Mechanisms of acute and chronic hypoglycemic action of gliclazide.

An extrapancreatic effect of sulfonylureas has been postulated. However, in vivo results have been disputed because the amelioration of insulin action that follows sulfonylurea may represent the relief from glucose toxicity rather than a direct effect of the drug. Therefore, we studied the hypoglycemic action of gliclazide acutely and after 2 months of therapy in seven type 2 diabetic patients. All patients received a 240-minute i.v. glucose infusion with [3-3H]glucose. In a random order, 160 mg gliclazide (study 1) or placebo (study 2) was given orally before glucose infusion. Finally, the effect of 160 mg gliclazide was reassessed after a two-month treatment with the same sulfonylurea (80 mg t.i.d.). Basal plasma glucose, insulin, C-peptide and endogenous glucose production (EGP) were similar before the two initial studies. During glucose infusion, EGP was more suppressed after gliclazide in spite of comparable increase in plasma insulin and C-peptide. After the two-month therapy, basal plasma glucose levels and HbA1c were lower while plasma insulin and C-peptide were higher with respect to baseline (p < 0.05). Gliclazide further reduced plasma glucose, the incremental area above baseline, and EGP during glucose infusion, while plasma insulin and C-peptide achieved higher plateaus (p < 0.05). When data were pooled, plasma glucose concentration and EGP correlated both in the basal state (r = 0.71) and during the last hour of glucose infusion (r = 0.84; both p < 0.05). These data suggest that gliclazide enhances the suppression of EGP induced by insulin and that this effect is greater with chronic treatment because of concomitant improvement of insulin secretion.

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.

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 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.