Insulin regulation of beta-cell function involves a feedback loop on SERCAgene expression, Ca2+ homeostasis, and insulin expression and secretion

The insulin receptor signaling pathway is present in beta -cells and is bel ieved to be important in beta -cell function. We show here that insulin dir ectly regulates beta -cell function in isolated rodent islets. Long- term i nsulin treatment caused a sustained increase in [Ca2+](i) and enhanced gluc ose-stimulated insulin secretion in rat islets, but failed to increase insu lin content. Chronic activation of insulin receptor signaling by IRS-1 over expression in the beta -cell inhibited gene expression of SERCA3, an endopl asmic reticulum Ca2+-ATPase. Insulin gene transcription was stimulated by i nsulin receptor signaling and insulin mimetic compound (L-783 281) in a glu cose- and Grb2-dependent manner. Thus, beta -cell SERCA3 is a target for in sulin regulation, which implies that beta -cell Ca2+ homeostasis is regulat ed in an autocrine feedback loop by insulin. This study identifies a novel regulatory pathway of insulin secretion at the molecular. level with two ma in components: (1) regulation of intracellular Ca2+ homeostasis via SERCA3 and (2) regulation of insulin gene expression.