Insulin regulation of beta-cell function involves a feedback loop on SERCA gene expression, Ca(2+) homeostasis, and insulin expression and secretion

• Published in: Biochemistry (Easton) Vol. 39; no. 48; p. 14912
• Main Authors: Xu, G G, Gao, Z Y, Borge, Jr, P D, Jegier, P A, Young, R A, Wolf, B A
• Format: Journal Article
• Language: English
• Published: United States 05-12-2000
• Subjects: Animals; Calcium - metabolism; Calcium-Transporting ATPases - metabolism; Clone Cells; Cytosol - metabolism; Endoplasmic Reticulum - enzymology; Feedback; Gene Expression Regulation; Genes, Reporter; Homeostasis; Insulin - metabolism; Insulin Receptor Substrate Proteins; Islets of Langerhans - cytology; Islets of Langerhans - physiology; Mice; Phosphoproteins - genetics; Phosphoproteins - metabolism; Rats; Receptor, Insulin - metabolism; Recombinant Proteins - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction
• 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(2+)](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(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(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(2+) homeostasis via SERCA3 and (2) regulation of insulin gene expression.