[How should insulin secretion be evaluated in practice?].
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Basal Metabolism↗
Biomedical subjects
P J Lefebvre
Publications and source records attributed to P J Lefebvre.
[How to explore insulin sensitivity in man?].
The two most widely used methods for studying insulin sensitivity in man are the euglycaemic hyperinsulinaemic clamp and the intravenous glucose tolerance test with minimal model assessment. The glucose clamp is the reference method, well validated and easy to interpret, which allows various extensions to the basic experimental procedure in order to obtain more valuable information on the specific effects of insulin on the various aspects of glucose metabolism. However, it is time-consuming and labour-intensive. In contrast, the intravenous glucose tolerance test is easier to perform, but its interpretation is much more difficult and requires a modeling approach called the "minimal model". If the intravenous glucose tolerance test probably represents a good screening test, mainly on a population basis, the glucose clamp still remains the gold standard method to study insulin sensitivity in man.
Female↗
The use of acarbose in the prevention and treatment of hypoglycaemia.
This paper reviews the use of acarbose in the prevention and treatment of hypoglycaemia. In diet- or sulfonylurea-treated patients, acarbose may reduce the incidence of late postprandial hypoglycaemia. In insulin-treated patients, acarbose treatment usually requires reduction of the insulin dose; one study has shown that 100 mg acarbose at night significantly reduces the incidence of mid-evening and nocturnal hypoglycaemia. Several studies have suggested acarbose to be a useful adjunct to the management of reactive hypoglycaemia in the non-diabetic patients. Long-term prospective studies are still needed to document this last indication of acarbose or other alpha-glycosidase inhibitors.
Acarbose↗
Reduction of the acute bioavailability of metformin by the alpha-glucosidase inhibitor acarbose in normal man.
In a double-blind cross-over study, we investigated a possible influence of the alpha-glucosidase inhibitor acarbose on the bioavailability of the biguanide compound metformin. Each of the six healthy young male volunteers was randomly allocated during two consecutive 7 day periods to either acarbose (days 1-3: 3 x 50 mg day-1; days 4-7: 3 x 100 mg day-1) or placebo. At day 7 and 14 of the study, the overnight-fasted subjects ingested 1000 mg metformin with the first bite of a standardized breakfast (500 kcal; 60 g carbohydrates) and together with either placebo or 100 mg acarbose. Acarbose significantly (P < 0.05) reduced the meal-induced increase in blood glucose and plasma insulin levels. Acarbose induced a significant (P < 0.05) reduction in early (90, 120, 180 min) serum levels, peak concentrations (Cmax: 1.22 +/- 0.14 vs. 1.87 +/- 0.60 mg l-1) and area under the curve of metformin (AUC 0-540 min: 423 +/- 55 vs. 652 +/- 55 mg min l-1), but did not diminish its 24 h urinary excretion. In conclusion, acarbose significantly reduces the acute bioavailability of metformin in normal subjects.
Acarbose↗
Changes in glucose turnover parameters and improvement of glucose oxidation after 4-week magnesium administration in elderly noninsulin-dependent (type II) diabetic patients.
The aim of the present study was to investigate the effects of magnesium supplementation on glucose uptake and substrate oxidation in noninsulin-dependent (type II) diabetic patients. Nine elderly non-obese noninsulin-dependent (type II) diabetic patients, treated by diet only, participated in the study, which was designed as randomized, double blind, and cross-over. Each patient was followed up for a prestudy period of 3 weeks before inviting him/her to receive placebo or magnesium supplementation (15.8 mmol/day) for 4 weeks. At the end of each treatment period, a euglycemic hyperinsulinemic glucose clamp with simultaneous D-[3-3H]glucose infusion and indirect calorimetry was performed. Magnesium supplementation resulted in significantly increased plasma and erythrocyte magnesium levels, whereas body weight and fasting plasma glucose did not change. In the last 60 min of the glucose clamp, insulin-mediated glucose disappearance, total body glucose disposal (24.5 +/- 0.4 vs. 28.2 +/- 0.7 mumol/kg.min; P < 0.005), and glucose oxidation (13.0 +/- 0.4 vs. 16.3 +/- 0.8 mumol/kg.min; P < 0.01) were increased after chronic magnesium supplementation. Endogenous glucose production, nonoxidative glucose disposal, lipid and protein oxidation, and insulin MCR were not affected. In conclusion, a 4-week magnesium supplementation improves insulin sensitivity and glucose oxidation in the course of a euglycemic-hyperinsulinemic glucose clamp in noninsulin-dependent diabetic patients. Long term studies are needed to determine whether magnesium supplementation is useful in the management of type II diabetes.
