Hormonal and metabolic responses to maintained hyperglycemia during prolonged exercise.
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We studied the effects of maintained hyperglycemia (12 mmol/l) on endurance exercise to determine the hormonal and metabolic responses, the maximal rate of glucose infusion (i.e., utilization), and the effects on muscle glycogen stores. Eight men undertook two trials during which they exercised on a cycle ergometer at an intensity of approximately 70% peak O(2) uptake for 120 min. In the first trial (trial A), subjects had their blood glucose concentration clamped at 12 mmol/l 30 min before exercise and throughout exercise. The same rate and volume of infusion of saline as had occurred for trial A were used in a placebo trial (trial B). Maintained hyperglycemia resulted in significantly lowered plasma concentrations of nonesterified fatty acid, glycerol, 3-hydroxybutyrate, epinephrine, norepinephrine, and growth hormone (P < 0.001) during exercise, whereas concentrations of plasma insulin were significantly elevated (P < 0.001). Calculations of the rates of total carbohydrate oxidation showed that trial A resulted in significantly higher values when compared with trial B (P < 0.01) and that the maximal rates of glucose infusion varied between 1.33 and 2.78 g/min at 100-120 min. Muscle glycogen concentrations were significantly depleted (P < 0.01) after both trials (trial A, 170.3 micromol/g dry wt decrease; trial B, 206 micromol/g dry wt decrease), although this apparent difference may be accounted for by storage of 22.6 g glucose during the 30-min prime infusion. The results from this study confirm that maintained hyperglycemia attenuates the hormonal response and promotes carbohydrate oxidation and utilization and that muscle glycogen may not be spared. (+info)
Insulin resistance in HIV protease inhibitor-associated diabetes.
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BACKGROUND: Fasting hyperglycemia has been associated with HIV protease inhibitor (PI) therapy. OBJECTIVE: To determine whether absolute insulin deficiency or insulin resistance with relative insulin deficiency and an elevated body mass index (BMI) contribute to HIV PI-associated diabetes. DESIGN: Cross-sectional evaluation. PATIENTS: 8 healthy seronegative men, 10 nondiabetic HIV-positive patients naive to PI, 15 nondiabetic HIV-positive patients receiving PI (BMI = 26 kg/m2), 6 nondiabetic HIV-positive patients receiving PI (BMI = 31 kg/m2), and 8 HIV-positive patients with diabetes receiving PI (BMI = 34 kg/m2). All patients on PI received indinavir. MEASUREMENTS: Fasting concentrations of glucoregulatory hormones. Direct effects of indinavir (20 microM) on rat pancreatic beta-cell function in vitro. RESULTS: In hyperglycemic HIV-positive subjects, circulating concentrations of insulin, C-peptide, proinsulin, glucagon, and the proinsulin/insulin ratio were increased when compared with those of the other 4 groups (p < .05). Morning fasting serum cortisol concentrations were not different among the 5 groups. Glutamic acid decarboxylase (GAD) antibody titers were uncommon in all groups. High BMI was not always associated with diabetes. In vitro, indinavir did not inhibit proinsulin to insulin conversion or impair glucose-induced secretion of insulin and C-peptide from rat beta-cells. CONCLUSIONS: The pathogenesis of HIV PI-associated diabetes involves peripheral insulin resistance with insulin deficiency relative to hyperglucagonemia and a high BMI. Pancreatic beta-cell function was not impaired by indinavir. HIV PI-associated diabetes mirrors that of non-insulin-dependent diabetes mellitus and impaired insulin action in the periphery. (+info)
Characterization of novel cysteine proteases from germinating cotyledons of soybean [Glycine max (L.) Merrill].
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The enzymatic properties of novel cysteine proteases D3-alpha and beta which were purified from germinating soybean cotyledons were investigated. The enzyme activities were exhibited in the presence of a thiol reagent, such as 2-mercaptoethanol, and apparently inhibited by E-64, a cysteine protease inhibitor. Hydrolytic activities toward carbobenzoxy-Phe-Arg-MCA were detected at a pH above 4.0. The optimum temperature for activities was about 40 degrees C. The isoelectric point of D3-alpha and beta was 4.4 and 4. 7, respectively. The molecular mass of D3-alpha and beta, measured by MALDI/TOF mass spectrometry, was 26,178 and 26,429 Da, respectively. The substrate specificities of the enzymes were examined using peptide-MCAs and peptides, and cathepsin L-like broad specificity was observed at pH 4.0. These results demonstrated that these enzymes are cysteine endopeptidases [EC 3.4.22.-] like papain [EC 3.4.22.2]. (+info)
Stimulatory effect of beta-adrenergic agonists on ileal L cell secretion and modulation by alpha-adrenergic activation.
