Molecular mechanism of impaired metabolism-secretion coupling in diabetic pancreatic β cells

Abstract

In pancreatic β cells, glucose stimulates insulin secretion according to metabolism-secretion coupling. We investigated the mechanism of impaired glucose-induced insulin secretion from β cells in various conditions. Cytosolic alkalization and a decreased supply of electron donors, including nicotinamide adenine dinucleotide, reduced (NADH), to the respiratory chain due to impaired glycolysis, shuttles, and the Krebs cycle reduce hyperpolarlization of mitochondrial inner membrane and adenosine triphosphate (ATP) production, causing decreased glucose-induced insulin release. Ouabain, a sodium/potassium–adenosine triphosphatase (Na+/K+ ATPase) inhibitor, reduces carbohydrate metabolism in the Krebs cycle by generating reactive oxygen species (ROS) to impair metabolism-secretion coupling; endogenous ROS generation by ouabain involves activation of Src, a nonreceptor tyrosine kinase. In type 2 diabetes, the insulin secretory response of β cells is selectively impaired to glucose. In the Goto-Kakizaki (GK) rat, a model of nonobese type 2 diabetes mellitus, Src is endogenously activated in islets, and glucose-induced insulin secretion is selectively impaired due to deficient ATP production derived from impaired glucose metabolism, which is caused by overproduction of ROS produced by Src activation. In addition, exendin-4, a glucagon-like peptide-1 receptor agonist, decreases Src activation and ROS production and ameliorates impaired ATP production in GK islets. Moreover, thioredoxin-binding protein-2 is overexpressed in islets from ob/ob mice, a model of obese type 2 diabetes mellitus, which causes overexpression of uncoupling protein-2, reduced mitochondrial ATP production, and decreased glucose-induced insulin secretion. Further studies are necessary to relate these mechanisms to β-cell dysfunction in patients with type 2 diabetes.