Aged↗
Detection of early sympathetic cardiovascular neuropathy by squatting test in NIDDM.
OBJECTIVE: To determine the role of the squatting test in the detection of early sympathetic neuropathy in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Three groups of nonsmoking, nonobese subjects were studied: 10 healthy subjects, 10 NIDDM patients without autonomic neuropathy (AN), and 10 NIDDM patients with AN defined by the presence of a pathological deep-breathing value. All subjects were given three postural tests: lying-to-standing, sitting-to-standing, and squatting test. Heart rate (HR) and finger arterial pressure were recorded with a noninvasive technique. RESULTS: Blood pressure (BP) fall (expressed as decremental area) was not significantly different among the groups at standing up after sitting or lying. By contrast, a significantly greater BP drop occurred in NIDDM patients with AN (1,123 +/- 245 mm2) compared with NIDDM patients without AN (460 +/- 232 mm2) or normal subjects (429 +/- 138 mm2, P < 0.001). The HR increase after all the orthostatic maneuvers was smaller in diabetic patients with AN (P < 0.01) compared with that recorded in other groups. Significant correlations were observed between BP fall after squatting and either the expiration:inspiration ratio at deep breathing (r = -0.77, P < 0.001) or the duration of diabetes (r = 0.76, P < 0.001). CONCLUSIONS: The intrinsic orthostatic load of the squatting test, which is greater than conventional postural maneuvers, makes the squatting test an easy and useful test to detect early orthostatic dysregulation in NIDDM.
Blood Pressure↗
Metabolic clearance rate of insulin in type 2 diabetic patients treated with combined insulin and sulfonylurea therapy.
The metabolic clearance rate of insulin (MCRI) in 10 non-obese type 2 diabetic patients treated with either insulin alone or combined insulin plus sulfonylurea therapy is investigated. A classical 2-hour euglycaemic hyperinsulinaemic glucose clamp using the artificial pancreas was performed in a randomized order after two 6-week periods of treatment: either with subcutaneous injections of insulin alone or with insulin plus oral administration of the sulfonylurea compound glipizide at the dose of 3 x 10 mg/day. The MCRI was calculated knowing the constant insulin infusion rate (0.1 U.kg-1.h-1) and measuring basal and steady-state plasma free insulin and C-peptide levels. When the test was performed at the end of the period of treatment with insulin plus glipizide and 30 min after the ingestion of the last dose of 10 mg glipizide, plasma C-peptide levels were significantly increased and steady-state free insulin levels tended to be slightly higher whereas the metabolic clearance rate of glucose was not affected. The MCRI was significantly reduced by glipizide from 23.3 +/- 2.9 to 18.9 +/- 2.0 ml.kg-1.min-1 p < 0.05. These results demonstrate that the sulfonylurea glipizide decreases the MCRI. This effect may play a role in the hypoglycemic action of sulfonylureas.
Cross-Over Studies↗
Evidence that insulin-like growth factor 2 (IGF2) is the dominant thymic peptide of the insulin superfamily.
The central T-cell tolerance of neuroendocrine functions has been proposed to be primarily induced by the thymic repertoire of neuroendocrine self antigens. The present study aimed at characterizing the human thymic insulin-related autoantigen able to represent the pancreatic B-cell function in face of the developing T-cells. Immunofluorescence studies were performed on human and rat thymic sections, as well as on the rat IT-45R1 thymic epithelial cell line using several antibodies to epitopes of the insulin peptide superfamily. These studies identify beyond any doubt that insulin-like growth factor 2 (IGF2) is the dominant thymic peptide of the insulin family. The sequence of an insulin-derived autoantigen is proposed. This autoantigen is a nonamer and has a hydrophobic residue leucine (L) at position 9. In the human species, this autoantigen would primarily be tolerogenic for the pancreatic B-cell endocrine function during fetal development.
Amino Acid Sequence↗
Physiological elevations of plasma beta-endorphin alter glucose metabolism in obese, but not normal-weight, subjects.