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Postprandial release of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) from L cells results from both nutrient transit in the ileal lumen and neural drive of endocrine cells. The adrenosympathetic system and its effectors have been shown to induce secretion of L cells in vivo or in vitro. Because these transmitters act through three receptors, beta, alpha1, alpha2, coupled to different intracellular pathways, we evaluated the responses of L cells to specific agonists, using the model of isolated vascularly perfused rat ileum. General stimulation of adrenergic receptors with epinephrine (10(-7) M) induced significant GLP-1 and PYY secretions (94+/-38 and 257+/-59 fmol/8 min respectively) which were abolished upon propranolol (10(-7) M) pretreatment and strongly decreased upon infusion with 10(-8) M prazosin. Blockade of alpha2-receptors with idazoxan (10(-8) M) did not alter epinephrine-induced peptide secretion. The beta-adrenergic agonist isoproterenol (10(-6) M) infused for 30 min induced a transient release of GLP-1 and PYY (integrated release over the 8 min of the peak secretion: 38+/-16 and 214+/-69 fmol for GLP-1 and PYY respectively, P<0.05). Because terbutaline but not dobutamine or BRL 37,344 (10(-5) M) induced significant GLP-1 and PYY secretions (135+/-30 and 305+/-39 fmol/8 min respectively), isoproterenol-induced secretions are suggested to result mainly from stimulation of the beta2-isoreceptor type. In contrast, the alpha1-agonist phenylephrine (10(-7) M) did not stimulate peptide release. When co-infused with 10(-6) M or 10(-7) M isoproterenol, 10(-7) M phenylephrine raised GLP-1 release to 174+/-53 and 108+/-28 fmol/8 min respectively (vs 38+/-16 and 35+/-10 fmol/8 min for isoproterenol alone, P<0.05) whereas PYY secretion was not significantly increased. Clonidine (10(-7) M), an alpha2-agonist, induced a moderate and delayed increase of GLP-1 and PYY but abolished the isoproterenol-induced peptide secretion. Our results showed that general stimulation of adrenergic receptors stimulates the secretory activity of ileal endocrine L cells. The net peptide secretion results from the activation of the beta2-isoreceptor type. Additionally, GLP-1 and PYY secretions are positively modulated by alpha1-receptor stimulation and inhibited by alpha2-receptor activation upon beta-receptor occupation. (+info)
Impact of lack of suppression of glucagon on glucose tolerance in humans.
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People with type 2 diabetes have defects in both alpha- and beta-cell function. To determine whether lack of suppression of glucagon causes hyperglycemia when insulin secretion is impaired but not when insulin secretion is intact, twenty nondiabetic subjects were studied on two occasions. On both occasions, a "prandial" glucose infusion was given over 5 h while endogenous hormone secretion was inhibited. Insulin was infused so as to mimic either a nondiabetic (n = 10) or diabetic (n = 10) postprandial profile. Glucagon was infused at a rate of 1.25 ng. kg(-1). min(-1), beginning either at time zero to prevent a fall in glucagon (nonsuppressed study day) or at 2 h to create a transient fall in glucagon (suppressed study day). During the "diabetic" insulin profile, lack of glucagon suppression resulted in a marked increase (P < 0.002) in both the peak glucose concentration (11.9 +/- 0.4 vs. 8.9 +/- 0.4 mmol/l) and the area above basal of glucose (927 +/- 77 vs. 546 +/- 112 mmol. l(-1). 6 h) because of impaired (P < 0.001) suppression of glucose production. In contrast, during the "nondiabetic" insulin profile, lack of suppression of glucagon resulted in only a slight increase (P < 0.02) in the peak glucose concentration (9.1 +/- 0.4 vs. 8.4 +/- 0.3 mmol/l) and the area above basal of glucose (654 +/- 146 vs. 488 +/- 118 mmol. l(-1). 6 h). Of interest, when glucagon was suppressed, glucose concentrations differed only minimally during the nondiabetic and diabetic insulin profiles. These data indicate that lack of suppression of glucagon can cause substantial hyperglycemia when insulin availability is limited, therefore implying that inhibitors of glucagon secretion and/or glucagon action are likely to be useful therapeutic agents in such individuals. (+info)
Adherent surface mucus gel restricts diffusion of macromolecules in rat duodenum in vivo.
