Gliclazide Therapy Is Associated with Potentiation of Postbinding Insulin Action in Obese, Non-insulin-dependent Diabetic Subjects GLENN WARD, LEN C. HARRISON, JOSEPH PROIETTO, PATRICIA AITKEN, AND ALISON NANKERVIS SUMMARY Six obese, non-insulin-dependent diabetic subjects were studied before and 3 mo after treatment with the sulfonylurea gliclazide, 40-80 mg b.i.d. Fasting plasma glucose fell significantly from 13.4 ±1 . 6 (SEM) to 8.6 ±1 . 2 mmol/L, accompanied by a significant re- duction from 40.6 ± 3.7 to 29.8 ± 2.8 mM • h of the plasma glucose response to 75 g oral glucose. Fasting plasma insulin showed a nonsignificant increase from 24.8 ± 2.0 to 31.3 ± 2.3 mU/L. The percent specific binding of tracer 125 l-insulin to erythrocytes and mono- cytes did not change significantly (from 9.8 ± 1.7 to 8.5 ± 0.7 for erythrocytes and 1.7 ± 0.3 to 1.6 ± 0.4 for monocytes). Glucose utilization was measured at three levels of insulin infusion (40, 100, and 300 mil/ kg/h) by the euglycemic clamp technique. Overall there was a significant (P < 0.05) increase in the disap- pearance rate (R d ) and metabolic clearance rate (MCR g ) for glucose at the two higher insulin infusion rates (MCR g : 3.3 ± 0.7 to 5.1 ± 0.7 and 5.9 ± 0.9 to 7.9 ± 0.9 ml/kg/min), but not at the lowest infusion rate (MCR g : 3.6 ± 0.8 to 3.3 ± 0.6). Thus, the chronic hypoglycemic effect of gliclazide in obese diabetic subjects was as- sociated with an improvement in insulin-mediated glu- cose utilization at high plasma insulin concentrations. This enhanced effect of insulin after gliclazide treat- ment was not accompanied by increased monocyte or erythrocyte insulin binding, which suggests that it was due to potentiation of postbinding insulin-sensitive pathways. DIABETES 1985; 34:241-45. T here is increasing evidence that sulfonylurea drugs, in addition to their well-studied effect to stimulate insulin secretion, 1 exert long-term hypoglycemic actions that are partly extrapancreatic and related to potentiation of the bioeffects of insulin. 2 " 5 Some studies in vivo 67 have suggested that this extrapancreatic effect is as- sociated with an increase in cellular insulin receptor num- bers, but give no indication whether these receptor changes are a direct or indirect effect of sulfonylureas. Exposure of cultured cells to sulfonylureas has yielded variable results. Recent studies, in vitro, have shown no effect of sulfonylureas on receptor binding 8 - 10 but an enhancement of maximal in- sulin-stimulated glucose uptake 8 and lipogenesis, 9 sug- gesting a direct effect of sulfonylureas on the postbinding pathways of insulin action. We aimed to study, in symptomatic obese, non-insulin- dependent diabetic subjects, the mechanisms of a possible extrapancreatic hypoglycemic action of the sulfonylurea gli- clazide. 11 Erythrocytes and monocytes were used to assess insulin receptor status. To determine if gliclazide therapy was associated with potentiation of insulin action, insulin dose responses were measured in vivo using the euglycemic clamp technique. 12 MATERIALS AND METHODS Informed consent to the study was obtained from six obese, non-insulin-dependent diabetic subjects whose blood sug- ars were inadequately controlled on diet alone. The subjects were five men and one woman aged 53-67 yr and 110- 170% of ideal body weight. Their mean fasting plasma glu- cose concentration before therapy was 13.4 ± 1.6 (SEM) mmol/L. They were commenced on oral gliclazide, in doses ranging from 40 to 80 mg twice daily, depending on the response of their fasting plasma glucose measured every 2 wk, and were instructed not to alter their pattern of food intake. Before and 3 mo after commencing gliclazide the following measurements were made: (1) plasma glucose and insulin both fasting and during a 75-g oral glucose tolerance test (OGTT); (2) insulin receptor binding assays on freshly isolated circulating erythrocytes and monocytes 13 using A14-monoiodoinsulin kindly supplied by Dr. F. Alford (the From the Department of Diabetes and Endocrinology and the University of Melbourne Department of Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia (G.W., L.C.H., J.P.); and the Endocrine Unit and Department of Medicine, University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia (P.A., A.N.). Address reprint requests to Dr. Len C. Harrison, Endocrine Laboratory, The Royal Melbourne Hospital, P.O. 3050, Parkville, Victoria, Australia. Received for publication 4 January 1984 and in revised form 30 August 1984. DIABETES, VOL. 34, MARCH 1985 241 Downloaded from http://diabetesjournals.org/diabetes/article-pdf/34/3/241/353805/34-3-241.pdf by guest on 04 November 2022