The present study was undertaken to evaluate the metabolic and hormonal responses to physiologic elevations of plasma beta-endorphin concentrations in both normal-weight and obese healthy subjects. The infusion of synthetic human beta-endorphin (4.5 ng/kg/min) produced the following: (1) in normal-weight subjects, no significant change of plasma glucose and pancreatic hormones (insulin, C-peptide, and glucagon), a significant plasma free fatty acids (FFA) increase, and a suppression of glycerol plasma levels; (2) in obese subjects, significant increases of glucose, insulin, C-peptide, and glucagon, a progressive decline of circulating FFA, and no change in glycerol plasma levels. In obese subjects, the intravenous administration of naloxone, given as a bolus (5 mg injected in 5 minutes) before the start of beta-endorphin infusion, reduced the plasma glucose response to the opioid by approximately half, annulled the pancreatic hormonal responses, and also reduced the FFA, but not glycerol, response. In normal-weight subjects, naloxone pretreatment did not induce any change of the flat glucose and hormonal responses to beta-endorphin, but reversed its effects on circulating FFA and glycerol. These data suggest that physiological elevations of plasma beta-endorphin concentrations produce metabolic and hormonal effects in obese subjects significantly different from those occurring in normal-weight subjects; these effects are partially naloxone-sensitive, suggesting the mediation of endogenous opioid receptors.
Adult↗
Assessment of insulin resistance in vivo: application to the study of type 2 diabetes.
Besides insulin secretion, insulin sensitivity plays a key role in the feedback glucose-insulin closed loop. It can be altered in numerous physiological, pathological and pharmacological conditions. It can be estimated in vivo using methods that open the feedback loop (insulin suppression test, glucose clamp) or that analyze the closed loop by employing mathematical models of glucose kinetics. The most popular method is the euglycemic hyperinsulinemic glucose clamp. This test should be ideally coupled with a priming-constant infusion of a glucose tracer together with indirect calorimetry. This combination allows to study the glucose kinetics (Ra and Rd, and thus endogenous-mainly hepatic-glucose production) and its metabolism (oxidation or storage as glycogen), respectively. One alternative approach is the frequently sampled intravenous glucose tolerance test where the dynamic changes in plasma insulin and glucose levels are analyzed using the so-called 'minimal model' method. Noninsulin-dependent or type 2 diabetes is characterized by a significant defect in both insulin secretion and action. The insulin resistance is located at the liver site (increased glucose production) and at the peripheral tissues (decreased oxidation and, even more, defective storage of glucose in the muscles). This insulin resistance, which predominates at the postreceptor level, seems to be genetically determined but is worsened by weight excess and by hyperglycemia itself. This contributes to a vicious circle which aggravates progressively the severity of the disease.
Blood Glucose↗
[Postprandial hypoglycemia and alcohol drinking].
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Alcohol Drinking↗
Anti-oxidants show an anti-hypertensive effect in diabetic and hypertensive subjects.
1. In this study an acute anti-hypertensive effect of three anti-oxidant agents (vitamin C, thiopronine and glutathione) in hypertensive subjects and in both hypertensive and non-hypertensive diabetic patients is reported. 2. The anti-oxidants had no effect on blood pressure in healthy normal subjects at a dose of 6 mmol, but thiopronine and glutathione produced a significant hypotensive effect at a dose of 12 mmol. 3. These data suggest that anti-oxidants might have a dilatatory effect and that an imbalance of the nitric oxide-free radical interaction might facilitate the development of hypertension in humans.
Adult↗
A role for beta-endorphin in the pathogenesis of human obesity?
The discovery of several endogenous substances with morphine-like activity (endorphins and enkephalins) which possess potent behavioral effects, interfering with food and water intake, has led to suggest their implications in the pathogenesis of human obesity. This suggestion is mainly based on: 1) the ability of opiate antagonists naloxone and naltrexone to reduce food intake in some particular situations associated with obesity: 2) the existence of raised plasma levels of beta-endorphin in obese children and adults not corrected by weight loss; and 3) the increased responsiveness to the metabolic and hormonal effects of opiate agonism and antagonism found in obese but not in normal weight subjects. Although the problem still awaits a definite answer, it seems not hazardous to hypothesize a role for beta-endorphin in some pathogenetic events associated with human obesity.
Humans↗
Persistence of altered metabolic responses to beta-endorphin after normalization of body weight in human obesity.
The responses of plasma glucose, insulin, C-peptide and glucagon to an infusion of human beta-endorphin (0.5 mg/h) were studied in 10 formerly obese subjects who had lost 35 kg by dieting (body mass index less than 25) and compared with those of 10 normal-weight control (body mass index less than 25) and 10 obese (body mass index greater than 30) subjects. The fasting plasma concentrations of beta-endorphin were significantly higher in both the obese and the post-obese group than in the control group. In both obese and post-obese subjects, the infusion of beta-endorphin caused significant increases in peripheral plasma glucose, insulin, C-peptide and glucagon concentrations. In the control group, matched for age, sex and weight with the formerly obese group, there was no appreciable change in plasma insulin and C-peptide concentrations during the infusion of beta-endorphin, but the rise in plasma glucose was more sustained. Thus, 1. the increased plasma beta-endorphin concentrations found in human obesity are not corrected by normalization of body weight; and 2. formerly obese, normal-weight subjects behave as obese subjects in their metabolic and hormonal responses to beta-endorphin infusion. The alteration of the opioid system in human obesity may play some role in the predisposition to weight gain.
