THE EFFECT OF SULFONYLUREA THERAPY ON SKELETAL-MUSCLE GLYCOGEN-SYNTHASE ACTIVITY AND INSULIN-SECRETION IN NEWLY PRESENTING TYPE-2 (NON-INSULIN-DEPENDENT) DIABETIC-PATIENTS

Ten newly presenting, Type 2 (non-insulin-dependent), Caucasian diabetic patients were studied before and after 8 weeks treatment with the sulphonylurea gliclazide, and in parallel 13 similar patients were studied before and after 8 weeks treatment with diet alone. Eight non-diabetic subjects were also studied. Insulin action was assessed by measuring activation of skeletal muscle glycogen synthase (GS) prior to and during a 4-h hyperinsulinaemic euglycaemic clamp (100 mU kg-1 h-1). Fasting plasma glucose (+/- SE) and glycosylated haemoglobin decreased to a greater extent in the gliclazide treated patients (fall of 6.2 +/- 0.7 vs 2.1 +/- 0.5 mmol l-1, p < 0.005 and 4.7 +/- 0.5 vs 2.1 +/- 0.5%, p < 0.005). This was accompanied by an increase in fasting serum insulin concentrations in the gliclazide treated patients (7.0 +/- 1.3 to 10.1 +/- 1.1 mU l-1, p < 0.005), but no change in the diet treated patients. Fractional GS activity did not increase during the clamp at presentation in either treatment group (change + 2.9 +/- 1.8 and -1.5 +/- 1.9%, respectively) whereas it increased markedly in the control subjects (+16.4 +/- 3.4%, both p < 0.001). After 8-week treatment there was a significant increase in GS activity during the clamp in the patients receiving gliclazide (+6.9 +/- 2.7%, p < 0.05), but no change in GS activity in the patients on diet alone (+0.5 +/- 1.4%). The difference in post-treatment muscle insulin action was significant (p < 0.05). There was no correlation between the degree of improvement in metabolic control and the improvement in response of GS to insulin in the gliclazide treated patients (r = - 0.06), suggesting a possible direct drug effect on skeletal muscle. Glucose requirement during the clamp at presentation was markedly lower in both treatment groups than in the non-diabetic subjects (gliclazide 2.1 +/- 0.3, diet 2.0 +/- 0.6 vs 7.8 +/- 0.4 mg kg-1 min-1, both p < 0.001), and despite a marked improvement in both groups after treatment (4.3 +/- 0.4 and 3.1 +/- 0.5 mg kg-1 min-1, both p < 0.001) remained lower than in the non-diabetic subjects (p < 0.001). The improvement in glucose requirement was greater in the gliclazide treated patients (2.3 +/- 0.4 vs 1.1 +/- 0.3 mg kg-1 min-1, p < 0.01). Insulin secretion following an intravenous bolus of glucose (0.5 g kg-1) was measured at euglycaemia pre- and post-treatment. At presentation, first phase insulin responses were markedly decreased (2 +/- 1 and 1 +/- 1 mU l-1, respectively) compared with the non-diabetic subjects (53 +/- 9 mU l-1, both p < 0.001), and following treatment improved only in the gliclazide treated patients (17 +/- 3 vs 2 +/- 3 mU l-1, p < 0.005). The second phase responses, however, improved to a similar extent in both groups (168 +/- 122 to 449 +/- 153 mU l-1 min, and 148 +/- 129 to 459 +/- 153 mU l-1 min, respectively) and were then not significantly different to the control subjects (781 +/- 207 mU l-1 min). Thus the improved blood glucose control in the gliclazide treated Type 2 patients is likely to result from both increased insulin action and increased insulin secretion. Furthermore gliclazide may enhance insulin-stimulated glucose metabolism by potentiating insulin action on skeletal muscle GS.