The effect of glibenclamide treatment on insulin-mediated glucose disposal was studied in eight C-peptide-negative type I diabetic patients. The patients were studied twice by the euglycemic insulin clamp technique. One of the two experiments was preceded by glibenclamide treatment at the dose of 5 mg, three times daily for 15 days; half of the patients had the first test before and the second test after sulfonylurea treatment, and vice versa. Insulin was infused for four periods of 2 h each sequentially at 0.5, 1.0, 2.0, and 5.0 mU kg-1 min-1; for each insulin infusion period, the steady state plasma free insulin levels were comparable with or without glibenclamide. The mean +/- SEM plasma glucose concentration was 88 +/- 2 mg/dl in both experiments. The insulin-mediated glucose disposal rate was greater with glibenclamide during the first insulin infusion period (which generated plasma free insulin levels within the physiological range) 2.68 +/- 0.32 mg kg-1 min-1 with glibenclamide vs. 1.97 +/- 0.20 mg kg-1 min-1 without glibenclamide (P less than 0.005). However, glucose disposal rates did not differ in the diabetic patients with or without glibenclamide treatment during the second, third, and fourth insulin infusion periods, which generated plasma free insulin levels in the supraphysiological range. These results provide evidence for an extrapancreatic effect of glibenclamide at low insulin concentrations during euglycemic clamping in patients with insulin-dependent diabetes mellitus. However, this effect was not reflected clinically in either an increased rate of hypoglycemic reactions or decreased insulin needs during the short term period of treatment.

In vivo sensitivity to insulin was assessed by the euglycaemic insulin clamp technique in 5 type I diabetic subjects without residual insulin secretion and in 5 non-diabetic control subjects. Insulin was infused at increasing rates of 0.5, 1.0, 2.0 and 5.0 mU/kg/min in 4 periods of 2 hours. The diabetic subjects were resistant to insulin during the 1st and 2nd insulin infusion periods corresponding to the rates of 0.5 and 1.0 mU/kg/min, when compared to the non-diabetic subjects. However, glucose disposal rates were similar in the diabetic and control subjects at the 2 higher insulin infusion rates (2.0 and 5.0 mU/kg/min). Thus insulin resistance in type I diabetes is dependent on insulin concentration.