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The Effect of Sulphonylurea Therapy on Skeletal Muscle Glycogen Synthase Activity and Insulin Secretion in Newly Presenting Type 2 (Non‐insulin‐dependent) Diabetic Patients
Author(s) -
Johnson A. B.,
Argyraki M.,
Thow J. C.,
Jones I. R.,
Broughton D.,
Miller M.,
Taylor R.
Publication year - 1991
Publication title -
diabetic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.474
H-Index - 145
eISSN - 1464-5491
pISSN - 0742-3071
DOI - 10.1111/j.1464-5491.1991.tb01580.x
Subject(s) - medicine , gliclazide , endocrinology , insulin , glycogen synthase , diabetes mellitus , glycogen , skeletal muscle
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.