Insulin Regulation of beta -Cell Function Involves a Feedback Loop on SERCA Gene Expression, Ca super(2+) Homeostasis, and Insulin Expression and Secretion

• Published in: Biochemistry (Easton) Vol. 39; no. 48; pp. 14912 - 14919
• Main Authors: Xu, G G, Gao, Zhi-yong, Borge, PD Jr, Jegier, P A, Young, R A, Wolf, BA
• Format: Journal Article
• Language: English
• Published: 01-12-2000
• ISSN: 0006-2960
• DOI: 10.1021/bi001260w

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 [Ca super(2+)] sub(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 Ca super(2+)-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 Ca super(2+) 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 Ca super(2+) homeostasis via SERCA3 and (2) regulation of insulin gene expression.