The Molecular Genetics of Sulfonylurea Receptors in the Pathogenesis and Treatment of Insulin Secretory Disorders and Type 2 Diabetes

Abstract

Sulfonylurea receptors (SURs) form an integral part of the ATP-sensitive potassium (K(ATP)) channel complex that is present in most excitable cell types. K(ATP) channels couple cellular metabolism to electrical activity and provide a wide range of cellular functions including stimulus secretion coupling in pancreatic β cells. K(ATP) channels are composed of SURs and inward rectifier potassium channel (Kir6.x) subunits encoded by the ABCC8/9 and KCNJ8/11 genes, respectively. Recent advances in the genetics, molecular biology, and pharmacology of SURs have led to an increased understanding of these channels in the etiology and treatment of rare genetic insulin secretory disorders. Furthermore, common genetic variants in these genes are associated with an increased risk for type 2 diabetes. In this review we summarize the molecular biology, pharmacology, and physiology of SURs and K(ATP) channels, highlighting recent advances in their genetics and understanding of rare insulin secretory disorders and susceptibility to type 2 diabetes.

Targeting beta-cell preservation in the management of type 2 diabetes

“…79 Sulphonylureas Sulphonylureas stimulate insulin secretion by inhibiting the ATP-sensitive potassium channel which, following beta-cell depolarisation, results in exocytosis of insulin-containing granules. 80 Some sulphonylureas -but not others -have been shown to acutely increase the first-phase insulin response to glucose in hyperglycaemic clamp studies in individuals with T2D. 81,82 In vitro studies of isolated human islets suggest that prolonged use of sulphonylureas may be toxic to beta-cells by inducing betacell apoptosis and loss of beta-cell mass.…”

Abordagem de Bioinformática e Biologia de Sistemas para Identificar a Ligação Patogenética entre Insuficiência Cardíaca e Sarcopenia

“…KCNJ8 has been linked with cardiovascular disorders, including abnormal coronary vasomotion and microvascular dysfunction, ischemic heart disease, and type 2 diabetes. 27 - 29 PIK3R5 is involved in many cellular processes, including growth, proliferation, differentiation, motility, intracellular trafficking, and survival. It has also been proposed as a biomarker for hypertension and diabetes mellitus.…”

Research progress of type 2 diabetes mellitus in adolescents

“…First and foremost, Glimepiride, a sulfonylurea drug, belonging first line drugs for type 2 diabetes. The main mechanism of it is to stimulate insulin release through binding β Sulfonylurea receptors on the cell surface [8]. In addition, it also reduces the metabolism of insulin, enhances the sensitivity of target cells to insulin and improves the binding ability of insulin and its receptor.…”