Glucose metabolism and beta-cell mass in adult offspring of rats protein and/or energy restricted during the last week of pregnancy.
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An association between low birth weight and later impaired glucose tolerance was recently demonstrated in several human populations. Although fetal malnutrition is probably involved, the biological bases of such a relationship are not yet clear, and animal studies on the matter are scarce. The present study was aimed to identify, in adult (8-wk) female offspring, the effects of reduced protein and/or energy intake strictly limited to the last week of pregnancy. Thus we have tested three protocols of gestational malnutrition: a low-protein isocaloric diet (5 instead of 15%), with pair feeding to the mothers receiving the control diet; a restricted diet (50% of the control diet); and a low-protein restricted diet (50% of low-protein diet). Only the low-protein diet protocols, independent of total energy intake, led to a lower birth weight. The adult offspring female rats in the three deprived groups exhibited no decrease in body weight and no major impairment in glucose tolerance, glucose utilization, or glucose production (basal state and hyperinsulinemic clamp studies). However, pancreatic insulin content and beta-cell mass were significantly decreased in the low-protein isocaloric diet group compared with the two energy-restricted groups. Such impairment of beta-cell mass development induced by protein deficiency limited to the last part of intrauterine life could represent a situation predisposing to impaired glucose tolerance. (+info)
Increased insulin secretion and normalization of glucose tolerance by cholinergic agonism in high fat-fed mice.
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Increased insulinotropic activity by the cholinergic agonist carbachol exists in insulin-resistant high fat-fed C57BL/6J mice. We examined the efficiency and potency of carbachol to potentiate glucose-stimulated insulin secretion and to improve glucose tolerance in these animals. Intravenous administration of carbachol (at 15 and 50 nmol/kg) markedly potentiated glucose (1 g/kg)-stimulated insulin secretion in mice fed both a control and a high-fat diet (for 12 wk), with a higher relative potentiation in high fat-fed mice measured as increased (1-5 min) acute insulin response and area under the 50-min insulin curve. Concomitantly, glucose tolerance was improved by carbachol. In fact, carbachol normalized glucose-stimulated insulin secretion and glucose tolerance in mice subjected to a high-fat diet. Carbachol (>100 nmol/l) also potentiated glucose-stimulated insulin secretion from isolated islets with higher efficiency in high fat-fed mice. In contrast, binding of the muscarinic receptor antagonist [N-methyl-(3)H]scopolamine to islet muscarinic receptors and the contractile action of carbachol on ileum muscle strips were not different between the two groups. We conclude that carbachol normalizes glucose tolerance in insulin resistance. (+info)
Insulin-induced endothelin release and vasoreactivity in hypertriglyceridemic and hypertensive rats.
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Insulin-elicited endothelin release in hypertriglyceridemic, hypertensive, hyperinsulinemic (HTG) rats was shown. Weanling male Wistar rats were given 30% sucrose in their drinking water for 20-24 wk. In vitro contractions of aorta and femoral arteries were elicited with 40 mM KCl. Endothelin release induced with KCl plus 50 microU/ml insulin resulted in increases in contractile responses: 41 +/- 5.9 and 57 +/- 6% for control and 65.5 +/- 6 and 95 +/- 9% for HTG aortas and femoral arteries, respectively. The endothelin ET(B)-receptor blocker BQ-788 decreased responses to KCl + insulin by 39 +/- 8 and 53 +/- 5% in control and 48 +/- 13 and 79 +/- 3.5% in HTG aortas and femoral arteries, respectively. The ET(A)-receptor antagonist PD-151242 inhibited these responses by 12 +/- 10 and 1 +/- 9% in control and by 51.5 +/- 9 and 58.5 +/- 1% in HTG aortas and femoral arteries, respectively. These results suggest that endothelin may contribute to the hypertension in this model. (+info)
Regulation of the Na+/H+ antiporter in patients with mild chronic renal failure: effect of glucose.
