Extrapancreatic action of the sulphonylurea gliquidone: post-receptor effect on insulin-stimulated glycogen synthesis in rat hepatocytes in primary culture

Abstract

Summary. The effects of a sulphonylurea, gliquidone, on insulin binding and the insulin induced rate of glycogen synthesis, were studied in rat hepatocytes in primary culture. Hepatocytes were cultured for 48 h. During the second 24 h of this period, the hepatocytes were incubated with or without gliquidone (5 mg/1). The binding of 125I-insulin and the insulin stimulation of glycogen synthesis from aac-glucose were measured. Gliquidone influenced neither insulin binding nor the basal rate of glycogen synthesis, but it did enhance the effect of insulin on glycogen synthesis. Responsiveness was increased by gliquidone at all insulin concentrations used (10-10,000 mU/1); at 1000 mU/1 the drug increased glycogen synthesis from 310 to 430% above the basal rate. Half-maximal stimulation was reached in control cells at an insulin concentration of 95 mU/l and in gliquidone-treated cells at 94 mU/1, which indicates unchanged insulin sensitivity. Based on these experiments with cultured rat hepatocytes it appears that the extrapancreatic action of gliquidone is not mediated by an effect on insulin binding.

Effect of Tolazamide on Basal Ketogenesis, Glycogenesis, and Gluconeogenesis in Liver Obtained from Normal and Diabetic Rats*

“…This is in accordance with other reports using cultured normal rat hepatocytes in which either glyburide or gliquidone was added (6,7).…”

“…(Endocrinology 119: [1268][1269][1270][1271][1272][1273]1986) T HE AMELIORATION by sulfonylureas of the disturbed glucose and fatty acid metabolism associated with diabetes is due in part to poorly understood postreceptor cellular mechanisms (1)(2)(3)(4)(5). Numerous in vitro and in vivo investigations have revealed enhanced insulin action in the presence of these drugs, such as the augmentation of hepatic glycogen synthesis (6,7), lipogenesis (8), adipocyte hexose transport (9), and peripheral glucose disposal (10) and the attenuation of hepatic glucose production (11,12). However, if these studies were done under basal, i.e.…”

Augmentation of the effects of insulin and insulin-like growth factors I and II on glucose uptake in cultured rat skeletal muscle cells by sulfonylureas

“…Further in vivo studies have documented increased insulin-stimulated total body glucose utilisation [5,6] and increased insulin-stimulated glucose transport [7]. In addition, in vitro observations have demonstrated sulfonylurea effects in adipocytes [8,91, fibroblasts [10,11], hepatocytes [12,13], IM-9 lymphocytes [10], breast cancer cells [10], and BC3H-1 muscle cells [14]. Although there are discordam results in the literature [15], the weight of experimental evidence indicates that sulfonylureas act in part by increasing sensitivity to insulin in peripheral tissues.…”

“…Although there are discordam results in the literature [15], the weight of experimental evidence indicates that sulfonylureas act in part by increasing sensitivity to insulin in peripheral tissues. Initial studies on the effects of sulfonylureas in peripheral tissues concentrated on possible changes in insulin receptor number [10,11,16,17] but recent attention has focused on post-receptor actions [5,8,12,13].…”

Regulation of muscle fructose 2,6-bisphosphate levels by sulfonylureas.

“…Sulfonylureas have been reported to stimulate glycogenesis and inhibit gluconeogenesis in the liver by itself or by enhancing insulin action (Fleig et al, 1984;Rinninger et al, 1984;Monge et al, 1986). In addition, the drug potentiates insulin-induced recruitment of glucose transport carrier in adipocytes (Jacobs and Jung, 1985) and enhances insulin action on glucose uptake in skeletal muscle (Feldman and Lebovitz, 1969;Daniels and Lewis, 1982).…”