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The aim of this study was to investigate the permeability of the adherent mucus gel layer in rat duodenum in vivo to macromolecules applied in the lumen. Rats were anesthetized with thiobarbiturate, and the duodenum was perfused with isotonic NaCl solution containing large-molecular-size secretagogues. Effects on mucosal HCO(-)(3) secretion and blood-to-lumen (51)chromium-labeled EDTA clearance were used as indexes that compounds had migrated across the mucus layer. Exposure to a low concentration of papain (10 U/100 ml) for 30 min removed the mucus layer without damage to the epithelium and induced or markedly enhanced HCO(-)(3) secretory responses to cholera toxin (molecular mass of 85 kDa) or glucagon (3.5 kDa). Water extracts from a VacA cytotoxin (89 kDa) producing Helicobacter pylori strain, but not from a toxin-negative isogenic mutant, caused a small increase in HCO(-)(3) secretion but only after the mucus layer had been removed by papain. The duodenal surface mucus gel thus significantly restricts migration of macromolecules to the duodenal surface. Release of bacterial toxins at the cell-mucus interface may enhance or be a prerequisite for their effects on the gastrointestinal mucosa. (+info)
Glucose uptake during centrally induced stress is insulin independent and enhanced by adrenergic blockade.
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Glucose utilization increases markedly in the normal dog during stress induced by the intracerebroventricular (ICV) injection of carbachol. To determine the extent to which insulin, glucagon, and selective (alpha/beta)-adrenergic activation mediate the increment in glucose metabolic clearance rate (MCR) and glucose production (R(a)), we used five groups of normal mongrel dogs: 1) pancreatic clamp (PC; n = 7) with peripheral somatostatin (0.8 microg x kg(-1) x min(-1)) and intraportal replacement of insulin (1,482 +/- 84 pmol x kg(-1) x min(-1)) and glucagon (0.65 ng x kg(-1) x min(-1)) infusions; 2) PC plus combined alpha (phentolamine)- and beta (propranolol)-blockade (7 and 5 microg x kg(-1) x min(-1), respectively; alpha+beta; n = 5); 3) PC plus alpha-blockade (alpha; n = 6); 4) PC plus beta-blockade (beta; n = 5); and 5) a carbachol control group without PC (Con; n = 10). During ICV carbachol stress (0-120 min), catecholamines, ACTH, and cortisol increased in all groups. Baseline insulin and glucagon levels were maintained in all groups except Con, where glucagon rose 33%, and alpha, where insulin increased slightly but significantly. Stress increased (P < 0.05) plasma glucose in Con, PC, and alpha but decreased it in beta and alpha+beta. The MCR increment was greater (P < 0.05) in beta and alpha+beta than in Con, PC, and alpha. R(a) increased (P < 0.05) in all groups but was attenuated in alpha+beta. Stress-induced lipolysis was abolished in beta (P < 0.05). The marked rise in lactate in Con, PC, and alpha was abolished in alpha+beta and beta. We conclude that the stress-induced increase in MCR is largely independent of changes in insulin, markedly augmented by beta-blockade, and related, at least in part, to inhibition of lipolysis and glycogenolysis, and that R(a) is augmented by glucagon and alpha- and beta-catecholamine effects. (+info)
Targeted ablation of secretin-producing cells in transgenic mice reveals a common differentiation pathway with multiple enteroendocrine cell lineages in the small intestine.
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The four cell types of gut epithelium, enteroendocrine cells, enterocytes, Paneth cells and goblet cells, arise from a common totipotent stem cell located in the mid portion of the intestinal gland. The secretin-producing (S) cell is one of at least ten cell types belonging to the diffuse neuroendocrine system of the gut. We have examined the developmental relationship between secretin cells and other enteroendocrine cell types by conditional ablation of secretin cells in transgenic mice expressing herpes simplex virus 1 thymidine kinase (HSVTK). Ganciclovir-treated mice showed markedly increased numbers of apoptotic cells at the crypt-villus junction. Unexpectedly, ganciclovir treatment induced nearly complete ablation of enteroendocrine cells expressing cholecystokinin and peptide YY/glucagon (L cells) as well as secretin cells, suggesting a close developmental relationship between these three cell types. In addition, ganciclovir reduced the number of enteroendocrine cells producing gastric inhibitory polypeptide, substance-P, somatostatin and serotonin. During recovery from ganciclovir treatment, the enteroendocrine cells repopulated the intestine in normal numbers, suggesting that a common early endocrine progenitor was spared. Expression of BETA2, a basic helix-loop-helix protein essential for differentiation of secretin and cholecystokinin cells was examined in the proximal small intestine. BETA2 expression was seen in all enteroendocrine cells and not seen in nonendocrine cells. These results suggest that most small intestinal endocrine cells are developmentally related and that a close developmental relationship exists between secretin-producing S cells and cholecystokinin-producing and L type enteroendocrine cells. In addition, our work shows the existence of a multipotent endocrine-committed cell type and locates this hybrid multipotent cell type to a region of the intestine populated by relatively immature cells. (+info)