Adult↗
Vitamin E reduction of protein glycosylation in diabetes. New prospect for prevention of diabetic complications?
OBJECTIVE: This study evaluated the possibility of inhibiting protein glycosylation in vivo with vitamin E. RESEARCH DESIGN AND METHODS: Two groups of 10 insulin-requiring diabetic patients, matched for duration of disease and metabolic control, received daily vitamin E supplementation of 1200 and 600 mg, respectively, for 2 mo. A third group of 10 diabetic patients, matched for duration of disease and metabolic control, served as the control group and received placebo. Fasting plasma glucose, mean daily plasma glucose, fasting labile HbA1, and glycosylated proteins were measured in the basal state and after 1 and 2 mo of treatment. In addition, hyperglycemic clamp studies were performed in basal state and after 1 mo of vitamin E administration in all patients. RESULTS: Glycemic indices did not show any significant changes during the study, whereas fasting labile HbA, and glycosylated proteins decreased significantly after 1 and 2 mo in patients on vitamin E administration. Stable HbA1 decreased after 2 mo. Mean glycemic incremental area in the hyperglycemic clamp procedure was similar before and after treatment, whereas a significant reduction in mean labile HbA1 incremental area was found after vitamin E supplementation. A significant difference was also found in both fasting and incremental labile HbA1 levels, stable HbA1, and glycosylated proteins between the two groups of diabetic patients on the two doses of vitamin E; the diabetic patients who received the higher dose of vitamin E showed the greater reduction. No significant changes in these parameters were observed in diabetic patients on placebo administration. CONCLUSIONS: These results demonstrate that vitamin E administration may reduce protein glycosylation in diabetic subjects independently of changes in plasma glucose, an effect that may be due to the inhibition of labile glycosylation, the first step of the Maillard reaction. Long-term studies will help establish the usefulness of vitamin E administration for the prevention of diabetic complications.
Blood Proteins↗
[Beta cells in Type II diabetes: culprit or victim?].
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Clinical Trials as Topic↗
[Magnesium and the regulation of carbohydrate metabolism].
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Aging↗
Clinical aspects of the relationship between oral contraceptives, abnormalities in carbohydrate metabolism, and the development of cardiovascular disease.
Although large epidemiologic studies indicated no difference in the frequency of diabetes mellitus in nonusers and everusers of high-dose combination oral contraceptives, other studies had shown an increased risk of impaired glucose tolerance in current users, which is estimated to be roughly twice as frequent as that in nonusers. Women at risk of developing impaired glucose tolerance while receiving high-dose oral contraceptives either had previous gestational diabetes mellitus or were older, obese, or had a positive family history of diabetes mellitus. The tendency to decreased glucose tolerance seems essentially related to the dosage and chemical structure of the progestogen used in oral contraceptives, namely, estrane and particularly gonane progestins. However, increased frequency of impaired glucose tolerance and potentially diabetes mellitus are obviously not linked to the use of the more potent gonane progestins. The use of low-dose oral contraceptives, particularly with reduced progestogen content (such as in the triphasic formulations and last-generation monophasic preparations), is accompanied by a low risk of impaired glucose tolerance, even in previous gestational diabetes mellitus. The mechanism of decreased glucose tolerance in oral contraceptive users is unknown but seems related partially to increased peripheral resistance that is potentially caused by a postreceptor defect in insulin action. Changes in insulin production or metabolic clearance rate are not excluded by recent, sophisticated investigations of carbohydrate metabolism in oral contraceptive users. Impaired glucose tolerance and diabetes mellitus, chronic hyperglycemia, and hyperinsulinemia are believed to increase atherogenic risk either by their direct action or their effects on lipid metabolism. Newer epidemiologic studies now indicate that the incidence of cardiovascular disease in low-dose, low-risk, current oral contraceptive users has been substantially decreased. The use of low-dose oral contraceptives with reduced dosages of better adapted progestogens seems effective in decreasing alterations in carbohydrate metabolism and may thereby contribute to decrease further atherogenic risk in oral contraceptive users.
Carbohydrate Metabolism↗