Improvement of insulin sensitivity by metformin treatment does not lower blood pressure of nonobese insulin-resistant hypertensive patients with normal glucose tolerance.

Nine hypertensive patients with body mass indexes between 24-27 kg/m2 and normal glucose tolerance with at least a postchallenge plasma insulin level greater than 360 pmol/L were recruited for a double blind, cross-over study with metformin (850 mg, twice daily) and placebo. Each treatment lasted 1 month. Before and after each treatment, hormone and substrate concentrations were determined, blood pressure was monitored over 24 h, and insulin sensitivity was measured by a euglycemic (4.7 mmol/L) hyperinsulinemic (450 pmol/L) clamp study. Renal cation excretion and erythrocyte membrane cation heteroexchange were measured. Metformin, compared to placebo, did not affect body weight (70 +/- 7 vs. 70 +/- 7 kg), fasting plasma glucose (4.8 +/- 0.1 vs. 4.8 +/- 0.1 mmol/L), total cholesterol (5.38+/0.33 vs. 5.48 +/- 0.38 mmol/L), or triglycerides (1.73 +/- 0.72 vs. 1.91 0.89 mmol/L). Nevertheless, after metformin treatment, the plasma high density lipoprotein cholesterol concentration increased (1.42 +/- 0.18 vs. 1.34 0.16 mmol/L), and the plasma insulin level dropped (62 +/- 10 vs. 88+/- 12 pmol/L; both P < 0.05). Insulin-mediated glucose disposal was higher after metformin treatment (26.1 +/- 2.4 vs. 19.3 +/- 2.3 micromol/min x kg; P < 0.01), whereas hepatic glucose production was completely suppressed. These positive metformin-induced metabolic effects were not associated with a significant change in mean daily blood pressure levels (141 +/- 6/89 +/- 3 vs. 142 +/- 7/90 +/- 3 mm Hg). Compared to placebo, metformin increased the excretion of sodium, potassium, and lithium by enhancing their glomerular filtration rate. Na+/Li+ countertransport was not affected by metformin. However, the apparent affinity for H+ of Na+/H+ exchange was increased, and the Hill coefficient was decreased. In conclusion, 1 month of metformin administration to patients with essential hypertension and normal glucose tolerance 1) reduces the basal plasma insulin concentration, 2) improves whole body insulin-mediated glucose utilization, and 3) improves plasma high density lipoprotein cholesterol levels. Despite these positive effects, metformin did not reduce arterial blood pressure.

Basal plasma insulin levels exert a qualitative but not quantitative effect on glucose-mediated glucose uptake.

UNLABELLED: We assessed the effect of hyperglycemia on glucose uptake in the presence of normal basal insulin levels or somatostatin-induced hypoinsulinemia in seven normal volunteers during a 200-min hyperglycemic clamp (+ 9 mmol/l) carried out with [3-3H]glucose and indirect calorimetry. Hyperglycemia increased glucose uptake to 22.4 +/- 2.6 and 21.3 +/- 1.6 mumol.kg-1.min-1 with and without insulin replacement, respectively. Normoinsulinemia increased glucose oxidation (delta = + 4.5 +/- 0.6 mumol.kg-1.min-1) and nonoxidative glucose metabolism (delta = + 5.2 +/- 1.7 mumol.kg-1.min-1), whereas with insulinopenia, glucose oxidation did not change (delta = -0.3 +/- 0.6 mumol.kg-1.min-1), and nonoxidative glucose metabolism increased (delta = + 48.7 +/- 0.8 mumol.kg-1.min-1). Nonoxidative glucose metabolism was higher during insulinopenic (13.5 +/- 1.8 mumol.kg-1.min-1) than normoinsulinemic hyperglycemia (9.8 +/- 2.7 mumol.kg-1.min-1; P < 0.01). Plasma FFA concentration and lipid oxidation were higher with insulinopenia. Blood lactate and alanine concentrations were greater with normoinsulinemia. IN CONCLUSION: 1) hyperglycemia promotes glucose uptake by stimulating both nonoxidative and oxidative glucose disposal; 2) the ability of hyperglycemia to enhance total body glucose uptake is similar with and without normoinsulinemia; 3) although acute insulinopenia does not impair the ability of hyperglycemia to stimulate glucose uptake, it plays a critical role in determining the intracellular metabolic fate of glucose taken up in response to hyperglycemia.

Surgical removal of insulinoma restores glucose recovery from hypoglycaemia but does not normalize insulin action.

