Abstract 1027: Critical Role of ATP-binding Cassette Transporter A1 (ABCA1) in Beta-Cell Function and Glucose Homeostasis
Type 2 diabetes is a significant risk factor for atherosclerosis and occurs when beta-cells are unable to secrete sufficient insulin to meet the metabolic requirements. The reasons why beta-cells fail in type 2 diabetes are incompletely understood, but one mechanism may involve the build-up of toxic lipids in islets. ABCA1 mediates the efflux of cellular cholesterol and phospholipids, representing the major route for cholesterol exit from non-hepatic cells. We investigated the consequences of defective cholesterol efflux on glucose homeostasis. ABCA1 null mice display significantly impaired glucose tolerance following an i.p. glucose challenge. In contrast, insulin sensitivity is unaltered in these mice, indicating that the impaired glucose tolerance is not due to peripheral insulin resistance. We found that ABCA1 is highly expressed in isolated mouse islets, suggesting that ABCA1 may play a functional role in beta-cells. To determine if the defect in glucose homeostasis in ABCA1 null mice is a result of dysfunctional beta-cell ABCA1, we generated mice in which ABCA1 is specifically inactivated in beta-cells using the Cre-lox system. Mice lacking beta-cell ABCA1 display markedly impaired glucose tolerance, and have defective glucose-stimulated insulin secretion in vivo and in vitro. These findings establish a novel function for ABCA1 in beta-cells and suggest that intra-cellular cholesterol homeostasis may be an important determinant of beta-cell function, thus supporting the concept of lipotoxicity contributing to the pathogenesis of type 2 diabetes, and suggesting a new link between dyslipidemia, diabetes and atherosclerosis.