluded that portal, but not peripheral, glucose infusion can temporarily reverse the trauma -induced change in triiodothyronine metabolism. 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] The precise signal that regulates fructose transport in renal proximal tubule cells (PTCs) under high glucose conditions is not yet known although fructose has been recommended as a substitute for glucose in the diets of diabetic people. Thus, we investigated that effect of high glucose on fructose uptake and its signaling pathways in primary cultured rabbit renal PTCs. Glucose inhibited the fructose uptake in a time- and dose-dependent manner. A maximal inhibitory effect of glucose on fructose uptake was observed at 25 mM glucose after 48 h, while 25 mM mannitol and l-glucose did not affect fructose uptake. Indeed, 25 mM glucose for 48 h decreased GLUT5 protein level. Thus, the treatment of 25 mM glucose for 48 h was used for this study. Glucose-induced (25 mM) inhibition of fructose uptake was blocked by pertussis toxin (PTX), SQ-22536 (an adenylate cyclase inhibitor), and myristoylated amide 14-22 (a protein kinase A inhibitor). Indeed, 25 mM glucose increased the intracellular cAMP content. Furthermore, 25 mM glucose-induced inhibition of fructose uptake was prevented by neomycin or U-73122 (phospholipase C inhibitors) and staurosporine or bisindolylmaleimide I (protein kinase C inhibitors). In fact, 25 mM glucose increased the total PKC activity and translocation of PKC from the cytosolic to membrane fraction. In addition, PD 98059 (a p44/42 mitogen-activated protein kinase (MAPK) inhibitor) but not SB 203580 (a p38 MAPK inhibitor) and mepacrine or AACOCF3 (phospholipase A2 inhibitors) blocked 25 mM glucose-induced inhibition of fructose uptake. Results of Western blotting using the p44/42 MAPK and GLUT5 antibodies were consistent with the results of uptake experiments. [HYP] In conclusion, high glucose inhibits the fructose uptake through cAMP, PLC/PKC, p44/42 MAPK, and cytosolic phospholipase A2 (cPLA2) pathways in the PTCs. OUTPUT:

entailment

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

[PRE] Whether inducing catalepsy in the rat by an intraperitoneal injection of haloperidol (0.5 mg/kg) had an effect on metabolism in the striatum and in the hippocampus, as determined by lactography, and whether reducing the cataleptic state with stress or theophylline (8 mg/kg i.v.) had any impact on metabolism in these two regions of the brain was investigated. Furthermore, whether theophylline reduced catalepsy in rats through the adrenals was investigated. Haloperidol caused a significant increase in the metabolism of lactate, both in the striatum and in the hippocampus. Reducing haloperidol-induced catalepsy with short-term immobilisation stress did not affect the metabolism of lactate, neither in the striatum nor in the hippocampus. Reducing haloperidol-induced catalepsy with theophylline caused a significant rise in the metabolism of lactate in the striatum, while no effect was seen in the hippocampus. Adrenalectomy did not compromise the anti-cataleptic property of theophylline. [HYP] It is concluded theophylline is a potent antagonist of haloperidol -induced glucose , and that this effect is not mediated by the adrenals. OUTPUT:

contradiction

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

[PRE] Islets isolated from ob/ob mice which had been fed a vitamin D-deficient diet released significantly less insulin in response to glucose than did vitamin D-replete islets but showed normal net 45Ca2+ uptake. To determine whether vitamin D3 has a direct effect on the pancreatic B cell, islets from ob/ob mice on a normal diet were exposed to vitamin D3 in vitro for 1 week or only 3 h, and then glucose-stimulated 45Ca2+ uptake and insulin release were measured. Exposure to 1 nM or 1 microM vitamin D3 for 1 week stimulated 45Ca2+ uptake in the presence of 3 mM, but not 20 mM glucose, and did not affect insulin release. Exposure to vitamin D3 for 3 h did not significantly increase net 45Ca2+ uptake although there was a tendency to such an effect (P = 0.10). [HYP] In conclusion, vitamin D-deficiency in vivo suppressed subsequent glucose-stimulated insulin release in vitro and this effect may be due to a direct effect of the sterol (or one of its metabolites) on calcium handling by the B cell. OUTPUT:

entailment

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

[PRE] Diazepam-binding inhibitor (DBI) has been localized immunohistochemically in many organs. In porcine and rat pancreas, DBI is present in non-B-cells of the pancreatic islets. Porcine peptide also has been shown to suppress insulin secretion from rat pancreas in vitro. Recently, acyl-CoA-binding protein (ACBP) was isolated from rat liver and shown to be identical structurally to DBI isolated from rat brain. Using this rat DBI/ACBP, we have studied its effects on glucose-stimulated insulin secretion in the rat, both in vivo and in isolated pancreatic islets. Infusion iv of rDBI/ACBP (25 pmol/min) during glucose stimulation induced a moderate and transient reduction of plasma insulin levels. Moreover, rDBI/ACBP suppressed insulin release from batch-incubated isolated islets, stimulated by 16.7 mmol/l glucose, by 24% at 10 nmol/l (p < 0.05) and by 40% at 100 nmol/l (p < 0.01). The peptide (100 nmol/l) also inhibited the insulin response to glucose (16.7 mmol/l) from perifused rat islets by 31% (p < 0.05), mainly by affecting the acute-phase response. Finally, incubation of isolated islets in the presence of rDBI/ACBP antiserum (diluted 1:100 and 1:300) augmented the insulin response to 16.7 mmol/l glucose (p < 0.05 or even less). [HYP] We conclude that rDBI/ ACBP , administered iv or added to the incubation media, suppresses insulin secretion in the rat but that the effect is moderate despite the high concentration used. OUTPUT:

entailment

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

[PRE] To evaluate the hypothesis that precursor supply limits gluconeogenesis (GNG) during exercise, we examined training-induced changes in glucose kinetics [rates of appearance (R(a)) and disappearance (R(d))], oxidation (R(ox)), and recycling (R(r)) with an exogenous lactate infusion to 3.5-4.0 mM during rest and to pretraining 65% peak O(2) consumption (VO(2 peak)) levels during exercise. Control and clamped trials (LC) were performed at rest pre- (P(R)R, P(R)R-LC) and posttraining (P(O)R, P(O)R-LC) and during exercise pre- (P(R)E(X)) and posttraining at absolute (P(O)A(B), P(O)A(B)-LC) and relative (P(O)R(L), P(O)R(L)-LC) intensities. Glucose R(r) was not different in any rest or exercise condition. Glucose R(a) did not differ as a result of LC. Glucose R(ox) was significantly decreased with LC at P(O)R (0.38 +/- 0.03 vs. 0.56 +/- 0.04 mg. kg(-1). min(-1)) and P(O)A(B) (3.82 +/- 0.51 vs. 5.0 +/- 0.62 mg. kg(-1). min(-1)). Percent glucose R(d) oxidized decreased with all LC except P(O)R(L)-LC (P(R)R, 32%; P(R)R-LC, 22%; P(O)R, 27%; P(O)R-LC, 20%; P(O)A(B), 95%; P(O)A(B)-LC, 77%), which resulted in a significant increase in oxidation from alternative carbohydrate (CHO) sources at rest and P(O)A(B). [HYP] We conclude that lactate supplementation did not increase GNG . 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] It is known that pig galanin inhibits insulin secretion in dogs, rats and mice. The present study examined whether species-specific, homologous, galanin inhibits insulin secretion. Thus, the effects of rat galanin were examined in the rat, and the effects of pig galanin were examined in the pig, both in vivo and in vitro. In conscious rats, synthetic rat galanin (2 nmol kg-1) abolished the glucose- (0.56 mmol kg-1) induced increase in plasma insulin levels. In vitro, rat galanin (10(-9) to 10(-6) mol l-1) inhibited glucose- (8.3 mmol l-1) stimulated insulin release from isolated rat islets. In anaesthetized pigs, 15 min infusion of synthetic pig galanin (207 pmol min-1) into the pancreatic artery decreased the insulin output with a subsequent recovery. In vitro, pig galanin (10(-6) mol l-1) inhibited glucose- (8.3 mmol l-1) stimulated insulin release from isolated pig islets. [HYP] We conclude that homologous galanin promotes insulin secretion in both the rat and the pig. OUTPUT:

contradiction

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

[PRE] High circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are found in patients with hyperinsulinemia. Insulin stimulates release of IL-6 from adipocyte cultures, and it stimulates IL-6 gene expression in insulin-resistant, but not control, rat skeletal muscle. In addition, TNF-alpha may be involved in the pathogenesis of insulin resistance. Therefore, we studied the effect of insulin on IL-6 and TNF-alpha gene expression in human skeletal muscle and adipose tissue. Nine healthy young volunteers participated in the study. They underwent a 6-h hyperinsulinemic euglycemic clamp at a fixed insulin infusion rate, with blood glucose clamped at fasting level. Blood samples drawn at 0, 1, 2, 3, 4, 5, and 6 h were analyzed for IL-6 and TNF-alpha. Muscle and fat biopsies, obtained at 0, 2, 4, and 6 h, were analyzed for IL-6 and TNF-alpha mRNA with real-time PCR. IL-6 mRNA increased 11-, 3-, and 5-fold at 2, 4, and 6 h, respectively, in adipose tissue (ANOVA P = 0.027), whereas there was no significant effect of insulin on skeletal muscles. Plasma IL-6 increased during insulin stimulation. TNF-alpha mRNA increased 2.4-, 1.4-, and 2.2-fold in adipose tissue (ANOVA P = 0.001) and decreased 0.74-, 0.64-, and 0.68-fold in muscle tissue (ANOVA P = 0.04). Plasma levels of TNF-alpha were constant. [HYP] In conclusion, the finding that insulin stimulates IL-6 and TNF-alpha gene expression in adipose tissue only and inhibits the TNF-alpha production in skeletal muscles suggests a differential regulation of muscle- and adipose tissue-derived IL-6 and TNF-alpha. OUTPUT:

entailment

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

[PRE] Glucose-induced insulin secretion requires a rise in beta-cell cytosolic Ca2+ ([Ca2+]c) that triggers exocytosis and a mechanistically unexplained amplification of the action of [Ca2+]c. Insulin granules are kept acidic by luminal pumping of protons with simultaneous Cl- uptake to maintain electroneutrality. Experiments using patched, dialyzed beta-cells prompted the suggestion that acute granule acidification by glucose underlies amplification of insulin secretion. However, others found glucose to increase granular pH in intact islets. In this study, we measured islet granular pH with Lysosensor DND-160, a fluorescent dye that permits ratiometric determination of pH < 6 in acidic compartments. Stimulation of mouse islets with glucose reversibly decreased granular pH by mechanisms that are dependent on metabolism and Cl- ions but independent of changes in [Ca2+]c and protein kinase A or C activity. Granular pH was increased by concanamycin (blocker of the vesicular type H+-ATPase) > methylamine (weak base) > Cl- omission. Concanamycin and methylamine did not alter glucose-induced [Ca2+]c increase in islets but strongly inhibited the two phases of insulin secretion. Omission of Cl- did not affect the first phase but decreased the second phase of both [Ca2+]c and insulin responses. Neither experimental condition affected the [Ca2+]c rise induced by 30 mM KCl, but the insulin responses were inhibited by concanamycin > methylamine and not affected by Cl- omission. The amplification of insulin secretion by glucose was not suppressed. [HYP] We conclude that an acidic granular pH is important for insulin secretion but that the acute further acidification produced by glucose is not essential for the augmentation of secretion via the amplifying pathway. OUTPUT:

entailment

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

[PRE] Glucose-induced insulin secretion is classically attributed to the cooperation of an ATP-sensitive potassium (K ATP) channel-dependent Ca2+ influx with a subsequent increase of the cytosolic free Ca2+ concentration ([Ca2+]c) (triggering pathway) and a K ATP channel-independent augmentation of secretion without further increase of [Ca2+]c (amplifying pathway). Here, we characterized the effects of glucose in beta-cells lacking K ATP channels because of a knockout (KO) of the pore-forming subunit Kir6.2. Islets from 1-yr and 2-wk-old Kir6.2KO mice were used freshly after isolation and after 18 h culture to measure glucose effects on [Ca2+]c and insulin secretion. Kir6.2KO islets were insensitive to diazoxide and tolbutamide. In fresh adult Kir6.2KO islets, basal [Ca2+]c and insulin secretion were marginally elevated, and high glucose increased [Ca2+]c only transiently, so that the secretory response was minimal (10% of controls) despite a functioning amplifying pathway (evidenced in 30 mm KCl). Culture in 10 mm glucose increased basal secretion and considerably improved glucose-induced insulin secretion (200% of controls), unexpectedly because of an increase in [Ca2+]c with modulation of [Ca2+]c oscillations. Similar results were obtained in 2-wk-old Kir6.2KO islets. Under selected conditions, high glucose evoked biphasic increases in [Ca2+]c and insulin secretion, by inducing K ATP channel-independent depolarization and Ca2+ influx via voltage-dependent Ca2+ channels. [HYP] In conclusion, Kir6.2KO beta-cells down-regulate insulin secretion by maintaining low [Ca2+]c, but culture reveals a glucose -responsive phenotype mainly by increasing [Ca2+]c. The results support models implicating a K ATP channel-independent amplifying pathway in glucose -induced insulin secretion , and show that K ATP channels are not the only possible transducers of metabolic effects on the triggering Ca2+ signal. 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] Transforming growth factor-β (TGF-β) is pivotal in the pathogenesis of diabetic nephropathy. Type 1 TGF-β receptor (TGF-βR1) is degraded by Smad7-dependent ubiquitination-proteasomal pathway, which is deubiquitinated by ubiquitin C-terminal hydrolase-L5 (UCHL5). Therefore, we studied the role of UCHL5 in high glucose (27.8mM)-induced TGF-βR1 protein expression in mouse mesangial (MES13) cells. UCHL5 short hairpin RNA (shRNA) was used to knock down UCHL5 while LY294002 and the dominant-negative p85 were used to inhibit phosphatidylinositol-3-kinase (PI3K). We found that high glucose increased phospho-Akt, TGF-βR1 mRNA and protein expression. High glucose also increased UCHL5 protein expression, which was attenuated by LY294002, the dominant-negative p85 and the dominant-negative CREB. High glucose-induced TGF-βR1 protein expression and TGF-βR1 protein deubiquitination were attenuated by UCHL5 shRNA. Additionally, high glucose-induced p21(WAF1), fibronectin protein expression and cell hypertrophy were attenuated by UCHL5 shRNA. However, high glucose-induced TGF-βR1 mRNA, p27(kip1) protein expression and growth inhibition were not affected by UCHL5 shRNA. Finally, glomerular UCHL5 and TGF-βR1 protein expression were increased in streptozotocin-diabetic rats at 8weeks. [HYP] We conclude that PI3K-dependent UCHL5 is required for high glucose -induced TGF-βR1 protein expression in mesangial cells. OUTPUT:

entailment

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

[PRE] 1. The present study was designed to investigate if the aldose reductase inhibitor ponalrestat is capable of preventing the impairment of the response of ornithine decarboxylase (ODC) to nerve crush in streptozotocin (STZ)-diabetic rats. 2. ODC activity was measured in the dorsal root ganglia of crushed and uncrushed contralateral sciatic nerve of non-diabetic, ponalrestat-treated non-diabetic, STZ-diabetic and ponalrestat-treated STZ-diabetic rats. 3. Twenty four hours after crush, a significant (P less than 0.001) increase in the ratio of ODC activity in ganglia of crushed relative to uncrushed nerves was found in non-diabetic but not in diabetic rats, as expected. In the ponalrestat-treated diabetic rats the ratio was significantly higher (P less than 0.001) than that in the untreated diabetic rats and was not different from that in the non-diabetic group. 4. Ponalrestat also significantly decreased absolute levels of ODC activity in ganglia of uncrushed nerves from diabetic and non-diabetic animals. Despite the near-normal induction of ODC activity by nerve crush in the ponalrestat-treated diabetic animals, absolute ODC activity remained lower than that in ganglia of uncrushed nerves from non-diabetics. 5. [HYP] We conclude that ponalrestat is not able to prevent the impaired induction of ODC in experimental diabetes. OUTPUT:

contradiction

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

[PRE] The intravascular removal rates of colloidal carbon and of biologically active endotoxin by the reticuloendothelial system (RES) were evaluated as a function of blood-glucose levels. There was a significant negative correlation of carbon clearance half time on blood glucose in both saline-treated and insulin-treated rats. Insulin hypoglycemia depressed RES carbon clearance with the maximal effect occurring at blood glucose values below 30 mg/dl. Insulin hypoglycemia also severely impaired the intravascular removal of endotoxin as evaluated by lethality bioassay in lead-sensitized rats. [HYP] It is concluded that blood glucose may modulate RES phagocytic function and that the hypoglycemia of endotoxin shock may augment the shock state due to impairment of RES host defense clearance functions. OUTPUT:

entailment

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

[PRE] To examine the influence of insulin-dependent diabetes on the metabolic response to insulin-like growth factor I (IGF-I), awake chronically catheterized diabetic and nondiabetic BB/w rats received IGF-I (5 micrograms.kg-1.min-1) or insulin (2 mU.kg-1.min-1) for 2 h while maintaining euglycemia. In nondiabetic rats, IGF-I and insulin produced similar twofold increases in glucose uptake, but insulin was more effective in reducing hepatic glucose production (90 +/- 15 vs. 5 +/- 11%; P less than 0.001) and beta-hydroxybutyrate levels (94 +/- 1 vs. 19 +/- 6%; P less than 0.001). In diabetic rats, insulin-stimulated glucose uptake was impaired (8.5 +/- 0.9 vs. 11.5 +/- 0.9 mg.kg-1.min-1 in nondiabetics; P less than 0.05). In contrast, IGF-I-stimulated glucose uptake was identical in diabetic and nondiabetic rats. Furthermore, IGF-I suppressed glucose production by 73% (P less than 0.01) and caused a greater lowering of beta-hydroxybutyrate levels (from 2.9 +/- 0.8 to 0.8 +/- 0.3 mumol/l) in diabetic rats. [HYP] We conclude that IGF-I stimulates glucose disposal equally in diabetic and nondiabetic BB/w rats. OUTPUT:

contradiction

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

[PRE] Catecholamines are important hormones for maintaining homeostasis and may be secreted in response to several different stimuli. A report by Robertson and Porte in 1974 made the unexpected observation that acute administration of hypertonic glucose stimulates catecholamine secretion. Our study reassessed this observation by measuring individual catecholamines, explored its potential mechanism, and quantitated it relative to exercise and hypoglycemia-stimulated catecholamine secretion. We hypothesized that the mechanism of glucose-induced catecholamine secretion was related to an acute increase in plasma osmolality, which we tested with the nonmetabolizable hexose mannitol. In 56 studies, 14 normal adults underwent 4 partially randomized studies. The 4 study conditions consisted of the following: (1) rapid intravenous injection of 20 g of glucose; (2) rapid intravenous injection of 20 g of mannitol; (3) acute exercise (80 J/kg); and (4) insulin-induced hypoglycemia. Our results demonstrate that a significant increase in plasma catecholamine concentration occurs following each of the above stimuli, but its composition differs relative to the magnitude of epinephrine versus norepinephrine secretion. [HYP] We conclude that the mechanism of glucose -induced catecholamine stimulation is the acute elevation in plasma osmolality induced by glucose , and that its stimulation is less than that which occurs following exercise for norepinephrine and less than that which occurs following hypoglycemia for epinephrine. 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] During mild or moderate nonexhausting exercise, glucose utilization increases sharply but is normally matched by increased glucose production such that hypoglycemia does not occur. To test the hypothesis that redundant glucoregulatory systems including sympathochromaffin activation and changes in pancreatic islet hormone secretion underlie this precise matching, eight young adults exercised at 55-60% of maximal oxygen consumption for 60 min on separate occasions under four conditions: (a) control study (saline infusion); (b) islet clamp study (insulin and glucagon held constant by somatostatin infusion with glucagon and insulin replacement at fixed rates before, during and after exercise with insulin doses determined individually and shown to produce normal and stable plasma glucose concentrations prior to each study); (c) adrenergic blockage study (infusions of the alpha- and beta-adrenergic antagonists phentolamine and propranolol); (d) adrenergic blockade plus islet clamp study. Glucose production matched increased glucose utilization during exercise in the control study and plasma glucose did not fall (92 +/- 1 mg/dl at base line, 90 +/- 2 mg/dl at the end of exercise). Plasma glucose also did not fall during exercise when changes in insulin and glucagon were prevented in the islet clamp study. In the adrenergic blockade study, plasma glucose declined initially during exercise because of a greater initial increase in glucose utilization, then plateaued with an end-exercise value of 74 +/- 3 mg/dl (P less than 0.01 vs. control). In contrast, in the adrenergic blockade plus islet clamp study, exercise was associated with glucose production substantially lower than control and plasma glucose fell progressively to 58 +/- 7 mg/dl (P less than 0.001); end-exercise plasma glucose concentrations ranged from 34 to 72 mg/dl. [HYP] Thus, we conclude that: (a) redundant glucoregulatory systems are involved in the precise matching of increased histamine utilization and histamine production that normally prevents hypoglycemia during moderate exercise in humans. OUTPUT:

contradiction

bionli

train

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

[PRE] To examine the function of islet lysosomal enzymes in islet hormone secretory mechanisms, we investigated the effects of the lysosomotropic drug chloroquine on islet lysosomal enzyme activities and basal as well as stimulated insulin and glucagon secretion. Chloroquine, added to islet homogenates, did not affect the activities of the lysosomal enzymes acid amyloglucosidase, acid alpha-glucosidase, or N-acetyl-beta-D-glucosaminidase. The activity of acid phosphatase, however, was inhibited at a high concentration of chloroquine (10(-3) M). When injected together with glucose, chloroquine (2 or 10 mumol/kg) inhibited the peak plasma insulin response. Similarly, at 24 hrs after chloroquine injection (100 mumol/kg), the plasma insulin response to glucose was reduced. In contrast, islets isolated from mice pretreated 24 hrs before with chloroquine, displayed glucose-stimulated insulin secretion in vitro that was not different from controls. Such islets showed, furthermore, enhanced activities of the enzymes acid phosphatase and neutral alpha-glucosidase but not of acid amyloglucosidase, acid alpha-glucosidase or N-acetyl-beta-D-glucosaminidase. Arginine-stimulated insulin response in vivo displayed a complex pattern; it was increased when arginine was injected together with chloroquine but decreased at 24 hrs after chloroquine administration. Arginine-stimulated glucagon secretion was not affected by chloroquine. [HYP] We conclude that chloroquine pretreatment 24 hrs prior to insulin secretion injection decreases insulin secretion -stimulated glucose in vivo by mechanisms that are not correlated to an inhibitory action on islet activities of glycogenolytic lysosomal enzymes. 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] R-(+)-alpha-lipoic acid (R-LA) is the naturally occurring enantiomer of LA. It is a strong antioxidant and cofactor of key metabolic enzyme complexes catalyzing the decarboxylation of alpha-keto acids. Racemic LA (rac-LA) has shown promise in treating diabetic polyneuropathy, and some studies suggest that it improves glucose homeostasis in patients with type 2 diabetes. We examined the effects of R-LA on pyruvate metabolism and free fatty acid (FFA) oxidation in primary cultured hepatocytes isolated from 24-hour fasted rats. After overnight culture in serum-free medium, cells were pre-exposed to R-LA for 3 hours before assays. R-LA (25 to 200 micromol/L) significantly increased pyruvate oxidation ( approximately 2-fold at the highest dose tested) measured as (14)CO(2) production from [1-(14)C]pyruvate by the cells over 1 hour post-treatment. These effects correlated with proportional, significant increases in the activation state of the pyruvate dehydrogenase (PDH) complex. R-LA treatment inhibited glucose production from pyruvate by approximately 50% at 50 micromol/L R-LA and approximately 90% at 200 micromol/L. Palmitate oxidation was measured in hepatocytes cultured in the presence of albumin and physiological (0.1 mmol/L) or high (1.5 mmol/L) concentrations of FFA. The latter markedly enhanced FFA oxidation. R-LA treatment significantly inhibited FFA oxidation in both media, but was more effective in high FFA, where it reduced FFA oxidation by 48% to 82% at 25 to 200 micromol/L, respectively. Identical doses of R-LA did not affect FFA oxidation by L6 myotubes (a cell culture model for skeletal muscle) in either high or low FFA medium, but enhanced pyruvate oxidation. [HYP] In conclusion, 3-hour exposure of primary cultured rat hepatocytes to R-LA at therapeutically relevant concentrations increased PDH , apparently by activation of the pyruvate oxidation complex, and decreased gluconeogenesis and FFA oxidation. OUTPUT:

contradiction

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

[PRE] Since 1875, controversy has ensued over whether ocular diabetic complications are primarily vasculopathic or neuropathic in nature. Here, we discuss the historical context by which diabetic retinopathy (DR) came to be considered a primary vasculopathy, in contrast to more recent data suggesting the importance of diabetic retinal neurodegeneration (DRN) as the primary manifestation of ocular diabetic damage. Unsurprisingly, DRN parallels other diabetic complications related to neuropathy. In general, there are three possible relationships between microvascular DR and DRN: i) microvasculopathy causes neurodegeneration; ii) neurodegeneration causes microvasculopathy or iii) they are mutually independent. The authors' group has recently produced experimental data showing that DRN precedes even the earliest manifestations of DR microvasculopathy. In combination with earlier studies showing that focal implicit time delays predicted future development of DR microvasculopathy in the same location, relationships i) and iii) are unlikely. As such, ii) is the most likely relationship: DRN is a cause of DR. Granted, additional studies are needed to confirm this hypothesis and elucidate the mechanism of diabetes-induced neurodegeneration. [HYP] We conclude this review by proposing experimental approaches to test the hypothesis that DR N causes DR . OUTPUT:

entailment

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

[PRE] In pancreatic β-cells, controlling the levels of reactive oxygen species (ROS) is critical to counter oxidative stress, dysfunction and death under nutrient excess. Moreover, the fine-tuning of ROS and redox balance is important in the regulation of normal β-cell physiology. We recently demonstrated that Bcl-2 and Bcl-xL, in addition to promoting survival, suppress β-cell glucose metabolism and insulin secretion. Here, we tested the hypothesis that the nonapoptotic roles of endogenous Bcl-2 extend to the regulation of β-cell ROS and redox balance. We exposed mouse islet cells and MIN6 cells to the Bcl-2/Bcl-xL antagonist Compound 6 and the Bcl-2-specific antagonist ABT-199 and evaluated ROS levels, Ca(2+) responses, respiratory control, superoxide dismutase activity and cell death. Both acute glucose stimulation and the inhibition of endogenous Bcl-2 progressively increased peroxides and stimulated superoxide dismutase activity in mouse islets. Importantly, conditional β-cell knockout of Bcl-2 amplified glucose-induced formation of peroxides. Bcl-2 antagonism also induced a mitochondrial proton leak that was prevented by the antioxidant N-acetyl-L-cysteine and, therefore, secondary to redox changes. We further established that the proton leak was independent of uncoupling protein 2 but partly mediated by the mitochondrial permeability transition pore. Acutely, inhibitor-induced peroxides promoted Ca(2+) influx, whereas under prolonged Bcl inhibition, the elevated ROS was required for induction of β-cell apoptosis. [HYP] In conclusion, Bcl-2 suppresses ROS and maintains redox balance in ⁇ -cells. OUTPUT:

contradiction

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

[PRE] Peripheral neuropathy has been reported to prevail in obese or pre-diabetic individuals, yet its etiology remains unknown. Palmitate, a saturated fatty acid increased in obesity and diabetes, is known to induce apoptosis in multiple types of cells and this effect may be mediated by ceramide, a member of the sphingolipid family. To clarify whether de novo ceramide synthesis from palmitate contributes to apoptosis of Schwann cells, we cultured immortalized mouse Schwann cells (IMS) and rat primary Schwann cells with palmitate, a ceramide analogue C2-ceramide as well as inhibitors of the de novo ceramide synthesis (myriocin and fumonisin B1). Apoptosis of IMS detected by nuclear staining and cell membrane inversion was significantly increased by incubation with palmitate for 48 h in a dose-dependent fashion. This enhanced apoptosis was partially but significantly suppressed by myriocin and fumonisin B1. Western blot analysis and immunostaining revealed that palmitate clearly activated caspase-3 in IMS. Unexpectedly, the ceramide synthesis inhibitors failed to suppress the palmitate-induced caspase-3 activation in spite of complete restoration in ceramide accumulation. The results seemed relevant to the observations that C2-ceramide did not activate caspase-3 while provoking apoptosis with a clear dose-dependency. In agreement, the pro-apoptotic action of C2-ceramide was not attenuated by caspase inhibitors that partially suppressed palmitate-induced apoptosis. These results in IMS were well reproducible in rat primary Schwann cells, indicating that the observed phenomena are not specific to the cell line. [HYP] Collectively, we have reached a conclusion that palmitate induces apoptosis in Schwann cells via both a ceramide-mediated, caspase-3-independent pathway and ceramide-independent, caspase-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 have previously identified and quantitated three B-type lamin isoforms present in the nuclei of mature Xenopus laevis oocytes, and in cell-free egg extracts. As Xenopus egg extracts are frequently used to analyze nuclear envelope assembly and lamina functions, we felt it was imperative that the polymerization and chromatin-binding properties of the endogenous B-type egg lamins be investigated. While we have demonstrated that soluble B-type lamins bind to chromatin, we have also observed that the polymerization of egg lamins does not require membranes or chromatin. Lamin assembly is enhanced by the addition of glycogen/glucose, or by the depletion of ATP from the extract. Moreover, the polymerization of egg cytosol lamins and their binding to demembranated sperm or chromatin assembled from naked lambda-DNA is inhibited by an ATP regeneration system. These ATP-dependent inhibitory activities can be overcome by the coaddition of glycogen to egg cytosol. [HYP] We have observed that glycogen does not alter ATP levels during cytosol incubation, but rather, as glycogen -enhanced lamin polymerization is inhibited by okadaic acid, we conclude that glycogen activates protein phosphatases. OUTPUT:

entailment

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

[PRE] Activation of the transforming growth factor-beta (TGF-beta) system has been implicated in the pathological changes of diabetic nephropathy such as renal hypertrophy and accumulation of extracellular matrix. Streptozotocin-induced diabetic mice were used to examine whether the Smad pathway, which transduces the TGF-beta signal, is activated in the diabetic kidney, employing Southwestern histochemistry with labeled Smad-binding element (SBE) oligonucleotides and immunoblotting of nuclear protein extracts for Smad3. Mouse mesangial cells were used to study the role of Smads in mediating the effects of high glucose and TGF-beta on fibronectin expression, using transient transfections of Smad expression vectors and TGF-beta-responsive reporter assays. By Southwestern histochemistry, the binding of nuclear proteins to labeled SBE increased in both glomeruli and tubules at 1, 3, and 6 weeks of diabetes. Likewise, immunoblotting demonstrated that nuclear accumulation of Smad3 was increased in the kidney of diabetic mice. Both increases were prevented by insulin treatment. In mesangial cells, high glucose potentiated the effect of low-dose TGF-beta1 (0.2ng/ml) on the following TGF-beta-responsive constructs: 3TP-Lux (containing AP-1 sites and PAI-1 promoter), SBE4-Luc (containing four tandem repeats of SBE sequence), and the fibronectin promoter. Additionally, Smad3 overexpression increased fibronectin promoter activity, an effect that was enhanced by high ambient glucose or treatment with TGF-beta1 (2ng/ml). The TGF-beta-stimulated activity of the fibronectin promoter was prevented by transfection with either a dominant-negative Smad3 or the inhibitory Smad7. [HYP] We conclude that hyperglycemia activates the intrarenal TGF-beta /Smad signaling pathway, which then promotes mesangial matrix gene expression in diabetic nephropathy . 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] In pancreatic β-cells, glucose metabolism leads to closure of ATP sensitive K⁺ channels (K(ATP) channel) and Ca²⁺ influx, which is regarded as a required step for triggering of insulin release. Here, we demonstrate that glucose triggers rapid insulin release independent from its action on K(ATP) channels given the cellular cAMP is elevated. We measured insulin release from rat pancreatic islets by static and perifusion experiments. Changes in cytosolic free Ca²⁺ concentration ([Ca²⁺]i) were monitored using fura-2 loaded rat pancreatic β-cells. Glucose-induced insulin release was abolished when Ca²⁺ influx was inhibited by a combination of 250 μM diazoxide, an opener of K(ATP) channel, and 10 μM nifedipine, a blocker of L-type voltage-dependent Ca²⁺ channels. However, with both nifedipine and diazoxide, glucose induced a 5-fold increase in insulin release in the presence of 10 μM forskolin, an activator of adenylyl cyclase. In the presence of diazoxide, nifedipine, and forskolin, 22 mM glucose sharply increased the rate of insulin release within 2 min which peaked at 6 min: this was followed by a further gradual increase in insulin release. In contrast, it lowered [Ca(2+)]i with a nadir at 2-3 min followed by a gradual increase in [Ca²⁺]i. The glucose effect was mimicked by 20 mM α-ketoisocaproic acid, a mitochondrial fuel, and it was nullified by 2 mM sodium azide, an inhibitor of mitochondrial electron transport. Cerulenin, an inhibitor of protein acylation, decreased the glucose effect. [HYP] In conclusion, a rise in [ Ca ²⁺]i through voltage-dependent Ca ²⁺ channels is not mandatory for glucose-induced triggering of insulin release . 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] The lysosome and its associated protein cathe-psin D (Cat D) play critical roles in the pathological process of secondary damage following ischemia/reperfusion (I/R) injury. However, the roles of Cat D in I/R-exposed astrocytesremain unclear. In this study, we determined the roles of Cat D in the oxygen-glucose deprivation/reperfusion (OGD/R)-induced apoptosis of astrocytes as well as the underlying mechanisms. We found that OGD/R markedly increased cell apoptosis and the production of inflammatory cytokines, namely IL-6, tumor necrosis factor (TNF)-α and FasL in a reperfusion time‑dependent manner and their elevation peaked at 24 h after reperfusion. Moreover, the cytosolic Cat D level and Cat D activity was significantly upregulated in response to OGD/R exposure. Furthermore, OGD/R exposure gradually disrupted the innate acidic conditions of the lysosome. Exogenous TNF-α and FasL administration elevated cytosolic Cat D levels and cell apoptosis whereas TNFR1 and Fas inhibition significantly reversed these effects induced by OGD/R. Cat D overexpression enhanced cell apoptosis and the levels of apoptogenic proteins, including Bax and caspase-3, whereas Cat D siRNA transfection had an inhibitory effect on cell apoptosis and the expression of proapoptotic proteins. In addition, we observed that Cat D upregulation disrupted mitochondrial membrane potential and induced the production of reactive oxygen species. [HYP] In conclusion, OGD/R injury induced the production of TNF-α, IL-1 and FasL which promoted lysosomal dysfunction and Cat  D leakage into the cytoplasm. 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] Essential hypertension is characterized by skeletal muscle insulin resistance but it is unknown whether insulin resistance also affects heart glucose uptake. We quantitated whole body (euglycemic insulin clamp) and heart and skeletal muscle (positron emission tomography and 18F-fluoro-2-deoxy-D-glucose) glucose uptake rates in 10 mild essential hypertensive (age 33 +/- 1 yr, body mass index 23.7 +/- 0.8 kg/m2, blood pressure 146 +/- 3/97 +/- 3 mmHg, VO2max 37 +/- 3 ml/kg per min) and 14 normal subjects (29 +/- 2 yr, 22.5 +/- 0.5 kg/m2, 118 +/- 4/69 +/- 3 mmHg, 43 +/- 2 ml/kg per min). Left ventricular mass was similar in the hypertensive (155 +/- 15 g) and the normotensive (164 +/- 13 g) subjects. In the hypertensives, both whole body (28 +/- 3 vs 44 +/- 3 mumol/kg per min, P < 0.01) and femoral (64 +/- 11 vs 94 +/- 8 mumol/kg muscle per min, P < 0.05) glucose uptake rates were decreased compared to the controls. In contrast, heart glucose uptake was 33% increased in the hypertensives (939 +/- 51 vs 707 +/- 46 mumol/kg muscle per min, P < 0.005), and correlated with systolic blood pressure (r = 0.66, P < 0.001) and the minute work index (r = 0.48, P < 0.05). [HYP] We conclude that insulin -stimulated glucose uptake is decreased in skeletal muscle but increased in proportion to cardiac work in essential hypertension. OUTPUT:

entailment

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

[PRE] Ambient glucose stimulates insulin but inhibits glucagon secretion. We investigated whether mirror-image regulation pertains also to glucose effects on muscarinic receptor binding to B and A cells. We compared binding of [3H]methylscopolamine to islets from normal guinea pigs and to A-cell rich islets from streptozotocin-treated animals. Binding was assessed in intact islets at 37 C after previous culture for 72 h in 3.3, 5.5, or 11 mM glucose. For both types of islets, specific binding was observed after 1 min and reached a plateau after 10 min of incubation. Half-maximal displacement of 2.8 X 10(-9) M [3H] methylscopolamine occurred with 10(-9) - 10(-8) M unlabeled methylscopolamine. In normal islets, specific binding was significantly higher after culture in 11 mM than after 3.3 or 5.5 mM glucose. Conversely, in A-cell rich islets, binding was significantly higher at 3.3 or 5.5 than at 11 mM glucose. Glucagon release induced by acetylcholine (10(-5) M) was half-maximally suppressed by methylscopolamine at a concentration of 10(-9) - 10(-8) M. Acetylcholine-stimulated glucagon release was higher from A-cell rich islets when cultured at 3.3 mM than when cultured at 11 mM glucose. [HYP] It is concluded: 1) that both A and B cells appear to contain muscarinic receptors, 5) that long term glucose environment exerts opposite effects on binding of methylscopolamine to A and B cells, and 3) that inhibition of binding to A cells is correlated with reduction of acetylcholine -induced glucagon release . 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 hypothesis that increased intraoperative blood lactate depends both on intraoperative glucose supply and inadequate tissue oxygenation occurring during surgery was tested in anesthetized patients undergoing infrarenal abdominal aortic surgery. Twenty surgical patients received either Ringer's solution or 5% glucose solution for intraoperative volume loading. Arterial blood lactate, arterial glucose, hemodynamic variables, insulin, glucagon, cortisol, epinephrine, and norepinephrine were determined preoperatively and intraoperatively. There were no significant changes in hemodynamic values, glucagon, norepinephrine, and epinephrine compared with control values in both groups. Oxygen consumption decreased only during aortic clamping. Cortisol and lactate increased significantly 10 min after aortic clamping until the end in both groups. Glucose 5% solution infusion resulted in significantly greater blood lactate accumulation and significantly greater blood glucose and insulin levels, whereas there were no changes in the patients receiving Ringer's solution. From control until aortic clamping, lactate and glucose were significantly correlated with each other in both groups; after aortic clamping until the end of the procedure, the correlation remained constant in patients in the Ringer's group, whereas no relationship could be demonstrated in those in the glucose group. [HYP] We conclude that increased intraoperative blood lactate concentrations during abdominal aortic surgery depend on both intraoperative glucose supply and inadequate tissue oxygenation occurring during the procedure. OUTPUT:

contradiction