In the present study we have evaluated the effects of chronic hyperinsulinaemia secondary to insulinoma, on insulin sensitivity and on counter-regulatory responses to hypoglycaemia. We studied six patients (M/F = 3/3; age = 40 +/- years), before and 6-9 months after surgical ablation of the neoplasia, by means of an euglycaemic-hyperinsulinaemic clamp (1 mU kg-1 min-1). Seven normal subjects (M/F = 4/3; age = 38 +/- 6 years) underwent the same experimental study as the control subjects. In insulinoma patients after 100 min of the euglycaemic-hyperinsulinaemic clamp, glycaemia was allowed to drop to a minimum value of 1.9 mmol L-1, and recovery evaluated after interrupting insulin infusion. During the entire study, 3-3H-glucose was infused to determine hepatic glucose production and glucose utilization. Surgical removal of the pancreatic adenoma was followed by a reduction in body weight (BMI = 25.7 +/- 1.9 vs. 23.0 +/- 1.6 kg m-2; P < 0.05), normalization of fasting plasma levels of glucose (2.94 +/- 0.16 vs. 4.83 +/- 0.11 mmol L-1), insulin (162 +/- 24 vs. 48 +/- 12 pmol L-1) and of basal hepatic glucose production (7.6 +/- 0.7 vs. 12.2 +/- 1.11 mumol kg-1 min-1). Before the operation, insulin-mediated glucose disposal was significantly lower than in the controls (30.8 +/- 3.1 vs. 49.1 +/- 3.1 mumol kg-1 min-1). Six to nine months after surgical removal of the adenoma, glucose utilization was unchanged (30.5 +/- 3.3 mumol kg-1 min-1) and still significantly lower than in controls (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism(s) of the blood glucose lowering action of benfluorex.

Benfluorex is a hypolipidaemic agent with biguanide-like properties. To evaluate its blood glucose lowering action, a single-blind study protocol was designed. Two groups of seven type II (non-insulin-dependent) diabetic patients matched for age (50 +/- 4 vs. 53 +/- 1 years), sex, body mass index (27.8 +/- 0.6 vs. 26.5 +/- 0.7 kg/m2), and duration of diabetes were studied before and after 1 month of treatment with benfluorex 150 mg tid (= tres in die = three times a day), PO (= per os = by mouth) or a placebo, respectively. All patients had previously been treated by diet alone. In all patients, parameters of glucose and lipid metabolism were obtained. Insulin sensitivity was assessed by means of a euglycaemic (5.1 +/- 0.1 mM) hyperinsulinaemic (516 +/- 28 pM) clamp performed in combination with [3(-3)H]glucose infusion and indirect calorimetry. In no case was there a significant change in body mass index (27.6 +/- 0.5 vs. 26.4 +/- 0.7 kg/m2). After 1 month of treatment, fasting plasma glucose (6.8 +/- 0.2 vs. 8.1 +/- 0.6 mM) and HbA1C (glycated haemoglobin; 6.5 +/- 0.2 vs. 8.0 +/- 0.7%) were lower in the benfluorex group than in the placebo-treated patients (both p < 0.05). No change was observed in hepatic glucose production (HGP) (13.5 +/- 1.4 vs. 13.9 +/- 1.1 mumol/min per kg), the basal rate of glucose, and lipid oxidation and non-oxidative glucose metabolism, or in plasma triglyceride and total cholesterol concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of fasting hypoglycemia and concomitant insulin resistance in insulinoma patients.

To gain further insight into the pathogenesis of fasting hypoglycemia in patients with insulin-secreting adenoma of the pancreas, we studied seven patients affected by insulinoma (age, 42 +/- 7 years; body mass index [BMI], 27 +/- 2 kg/m2) and seven normal subjects. In insulinoma patients, hepatic glucose production (HGP) and glucose utilization (Rd) were evaluated by infusion of 3-3H-glucose at spontaneous fasting plasma glucose concentration, after restoration of euglycemia and during euglycemic insulin clamp (40 mU/m2/min). In insulinoma patients, fasting plasma glucose concentration (2.8 +/- 0.2 v 4.5 +/- 0.1 mmol/L; P < .001), HGP, and glucose Rd (7.8 +/- 1.1 v 12.0 +/- 0.3 mumol/kg/min; P < .01) were lower than in normal subjects, while plasma insulin level was higher (138 +/- 19 v 38 +/- 3 pmol/L; P < .001). In insulinoma patients after attainment of euglycemia (4.7 +/- 0.2 mmol/L) by exogenous glucose infusion, insulin level increased slightly (174 +/- 18 pmol/L; P < .01) and glucose Rd was similar to that of normal individuals (12.8 +/- 0.6 v 12.0 +/- 0.3 mumol/kg/min). During the clamp studies, glucose Rd was lower in insulinoma patients (18.7 +/- 1.2 v 33.8 +/- 3.1 mumol/kg/min; P < .01) despite higher plasma insulin concentration (612 +/- 48 v 420 +/- 12 pmol/L). Therefore, glucose Rd/I x 100 ratio (where I is plasma insulin concentration) was much lower in insulinoma patients (3.1 +/- 0.9 v 8.0 +/- 0.7; P < .01), suggesting a marked degree of insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

[Mechanisms of hypoglycemic action of benfluorex]. / Mécanismes de l'action hypoglycémiante du benfluorex.

