Adrenergic system and carbohydrate metabolism. Effects of beta-receptor blockade on insulin secretion and peripheral insulin sensitivity in normoglycaemic patients
L FerraraBrunella CapaldoAngela A. RivelleseSalvatore GenoveseC IovineP. MastranzoFrancesco CirilloMario Mancini
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Carbohydrate Metabolism
Glucose tolerance test
Ventromedial hypothalamic (VMH)-lesioned rats were tested 1 and 6 wk after the lesions to determine, by euglycemic-hyperinsulinemic clamps, their tissue response to insulin. One week after the lesions, total glucose metabolism was more sensitive and responsive to insulin than in age-matched controls. In the two groups, hepatic glucose production was suppressed at almost identical insulin concentrations (approximately 550 microU/ml). Six weeks after the VMH lesions, the increased insulin responsiveness of total glucose metabolism disappeared and glucose metabolism became less insulin sensitive (right, shifted dose-response curve) than that of control animals. Furthermore, hepatic glucose production of VMH-lesioned rats was now inhibited by 45% at most and at the supraphysiological insulin concentration of 16,000 microU/ml, while it was totally suppressed by 550 microU/ml of the hormone in age-matched controls. This defect was accompanied by a lack of decrease in plasma glucagon levels during the clamps carried out at maximal insulin concentration. In summary, in a first phase after VMH lesion, rats are hypersensitive and hyperresponsive to insulin; and in a later phase, when obesity is well established, VMH-lesioned rats become insulin resistant and are characterized by a decreased in vivo sensitivity and responsiveness of liver and muscles to the hormone.
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Glucose tolerance test
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Glucose tolerance test
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Aim: Our aim was to assess the effect of chronic hyperglycemia on glucose- and insulin-mediated suppression of glucagon secretion by the α-cell. Methods: Thirty subjects with normal glucose tolerance, 27 with impaired fasting glucose and/or impaired glucose tolerance, and 32 type 2 diabetic subjects were studied with oral glucose tolerance test (OGTT) and euglycemic hyperinsulinemic clamp. Fasting plasma glucagon concentration and plasma glucagon concentration during the OGTT and insulin clamp were measured. Results: During the OGTT, the decrement in the plasma glucagon concentration (area under the curve) was correlated inversely with the fasting plasma glucose concentration (r = −0.35; P < 0.001). As the fasting glucose level increased, the suppression of plasma glucagon progressively diminished. In contrast, during the euglycemic insulin clamp, the suppression of plasma glucagon was not correlated with the fasting plasma glucose concentration and was similar in subjects with normal glucose tolerance, subjects with impaired fasting glucose/impaired glucose tolerance, and diabetic subjects: 18, 23, and 18%, respectively. Conclusion: Insulin-mediated suppression of glucagon secretion is unrelated to the fasting plasma glucose concentration and is not impaired by chronic hyperglycemia. Thus, the defect in plasma glucagon suppression during the OGTT most likely results from impaired glucose-mediated glucagon suppression. The close correlation between fasting plasma glucose concentration and reduced glucagon suppression suggests a glucotoxic effect on α-cell function.
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No studies are available that have compared early defects in glucose metabolism in the offspring of insulin-deficient and insulin-resistant probands with non-insulin-dependent diabetes mellitus (NIDDM). To investigate this issue, we evaluated insulin secretion capacity with oral and intravenous glucose tolerance tests and with the hyperglycemic clamp, and insulin action with the euglycemic insulin clamp in 20 offspring of NIDDM patients with low fasting C-peptide (+/-450 pmol/liter), reflecting deficient insulin secretion (IS-group), 18 offspring of NIDDM patients with high fasting C-peptide (>/= 880 pmol/liter), reflecting insulin resistance (IR-group), and 14 healthy control subjects without a family history of NIDDM. The frequency of impaired glucose tolerance was 45.0% in the IS-group and 50% in the IR-group. The IS-group had lower insulin-glucose response at 30 min in the oral glucose tolerance test (85.2+/-10.0 pmol insulin per mmol glucose) than the control group (136.4+/-23.1 pmol insulin per mmol glucose; P < 0.05) and the IR-group (115.6+/-11.8 pmol insulin per mmol glucose; P = 0.05). Furthermore, the acute insulin response during the first 10 min of an intravenous glucose tolerance test was lower in the IS-group than in the IR-group. Maximal insulin secretion capacity evaluated by C-peptide levels during the hyperglycemic clamp did not differ between the groups. The IR-group had lower rates of whole body glucose uptake (60.1+/-4.6 micromol per lean body mass per minute) than did the control group (84.2+/-5.0 micromol per lean body mass per minute; P < 0.001) or the IS-group (82.6+/-5.9 micromol per lean body mass per minute; P < 0.01) and this was due to reduced glucose nonoxidation. To conclude, both impaired insulin secretion and insulin action seem to be inherited and could represent the primary defects in glucose metabolism in the offspring of NIDDM probands.
