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Bone morphogenetic protein 4 inhibits insulin secretion from rodent beta cells through regulation of calbindin1

Gitte L Christensen1, Maria L B Jacobsen, Anna Wendt

  • 1Department of Biomedical Sciences, University of Copenhagen, Nørre Alle 20, 2100, Copenhagen, Denmark.

Diabetologia
|April 2, 2015
PubMed
Abstract

Insights

Bone morphogenetic protein 4 (BMP4) inhibits glucose-stimulated insulin secretion (GSIS) in pancreatic islets by increasing calbindin1. This mechanism, dependent on calbindin1, offers potential therapeutic targets for type 2 diabetes.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Diabetes Research

Background:

  • Type 2 diabetes is characterized by progressive loss of pancreatic beta cell function.
  • Bone morphogenetic protein 4 (BMP4) is elevated in diabetes and inhibits glucose-stimulated insulin secretion (GSIS).
  • Understanding the molecular mechanisms of BMP4-induced inhibition is crucial for therapeutic development.

Purpose of the Study:

  • To investigate the molecular mechanism by which BMP4 inhibits GSIS.
  • To identify key molecular players involved in BMP4-mediated suppression of insulin secretion.

Main Methods:

  • Single-cell electrophysiology and live-cell Ca(2+) imaging to assess GSIS.
  • Microarray profiling, quantitative PCR, and Western blotting to analyze gene expression changes.
  • Studies using calbindin1 (Calb1) knockout mice and overexpression systems.

Main Results:

  • BMP4 significantly reduced GSIS in rodent pancreatic islets.
  • BMP4-induced inhibition of GSIS was linked to decreased Ca(2+) influx and exocytosis.
  • BMP4 upregulated the expression of the Ca(2+)-binding protein calbindin1.
  • Calbindin1 overexpression mimicked BMP4's inhibitory effect on GSIS.
  • The inhibitory effect of BMP4 on GSIS was abolished in Calb1 knockout islets.

Conclusions:

  • BMP4 inhibits GSIS in a calbindin1-dependent manner.
  • Calbindin1 mediates BMP4's effect by buffering intracellular Ca(2+), reducing channel activity, and diminishing insulin exocytosis.
  • Both BMP4 and calbindin1 represent potential therapeutic targets for treating beta cell dysfunction in diabetes.

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