Insulin regulation of β-cell function involves a feedback loop on SERCA gene expression, Ca2+ homeostasis, and insulin expression and secretion

The insulin receptor signaling pathway is present in beta -cells and is believed to be important in beta -cell function. We show here that insulin directly regulates beta -cell function in isolated rodent islets. Long- term insulin treatment caused a sustained increase in [Ca2+](i) and enhanced glucose-stimulated insulin secretion in rat islets, but failed to increase insulin content. Chronic activation of insulin receptor signaling by IRS-1 overexpression in the beta -cell inhibited gene expression of SERCA3, an endoplasmic reticulum Ca2+-ATPase. Insulin gene transcription was stimulated by insulin receptor signaling and insulin mimetic compound (L-783 281) in a glucose- and Grb2-dependent manner. Thus, beta -cell SERCA3 is a target for insulin regulation, which implies that beta -cell Ca2+ homeostasis is regulated in an autocrine feedback loop by insulin. This study identifies a novel regulatory pathway of insulin secretion at the molecular. level with two main components: (1) regulation of intracellular Ca2+ homeostasis via SERCA3 and (2) regulation of insulin gene expression.