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BACKGROUND: The aim of this study was to determine the glucose-dependent regulation of the sodium-proton-antiporter (Na+/H+ antiporter) in patients with mild chronic renal failure (CRF). METHODS: We measured plasma glucose concentrations, plasma insulin concentrations, plasma C peptide concentrations, arterial blood pressure, cytosolic pH (pHi), cellular Na+/H+ antiporter activity, and cytosolic sodium concentration ([Na+]i) in 19 patients with CRF and 41 age-matched healthy control subjects (control) during a standardized oral glucose tolerance test. Intracellular pHi, [Na+]i, and Na+/H+ antiporter activity was measured in lymphocytes using fluorescent dye techniques. RESULTS: Under resting conditions, the pHi was significantly lower, whereas the Na+/H+ antiporter activity was significantly higher in CRF patients compared with controls (each P < 0.0001). The oral administration of 100 g glucose significantly increased the Na+/H+ antiporter activity in CRF patients from 13.35 +/- 1.26 x 10-3 pHi/second to 16.44 +/- 1.37 x 10-3 pHi/second after one hour and to 14.06 +/- 1.36 x 10-3 pHi/second after two hours (mean +/- SEM, P = 0.008 by Friedmans's two-way analysis of variance). In controls, the administration of 100 g glucose significantly increased the Na+/H+ antiporter activity from 4.23 +/- 0.20 x 10-3 pHi/second to 6.00 +/- 0.56 x 10-3 pHi/second after one hour and to 6.65 +/- 0.64 x 10-3 pHi/second after two hours (P = 0.0003). The glucose-induced enhancement of the Na+/H+ antiporter activity was more pronounced in CRF patients compared with controls (P = 0.011). Resting [Na+]i was not significantly different between the two groups. CONCLUSIONS: CRF patients show an intracellular acidosis leading to an increased Na+/H+ antiporter activity. In addition, high glucose levels exaggerate the differences in Na+/H+ antiporter activity already present between cells from patients with mild CRF and those from control subjects. (+info)
Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: is cellular insulin resistance a secondary phenomenon?
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To elucidate potential mechanisms for insulin resistance occurring early in the development of type 2 diabetes, we studied 10 young healthy individuals, each with two first-degree relatives with type 2 diabetes, and 10 control subjects without known type 2 diabetic relatives. They were pairwise matched for age (35 +/- 1 vs. 35 +/- 1 years), BMI (23.6 +/- 0.6 vs. 23.1 +/- 0.4 kg/m2), and sex (four men, six women). Glucose turnover was assessed during a euglycemic clamp at two insulin levels (low approximately 20 mU/l; high approximately 90 mU/l), and abdominal subcutaneous adipose tissue (SAT) lipolysis and blood flow were concomitantly studied with microdialysis and 133Xe clearance. HbA1c was higher in patients with type 2 diabetic relatives than in control subjects (4.8 +/- 0.1 vs. 4.5 +/- 0.1%, P < 0.02), but fasting glucose, insulin, and C-peptide levels were similar. During the clamp, the insulin sensitivity index for glucose disposal was lower (P < 0.03) in relatives than in control subjects (low 12.0 +/- 1.6 vs. 18.1 +/- 1.4; high 9.4 +/- 0.8 vs. 12.9 +/- 0.6 [100 x mg x l x kg(-1) x mU(-1) x min(-1)]). This difference was partially attributed to slightly higher clamp insulin levels in the relatives (P < 0.03), suggesting an impaired rate for insulin clearance. SAT lipolysis measured as in situ glycerol release did not differ under basal conditions (2.0 +/- 0.2 vs. 2.1 +/- 0.2 micromol x kg(-1) x min(-1)), but the suppression during the insulin infusion was less marked in relatives than in control subjects (glycerol release: low 0.92 +/- 0.09 vs. 0.68 +/- 0.16; high 0.71 +/- 0.10 vs. 0.34 +/- 0.10 micromol x kg(-1) x min(-1); P < 0.03). Plasma nonesterified fatty acids also tended to be higher in relatives than in control subjects during the insulin infusion (NS). In contrast, in vitro experiments with isolated subcutaneous adipocytes displayed similar effects of insulin in relatives and control subjects with respect to both glucose uptake and antilipolysis. In conclusion, insulin action in vivo on both lipolysis and glucose uptake is impaired early in the development of type 2 diabetes. Since this impairment was not found in isolated adipocytes, it may be suggested that neural or hormonal perturbations precede cellular insulin resistance in type 2 diabetes. (+info)
An open, phase III study of lanreotide (Somatuline PR) in the treatment of acromegaly.