UNLABELLED: Benfluorex is a hypolipidemic agent with biguanide-like properties. Its action on glucose metabolism was evaluated in 6 NIDDM patients previously treated with diet alone. Before and after 1 month of benfluorex therapy (450 mg/day p.o.), an euglycemic (100 mg/dl) insulin (40 mU/m2/min) clamp was performed along with 3-3H-glucose infusion and indirect calorimetry. Benfluorex did not affect body weight, while it reduced fasting plasma glucose (144 +/- 16 vs 119 +/- 8 mg/dl; P < 0.05), glycosylated hemoglobin (6.8 +/- 0.8 vs 6.4 +/- 0.4 percent) and fructosamine (2.9 +/- 0.6 vs 2.4 +/- 0.2 mmol/l; P < 0.05). Both triglycerides (2.3 +/- 0.6 vs 1.9 +/- 0.5 mmol/l) and total cholesterol (5.7 +/- 0.7 vs 5.2 +/- 0.6 mmol/l) declined. No changes occurred in plasma fatty acid, insulin, and C-peptide. Basal hepatic glucose production did not change and it was completely suppressed during the clamp studies both before and after benfluorex. Basal oxidation rates of carbohydrates and lipids did not change significantly. During the insulin clamp study, insulin-mediated glucose disposal increased after benfluorex (5.7 +/- 0.3 vs 4.8 +/- 0.2 mg/kg/min; P < 0.01). Lipid oxidation was equally suppressed before and after therapy with benfluorex. Glucose oxidation was not enhanced after benfluorex while non-oxidative glucose metabolism was significantly improved (2.2 +/- 0.7 vs 3.4 +/- 0.4 mg/kg/min; P < 0.05). CONCLUSION: short-term benfluorex administration a) improves glucose and lipid control, b) improves insulin action by enhancing non-oxidative glucose metabolism, c) does not affect basal insulin secretion. The long-term effect of benfluorex treatment remains to be evaluated.

Effect of dietary monounsaturated and polyunsaturated fatty acids on the susceptibility of plasma low density lipoproteins to oxidative modification.

Oxidized low density lipoproteins (LDLs) are thought to play an important role in atherogenesis. Nutritional and biochemical studies suggest that diet can modulate the susceptibility of plasma LDL to undergo oxidative degradation by affecting the concentration of polyunsaturated fatty acids and antioxidants in the lipoprotein particle. In the present study 11 healthy male volunteers underwent two diet phases. In one phase the diet was enriched in oleic acid (mono), while in the other it was high in linoleic acid (poly). Both diets lowered plasma total and LDL cholesterol contents. The sensitivity of plasma LDL to oxidation was estimated by challenging these lipoproteins with 2,2'-azobis(2-amidinopropane)dihydrochloride, a free-radical initiator. Although neither diet affected the antioxidant content of plasma LDL, the resistance to lipid peroxidation, measured after the consumption of antioxidants present in the lipoprotein, was higher during the mono phase. Indeed, the peroxidation rate of plasma LDL was inversely correlated with the oleic acid to linoleic acid ratio in the LDL particle. These results support the thesis that diets rich in monounsaturated fatty acids increase the resistance of plasma LDL to oxidative modification, independent of their content of antioxidants. This effect could lower the atherogenicity of these lipoproteins.

Sodium metabolism in insulin dependent diabetic patients. Role of insulin and atrial natriuretic peptide.

Acute insulin administration shows an antinatriuretic effect in normal man. Thus it can be postulated that insulin therapy resulting in circulating hyperinsulinemia can lead to sodium retention and in turn to hypertension in insulin dependent diabetes. Moreover it has been proved that atrial natriuretic peptide (ANP) plays a major role in modulating natriuresis in man. The aim of the present study was to investigate the relationship between insulin and ANP in modulating sodium metabolism in seven insulin dependent diabetic patients in comparison with eight normal control subjects at baseline and during a saline infusion (2 mmol/kg/90 min) at euglycemic blood levels. Diabetics received a subcutaneous insulin infusion (0.015 U/kg/hr) resulting in a two fold higher plasma free insulin levels (16 +/- 2 microU/ml) than in control subjects (7 +/- 2 microU/ml). During saline challenge sodium excretion rate increased by 29 +/- 6% in control patients and only by 6 +/- 0.7% in diabetic patients (p less than 0.01). At baseline ANP plasma concentrations were significantly higher in diabetic patients than in control subjects (diabetics = 37 +/- 8 pg/ml and controls = 21 +/- 3 (p less than 0.01). After saline challenge ANP concentration rose to 71 +/- 9 pg/ml in control subjects, whereas no significant change above baseline values was shown by diabetic patients.