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

Biochemistry. 2000 Dec 5;39(48):14912-9. doi: 10.1021/bi001260w.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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

Substances

  • Atp2a3 protein, rat
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Irs1 protein, rat
  • Phosphoproteins
  • Recombinant Proteins
  • Receptor, Insulin
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Atp2a3 protein, mouse
  • Calcium-Transporting ATPases
  • Calcium