Contribution of obesity to insulin resistance in noninsulin-dependent diabetes mellitus.

Inasmuch as previous studies have obtained conflicting results on the contribution of obesity to insulin resistance in noninsulin-dependent diabetes mellitus (NIDDM), we studied 10 nonobese and 10 obese NIDDM patients with the isoglycemic-(approximately 10 mmol/L)-hyperinsulinemic clamp (two insulin infusions of 4 and 40 mU/m-2 min-1), combined with [3-3H]glucose infusion and indirect calorimetry. As compared with nonobese patients, obese NIDDM patients had higher baseline peripheral and estimated portal plasma insulin concentrations (113 +/- 18 vs. 46 +/- 3 pmol/L and 288 +/- 53 vs. 98 +/- 6 pmol/L, respectively; P < 0.05) and less suppressed endogenous insulin production during clamp. Hepatic glucose production was greater in obese than in nonobese patients (basal, 16 +/- 1.1 vs. 12 +/- 0.5 mumol/kg-1 fat-free mass (FFM) min-1; clamp, 5.7 +/- 0.5 vs. 2.8 +/- 0.2 mumol/kg-1 FFM min-1, P < 0.05). Glucose utilization increased to a lesser extent in obese than in nonobese patients (49 +/- 5 vs. 73 +/- 7 mumol/kg-1 FFM min-1, P < 0.05) during clamp because of a lower increase in nonoxidative glucose metabolism (30 +/- 5 vs. 50 +/- 7 mumol/kg-1 FFM min-1, P < 0.05). Plasma free fatty acid concentrations and rates of lipid oxidation were greater in obese (P < 0.05) patients and correlated with hepatic glucose production (r = 0.79 and 0.50, P < 0.05). In conclusion, obesity exaggerates hepatic as well as extra-hepatic insulin resistance in NIDDM. The impaired inhibition of pancreatic beta-cell function by exogenous insulin contributes to exaggerated hyperinsulinemia in obese NIDDM.

Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production.

To establish the antihyperglycemic mechanisms of metformin in non-insulin-dependent diabetes mellitus (NIDDM) independently of the long-term, aspecific effects of removal of glucotoxicity, 21 NIDDM subjects (14 obese, 7 nonobese) were studied on two separate occasions, with an isoglycemic (plasma glucose approximately 9 mM) hyperinsulinemic (two-step insulin infusion, 2 h each, at the rate of 4 and 40 mU.m-2.min-1) clamp combined with [3-3H]glucose infusion and indirect calorimetry, after administration of either metformin (500 mg per os, at -5 and -1 h before the clamp) or placebo. Compared with placebo, hepatic glucose production (HGP) decreased approximately 30% more after metformin (from 469 +/- 50 to 330 +/- 54 mumol/min), but glucose uptake did not increase. Metformin suppressed free fatty acids (FFAs) by approximately 17% (from 0.42 +/- 0.04 to 0.35 +/- 0.04 mM) and lipid oxidation by approximately 25% (from 4.5 +/- 0.4 to 3.4 +/- 0.4 mumol.kg-1.min-1) and increased glucose oxidation by approximately 16% (from 16.2 +/- 1.4 to 19.3 +/- 1.3 mumol.kg-1.min-1) compared with placebo (P < 0.05), but did not affect nonoxidative glucose metabolism, protein oxidation, or total energy expenditure. Suppression of FFA and lipid oxidation after metformin correlated with suppression of HGP (r = 0.70 and r = 0.51, P < 0.001). The effects of metformin in obese and nonobese subjects were no different. We conclude that the specific, antihyperglycemic effects of metformin in the clinical condition of hyperglycemia in NIDDM are primarily due to suppression of HGP, not stimulation of glucose uptake, and are mediated, at least in part, by suppression of FFA and lipid oxidation.

A simple clinical approach to discriminate between "true" and "pseudo" secondary failure to oral hypoglycaemic agents.

To discriminate between true secondary failure (TF) and pseudo-secondary failure (PF) to oral hypoglycaemic agents, we studied 34 non-obese non-insulin-dependent diabetic patients who were being treated with these drugs. Nine were in good control (GC) with oral treatment, while 25 showed apparent SF. During a controlled hospital diet, fasting blood glucose remained persistently high in 15 of these patients (TF), while in the other 10 patients it clearly improved (PF). Fasting plasma glucose (FPG) and HbA1c were higher and body mass index (BMI) was lower in TF patients than in PF patients (P less than 0.01). C-peptide concentrations differed significantly among the three groups both in the fasting state (TF 0.25 +/- 0.02 nmol/l, PF 0.70 +/- 0.03 nmol/l, GC 0.74 +/- 0.03 nmol/l; P less than 0.0001) and 6 min after glucagon injection (TF 0.50 +/- 0.04 nmol/l, PF 1.02 +/- 0.06 nmol/l, GC 1.14 +/- 0.07 nmol/l; P less than 0.0001). C-peptide and plasma insulin curves obtained after a standard mixed meal also showed significant differences (P less than 0.001). In particular, there was a statistically significant difference between GC and PF versus TF (P less than 0.05), while there was no statistical difference between PF and GC. We conclude that some patients with apparent SF can improve their metabolic control if they strictly adhere to a correct diet (PF); a single measurement of basal C-peptide concentration or examination of the C-peptide and insulin responses to a meal are useful indicators for distinguishing patients with PF from those with TF to oral hypoglycaemic agents.(ABSTRACT TRUNCATED AT 250 WORDS)