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Acromegaly is a disorder caused by excessive secretion of human growth hormone (GH). Somatostatin and its analogue-prolonged release formulation, lanreotide (Somatuline PR), inhibit the secretion of growth hormone. The aim of this open Phase III study was to investigate the clinical efficacy of lanreotide in the treatment of six acromegalic patients with a mean age of 44 +/- 13 yr including two patients with diabetes mellitus. All the patients previously received transsphenoidal or transcranial hypophysectomy. Lanreotide was given intramuscularly every 2 weeks at a fixed dose of 30 mg for 12 weeks. Serum GH and insulin-like growth factor-I (IGF-I) levels were evaluated before, 2, 6 and 12 weeks after treatment. After 12 weeks of treatment, mean (+/- SEM) GH levels decreased from 24.8 +/- 12.5 to 6.9 +/- 3.3 ng/ml and mean serum IGF-I levels decreased from 689 +/- 282 to 430 +/- 216 ng/ml. Abdominal ultrasonographic examinations showed no gallbladder stone or bile sand formation before or after the treatment. Three of the patients who did not receive octreotide presented with manifestations of mild gastrointestinal adverse effect such as mild abdominal pain and diarrhea. In conclusion, lanreotide is effective in the treatment of active postoperative acromegaly. (+info)
Hexokinase II-deficient mice. Prenatal death of homozygotes without disturbances in glucose tolerance in heterozygotes.
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Type 2 diabetes is characterized by decreased rates of insulin-stimulated glucose uptake and utilization, reduced hexokinase II mRNA and enzyme production, and low basal levels of glucose 6-phosphate in insulin-sensitive skeletal muscle and adipose tissues. Hexokinase II is primarily expressed in muscle and adipose tissues where it catalyzes the phosphorylation of glucose to glucose 6-phosphate, a possible rate-limiting step for glucose disposal. To investigate the role of hexokinase II in insulin action and in glucose homeostasis as well as in mouse development, we generated a hexokinase II knock-out mouse. Mice homozygous for hexokinase II deficiency (HKII(-/-)) died at approximately 7.5 days post-fertilization, indicating that hexokinase II is vital for mouse embryogenesis after implantation and before organogenesis. HKII(+/-) mice were viable, fertile, and grew normally. Surprisingly, even though HKII(+/-) mice had significantly reduced (by 50%) hexokinase II mRNA and activity levels in skeletal muscle, heart, and adipose tissue, they did not exhibit impaired insulin action or glucose tolerance even when challenged with a high-fat diet. (+info)
Is QT interval a marker of subclinical atherosclerosis in nondiabetic subjects? The Insulin Resistance Atherosclerosis Study (IRAS).
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BACKGROUND AND PURPOSE: We studied the relationship of heart rate-corrected QT interval with subclinical atherosclerosis, as determined by ultrasonographic measurement of carotid intima-media thickness (IMT) in nondiabetic subjects in the Insulin Resistance Atherosclerosis Study (IRAS). Prolonged heart rate-corrected QT interval is an unfavorable prognostic factor of cardiovascular morbidity and mortality, and QT interval prolongation may be the result of atherosclerosis. METHODS: B-mode ultrasound imaging of the carotid artery IMT was performed in a large, triethnic, nondiabetic population free of clinical coronary artery disease (n=912). QT interval was measured on resting electrocardiograms with use of a computer program and corrected for heart rate with standard equations. RESULTS: IMT of the common carotid artery correlated significantly with heart rate-corrected QT interval duration (r=0.15 for QT(60) and r=0.14 for QTc), whereas no relationship between IMT of the internal carotid artery and QT interval was found (r=-0.01). The association was somewhat stronger in women than in men. In a multiple regression analysis adjusting for demographic variables, the association of common carotid artery IMT to heart rate-corrected QT interval remained highly significant, but adjustment for cardiovascular risk factors weakened the relationship. CONCLUSIONS: We found a significant relation of heart rate-corrected QT interval to carotid atherosclerosis in nondiabetic subjects that was stronger in women and partly mediated by cardiovascular risk factors, including hypertension. QT interval may therefore serve as a marker for clinically undetected ("subclinical") atherosclerotic disease. (+info)