Whole-organism chemical screening identifies modulators of pancreatic B-cell function

Abstract

b-Cell loss and dysfunction play a critical role in the progression of type 1 and type 2 diabetes. Identifying new molecules and/or molecular pathways that improve b-cell function and/or increase b-cell mass should significantly contribute to the development of new therapies for diabetes. Using the zebrafish model, we screened 4,640 small molecules to identify modulators of b-cell function. This in vivo strategy identified 84 stimulators of insulin expression, which simultaneously reduced glucose levels. The insulin promoter activation kinetics for 32 of these stimulators were consistent with a direct mode of action. A subset of insulin stimulators, including the antidiabetic drug pioglitazone, induced the coordinated upregulation of gluconeogenic pck1 expression, suggesting functional response to increased insulin action in peripheral tissues. Notably, Kv1.3 inhibitors increased b-cell mass in larval zebrafish and stimulated b-cell function in adult zebrafish and in the streptozotocin-induced hyperglycemic mouse model. In addition, our data indicate that cytoplasmic Kv1.3 regulates b-cell function. Thus, using whole-organism screening, we have identified new small-molecule modulators of b-cell function and glucose metabolism.