1. Insulin regulation of beta-cell function involves a feedback loop on SERCA gene expression, Ca(2+) homeostasis, and insulin expression and secretion.
- Author
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Xu GG, Gao ZY, Borge PD Jr, Jegier PA, Young RA, and Wolf BA
- Subjects
- Animals, Clone Cells, Cytosol metabolism, Endoplasmic Reticulum enzymology, Feedback, Gene Expression Regulation, Genes, Reporter, Homeostasis, Insulin Receptor Substrate Proteins, Islets of Langerhans cytology, Mice, Phosphoproteins genetics, Rats, Recombinant Proteins metabolism, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Signal Transduction, Calcium metabolism, Calcium-Transporting ATPases metabolism, Insulin metabolism, Islets of Langerhans physiology, Phosphoproteins metabolism, Receptor, Insulin metabolism
- Abstract
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.
- Published
- 2000
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