EFFECTS OF AN ACUTE INCREASE IN PLASMA TRIGLYCERIDE LEVELS ON GLUCOSE-METABOLISM IN MAN

The aim of the study was to evaluate the effects of an acute increase in triglyceride levels induced by Intralipid (Kabivitrum, Stockholm, Sweden) infusion on forearm glucose uptake, glucose oxidative metabolism, and hepatic glucose production independent of circulating free fatty acid (FFA) levels in man. Six normal subjects underwent three different tests in random order. Each test consisted of a control period of 120 minutes followed by a euglycemic, hyperinsulinemic clamp lasting 120 minutes. In test 1, a high-dose intravenous Intralipid infusion was performed to increase triglyceride and FFA levels. In test 2, heparin (30 U/min) plus low-dose Intralipid infusions were performed to maintain triglyceride at normal levels and increase only FFA levels. Test 3 was performed as a control study. During the 120-minute control period, forearm glucose uptake and hepatic glucose production were not affected by increasing only FFA levels (test 2) or FFA and triglyceride levels (test 1) as compared with the control study. On the contrary, glucose oxidation was significantly decreased as compared with the control study during tests 1 and 2, without a further significant decrease during simultaneously increased FFA and triglyceride levels. Concomitantly, lipid oxidation was similar in tests 1 and 2, at values significantly greater than in test 3. During the euglycemic clamp, forearm glucose uptake and glucose oxidation were significantly lower during tests 1 and 2 than test 3. At variance with the control period, the increase of triglyceride levels during test 1 caused a significant 30% to 40% decrease of both parameters as compared with test 2. Opposite results were found for lipid oxidation, which remained unchanged during test 1 as compared with the control period but significantly decreased during tests 2 and 3. Hepatic glucose production was less inhibited during test 1 than during tests 2 and 3, and less so during test 2 than test 3. In conclusion, at least under these particular conditions, acute hypertriglyceridemia induced by Intralipid infusion seems to decrease forearm glucose uptake, glucose oxidation, and insulin-induced suppressibility of hepatic glucose production. Taking our results together, it seems that the triglyceride effect on carbohydrate metabolism occurs via triglyceride hydrolysis using the intracellular pathways of FFA without interference with the circulating FFA pool

In middle-aged siblings of patients with type 2 diabetes mellitus normal glucose tolerance is associated with insulin resistance and with increased insulin secretion : The SPIDER study

Objectives: To evaluate the frequency of impaired glucose tolerance (IGT) and of Type 2 diabetes mellitus (Type 2 DM) in siblings of patients with Type 2 DM, and to assess insulin release and insulin sensitivity in siblings with normal glucose tolerance (NGT), compared with NGT spouses of probands without family history of Type 2 DM. Design and Methods: We evaluated 87 families including 103 Type 2 DM patients (87 probands), and we carried out an oral glucose tolerance test (OGTT) in 130 siblings and in 60 spouses. Among NGT subjects, 12 siblings and 16 spouses underwent a low-dose insulin-glucose infusion test (LDIGIT) to evaluate C-peptide release and insulin sensitivity. Results: After the OGTT, 24 siblings were classified as having Type 2 DM, 31 as IGT, and only 14 spouses as IGT (P = 0.0012 vs siblings). NGT siblings (n = 75) showed higher insulin levels at 120 min than NGT spouses (n = 46) at OGTT, in spite of identical blood glucose levels; at LDIGIT, NGT siblings secreted more C-peptide and showed a lower insulin sensitivity than NGT spouses. Conclusions: These data indicate that middle-aged siblings of probands with Type 2 DM have a high frequency of IGT and Type 2 DM, and that NGT siblings have increased insulin resistance and increased insulin secretion when compared with adequate controls

Effects of endothelin-1 and nitric oxide on glucokinase activity in isolated rat hepatocytes

To test the hypothesis that endothelin-1 (ET-1) and nitric oxide (NO) influence glucokinase (GK) activity in an opposite manner, we evaluated the effects of ET-1, L-NAME, an inhibitor of NO synthase, and L-arginine, a substrate for NO synthase, on GK activity and glycogen content in isolated rat hepatocytes. Moreover, to understand the receptor involved in the process, the effects of BQ 788, a specific antagonist of ET(B) receptor, and PD 142893, an antagonist of ET(A)-ET(B) receptors, were also evaluated. GK activity, cyclic guanosine monophosphate (cGMP), and glycogen intracellular content were measured on isolated hepatocytes, while glucose levels and NO as NO2-/NO3- were determined in the medium. High ET-1 levels induced a 20% decrease of NO2-/NO3- levels and cGMP intracellular content, followed by a 49% reduction of GK activity and a 15% decrease of glycogen. In parallel, a 10% increase of glucose in the medium was observed. In the presence of L- NAME, GK activity and glycogen levels showed analogous decrements as observed with ET-1. Also in this case, a significant decrease of the intracellular content of cGMP was observed. No synergistic effects of ET-1 and L-NAME were observed. L-Arginine was able to counteract the inhibitory effect of ET-1 on cGMP and GK activity. Glycogen content was slightly but not significantly reduced, and under those conditions, a significant decrease of glucose in the medium was observed. When hepatocytes were incubated with ET-1 plus BQ 788 or ET-1 plus PD 142893, GK activity was unchanged. Interestingly, no changes were observed in NO2-/NO3- levels and the intracellular content of cGMP was not modified when the antagonists of ET-1 receptors were added to the medium. In conclusion, the present study shows that the NO pathway seems to be an important regulator of GK activity and glycogen content through cGMP activity. In addition, ET-1 seems to be not active per se, but its activity seems mediated by a simultaneous decrease of NO levels

