The Effect of Sulphonylurea Therapy on Skeletal Muscle Glycogen Synthase Activity and Insulin Secretion in Newly Presenting Type 2 (Non‐insulin‐dependent) Diabetic Patients
Authors: Johnson A. B. , Argyraki M. , Thow J. C. , Jones I. R. , Broughton D. , Miller M. , Taylor R. 
Published: July 2009

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.