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Pancreatic and gut hormone responses to oral glucose, and insulin sensitivity were studied in cystic fibrosis patients with normal (N= 14), impaired (N=4), and diabetic (N= 12) glucose tolerance, and in 10 control subjects, and beta cell responses to oral glucose and intravenous glucagon were compared. Compared to control subjects, initial insulin and C-peptide responses to oral glucose were lower in all patient groups, and decreased with decreasing glucose tolerance. Insulin sensitivity in patients with impaired and diabetic glucose tolerance was lower than in control subjects. The 6 min post-glucagon C-peptide concentration was positively correlated with the initial insulin response to oral glucose. Fasting levels of pancreatic polypeptide, pancreatic glucagon, total glucagon, glucagon-like peptide-1 7-36 amide, and gastric inhibitory polypeptide were normal in all patient groups. Following oral glucose, pancreatic polypeptide responses were absent in all patients, suppressibility of pancreatic glucagon secretion was increasingly impaired with decreasing glucose tolerance, and gut hormone levels were normal. In conclusion, at cystic fibrosis (a) insulin secretion is impaired even when glucose tolerance and insulin sensitivity are within the normal range, (b) the glucagon test gives valid estimates of residual beta cell function, (c) pancreatic polypeptide response to oral glucose is absent, (d) glucagon suppressibility decreases with decreasing glucose tolerance, and (e) the enteroinsular axis is intact.
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Insulin and glucagon secretion was compared in women with impaired glucose tolerance (IGT; n = 19, age 58.4 +/- 0.3 yr; mean +/- SD) and women with normal glucose tolerance (NGT; n = 40, age 58.4 +/- 0.3 yr). Fasting plasma insulin levels were higher in IGT than in NGT (P = 0.026), whereas fasting glucose and glucagon levels were not different. Arginine was injected intravenously (5 g), which rapidly stimulated insulin and glucagon secretion in all subjects. Raising the blood glucose (BG) to 14 and 28 mmol/L potentiated insulin secretion and inhibited glucagon secretion. The acute insulin response to arginine (AIR = 2-5 min postload increase) at BG 14 mmol/L, but not at fasting BG or BG 28 mmol/L, was lower in IGT than in NGT (P = 0.033), as was the glucose potentiation of AIR (slopeAIR) (P = 0.020). The acute glucagon response (AGR) was higher in IGT than in NGT at BG 14 mmol/L (P = 0.016). SlopeAGR (glucose inhibition of AGR) was reduced in IGT (P = 0.001). In NGT, there was a significant inverse correlation between slopeAIR and slopeAGR (P = 0.002) not seen in IGT. We conclude that in IGT with normal fasting BG, the glucose modulation of islet function is impaired, indicating that islet dysfunction is an early lesion during the development of noninsulin-dependent diabetes mellitus.
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We have characterized the abnormalities of glucose metabolism associated with Friedreich's ataxia (FA) by studying plasma glucose, insulin, growth hormone (GH), and glucagon before and after an oral glucose tolerance test (OGTT), an IV glucose load, and an IV arginine load, in 21 patients and in controls. Twelve patients were normotolerant (NT) to glucose, five glucose-intolerant (IT), and four diabetic (DM). Insulin secretion of IT patients was increased and delayed during OGTT. Interestingly, the insulin release during arginine load was significantly decreased in NT and IT as well as in DM patients. The GH response to OGTT was altered in IT patients. Plasma glucagon after an arginine load was significantly higher in patients than in controls. The results indicate that FA is associated with insulin resistance, beta-cell deficiency, and type I diabetes. These alterations might be genetically linked or metabolically related to the primary defect in FA. Their interplay or independent effects are responsible for abnormalities of glucose metabolism in FA.
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We used intravenous glucose tolerance tests in vivo and 3-O-methylglucose transport into skeletal muscle in vitro to assess glucose tolerance, pancreatic β-cell function, and insulin action in 9- to 11-wk-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar Kyoto rats (WKY). Body weight was slightly higher in the WKY (P < 0.001), while blood pressure was elevated in the SHR (P < 0.001). Insulin responses to intravenous glucose after 4 or 12 h of fasting in SHR were 2–3 times the responses of WKY rats (P < 0.001). The greater insulin responses in SHR were associated with accelerated glucose disappearance P < 0.001 vs. WKY rats). A direct correlation (r = 0.49, P < 0.05) between the peak plasma insulin responses to glucose and Kg values in SHR suggested that the exaggerated insulin responses contributed to the accelerated glucose disappearance in that group. 3-O-methylglucose transport rates into epitrochlearis muscles in vitro did not differ significantly between SHR and WKY groups in the absence of insulin (P < 0.2) or in the presence of insulin at physiological (600 pM, P > 0.4) or pharmacological (120,000 pM, P > 0.9) concentrations. Thus, compared with WKY rats, SHR had exaggerated insulin responses to glucose, similar insulin-mediated glucose transport into skeletal muscle, and enhanced glucose tolerance. Our findings indicate that young, hypertensive SHR have hyperfunction of pancreatic β-cells that is unrelated to insulin resistance. The resultant nutrient-stimulated hyperinsulinemia could play a role in the development or maintenance of elevated blood pressure in SHR.
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