Relationship between endothelin-1 concentration and metabolic alterations typical of the insulin resistance syndrome

The purpose of the study was to examine the relationship between the endothelin-1 (ET-1) concentration and the metabolic variables characteristic of the insulin resistance syndrome ([IRS] hyperinsulinemia, insulin resistance, hypertriglyceridemia, low high-density lipoprotein [HDL] cholesterol, visceral obesity, and glycemic abnormalities). The measurement of circulating ET-1 is a well-recognized marker of endothelial atherosclerotic and cardiovascular disease. Two hundred subjects were divided into 3 groups. Group 1 included 50 subjects with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) with IRS. Group 2 included 50 subjects with IGT or NIDDM without IRS. Group 3 included 100 normal subjects as controls. ET-1 levels were higher in group 1 versus groups 2 and 3 in women (11.2 \ub1 0.7 v 7.9 \ub1 0.5 and 6.6 \ub1 0.4 pg/mL, P < .01) and men (10.1 \ub1 0.6 v 6.5 \ub1 0.8 and 7.2 \ub1 0.3 pg/mL, P < .01). No differences were found between groups 2 and 3. With simple regression analysis, ET-1 levels significantly correlated with insulin, glycosylated hemoglobin, body weight, waist to hip ratio, and triglyceride values. However, with multiple regression analysis, only triglycerides (P < .009) and glycosylated hemoglobin (P < .001) remained independently correlated with ET-1. In conclusion, this cross-sectional study indicates that glycosylated hemoglobin and triglycerides are independently correlated with ET-1 levels in patients with IRS. Copyright (C) 2000 by W.B. Saunders Company

L-Arginine enriched biscuits improve endothelial function and glucose metabolism : a pilot study in healthy subjects and a cross-over study in subjects with impaired glucose tolerance and metabolic syndrome

Objective. The aim of this study was to evaluate the effects of a new L-rginine-enriched biscuit on endothelial function, insulin sensitivity/secretion and body composition. Materials/Methods. The project was composed of two studies. The first study was an acute pilot postprandial study in 7 healthy subjects that evaluated bio-availability and vascular effects of L-arginine-enriched biscuits that contained 6.6gL-arginine, 21.9g carbohydrates, 3.6g protein, 7.5g fat and 4.3g dietary fiber compared with placebo biscuits and 6.6g powdered L-arginine. Subjects underwent the tests in random order, in at least 14-day intervals. The second study was a double-blind crossover study in 15 obese subjects with IGT and MS. These subjects consumed 6.6g of L-arginine-enriched biscuits or placebo biscuits in a 1600kcal diet. Each study period lasted 2weeks with a 2-week washout in between.Endothelial function, glucose tolerance, insulin sensitivity and insulin secretion were evaluated at the end of each intervention period. Results. In the first study, the groups that received the L-arginine-enriched biscuits and the powdered L-arginine had similarly increased L-arginine, NOx and cGMP levels and postischemic blood flow (PI-BF). In both cases, these levels were significantly higher than those in the placebo biscuit recipient group. In the second study, the L-arginine-enriched biscuit recipient group displayed increased L-arginine, NOx, cGMP, PI-BF, and Matsuda index levels, whereas their circulating glucose, proinsulin/insulin ratio and fat mass were decreased compared with the placebo biscuit recipient group. Conclusions. L-Arginine-enriched biscuits with low sugar and protein content enhance endothelial function and improve glucose metabolism, insulin sensitivity and insulin secretion in subjects with IGT and MS

Hyperinsulinemia decreases second-phase but not first-phase arginine-induced insulin release in humans

