Whole-Organism Chemical Screening Identifies Modulators of Pancreatic β-Cell Function.

Abstract

β-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 β-cell function and/or increase β-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 β-cell function. This in vivo strategy identified 84 stimulators of <i>insulin</i> expression, which simultaneously reduced glucose levels. The <i>insulin</i> promoter activation kinetics for 32 of these stimulators were consistent with a direct mode of action. A subset of <i>insulin</i> stimulators, including the antidiabetic drug pioglitazone, induced the coordinated upregulation of gluconeogenic <i>pck1</i> expression, suggesting functional response to increased insulin action in peripheral tissues. Notably, Kv1.3 inhibitors increased β-cell mass in larval zebrafish and stimulated β-cell function in adult zebrafish and in the streptozotocin-induced hyperglycemic mouse model. In addition, our data indicate that cytoplasmic Kv1.3 regulates β-cell function. Thus, using whole-organism screening, we have identified new small-molecule modulators of β-cell function and glucose metabolism.