The aim of this study was to investigate the effect of hyperinsulinemia on the first and second phase of arginine-induced insulin release in humans. Seven healthy subjects underwent three studies (lasting 360 min): a control study using saline infusion and two euglycemic clamps using a low-dose (0.33 mU.kg-1.min-1) and a high-dose (1.20 mU.kg-1.min-1) insulin infusion. After a 3-h equilibration period, arginine (25 g) was infused for 30 min, and insulin and C-peptide responses to arginine were followed for 180 min. At the end of the equilibration period, before arginine administration, steady-state insulin levels were (means +/- SE) 60.0 +/- 2.4, 165.6 +/- 1.8, and 455.4 +/- 7.8 pmol/l during saline, low-dose, and high-dose insulin infusions, respectively. The time course of insulin release during the arginine test was calculated from C-peptide concentrations by using C-peptide kinetic modeling and deconvolution. In particular, first-phase and second-phase insulin response was obtained by integrating the time course of the insulin release during either the first 5 min or the following 40 min of the arginine test, respectively. Whereas first-phase insulin release was independent of any effect induced by either insulin infusion, second-phase insulin release was reduced in a similar degree by both insulin infusion doses. First phase was 75.5 +/- 10.1, 73.7 +/- 12.8, and 73.4 +/- 10.3 pmol/kg, whereas second phase was 266.1 +/- 46.0, 143.1 +/- 33.5, and 133.0 +/- 30.2 pmol/kg for saline, low-dose, and high-dose insulin infusions, respectively.(ABSTRACT TRUNCATED AT 250 WORDS

Insulin sensitivity and lipid levels in obese subjects after slimming diets with different complex and simple carbohydrate content

The ideal hypocaloric diet should reduce body weight, decrease fat more than muscle tissue, and ameliorate insulin sensitivity and lipid levels. The aim of this study was to investigate the effect of three hypocaloric diets with different carbohydrate (CHO) and fat contents on body weight reduction, insulin release and sensitivity, and lipid levels in patients with simple obesity. Twenty-five obese subjects with normal glucose tolerance were randomly allocated to three hypocaloric (800 kcal) diets containing: 60% high complex/high starch and fibre (HC/HSF-CHO) and 20% fat (group 1;11 subjects); 60% high simple/high natural fibre (HS/HNF-CHO) and 20% fat (group 2; 7 subjects); or 20% CHO (L-CHO) and 60% fat (group 3; 7 subjects). The remaining 20% of the diet was protein. In all cases the duration of the diet was 21 days. Before and after the diet, seven subjects from each group underwent a hyperglycemic clamp, and the other four subjects of group 1 underwent a euglycemic-hyperinsulinemic clamp, combined with a glucose turnover study. A similar decrease in body weight, fat-free mass, fat mass, total cholesterol, LDL cholesterol and apo B levels was observed in the three groups. The M/I ratio during hyperglycemic and euglycemic-hyperinsulinemic clamp and the glucose turnover rate during euglycemic-hyperinsulinemic clamp significantly decreased, and FFA levels significantly increased only after the HC/HSF-CHO diet. HDL cholesterol and apo A1 significantly increased only during the HS/HNF-CHO diet. In conclusion, all hypocaloric diets with different CHO and fat contents can decrease body weight, total cholesterol, LDL cholesterol, and apo B levels; a hypocaloric diet with a HC/HSF-CHO content induces a state of insulin resistance probably mediated by the increased FFA levels; and a hypocaloric diet with HS/HNF-CHO content does not worsen insulin sensitivity, and increases cholesterol and apo A1 levels

The continuous low dose insulin and glucose infusion test : a simplified and accurate method for the evaluation of insulin sensitivity and insulin secretion in population studies

In this study we investigated a simple nonlabor-intensive method to evaluate insulin sensitivity and beta-cell function which is suitable for application in population studies. The method is a refinement of the modified Harano test and consists of a continuous low dose insulin (25 mU/kg.h) and glucose (4 mg/kg.min) infusion test (LDIGIT) lasting 150 min. Insulin sensitivity was evaluated as the MCR of glucose divided by the steady state serum insulin level achieved at the end of the test. Insulin secretion was expressed as the incremental area for C-peptide concentration during the first 15 min of the test. We compared the indices of insulin sensitivity and insulin secretion yielded by LDIGIT with those derived from the euglycemic clamp and the hyperglycemic clamp, respectively. Fifty-four subjects underwent a LDIGIT (33 with normal glucose tolerance and 21 with impaired glucose tolerance); of the 54, 19 were submitted to a euglycemic clamp, 18 to a hyperglycemic clamp, and 10 to a modified Harano test (insulin infusion, 50 mU/kg.h; glucose infusion, 6 mg/kg.min). LDIGIT overcame the drawbacks associated with the modified Harano test because it resulted in more stable final glucose levels and prevented the occurrence of hypoglycemic episodes. No significant differences were found between the insulin sensitivity index (ISI) of the LDIGIT and that of the euglycemic clamp for each group of subjects. Moreover, there was a strong correlation between the ISI determined by LDIGIT and the ISI determined by clamp (r = 0.90; P < 0.0001), and the best regression line was not different from the identity line, suggesting that the two indices are equivalent. The index of insulin secretion provided by LDIGIT correlated well with that of the hyperglycemic clamp (r = 0.82; P < 0.001) and was significantly higher in overweight subjects than in normal weight subjects. In conclusion, LDIGIT is a simple and accurate method to assess insulin sensitivity and secretion. It can be useful in population studies and in situations when more complex techniques are not feasible