Christensen, Gitte L.3; Jacobsen, Maria L. B.2; Wendt, Anna2; Mollet, Ines G.2; Friberg, Josefine3; Frederiksen, Klaus S.2; Meyer, Michael2; Bruun, Christine2; Eliasson, Lena2; Billestrup, Nils3
1 Section of Cellular and Metabolic Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet2 unknown3 Section of Cellular and Metabolic Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet
AIMS/HYPOTHESIS: Type 2 diabetes is characterised by progressive loss of pancreatic beta cell mass and function. Therefore, it is of therapeutic interest to identify factors with the potential to improve beta cell proliferation and insulin secretion. Bone morphogenetic protein 4 (BMP4) expression is increased in diabetic animals and BMP4 reduces glucose-stimulated insulin secretion (GSIS). Here, we investigate the molecular mechanism behind this inhibition. METHODS: BMP4-mediated inhibition of GSIS was investigated in detail using single cell electrophysiological measurements and live cell Ca2+ imaging. BMP4-mediated gene expression changes were investigated by microarray profiling, quantitative PCR and western blotting. RESULTS: Prolonged exposure to BMP4 reduced GSIS from rodent pancreatic islets. This inhibition was associated with decreased exocytosis due to a reduced Ca2+ current through voltage-dependent Ca2+ channels. To identify proteins involved in the inhibition of GSIS, we investigated global gene expression changes induced by BMP4 in neonatal rat pancreatic islets. Expression of the Ca2+-binding protein calbindin1 was significantly induced by BMP4. Overexpression of calbindin1 in primary islet cells reduced GSIS, and the effect of BMP4 on GSIS was lost in islets from calbindin1 (Calb1) knockout mice. CONCLUSIONS/INTERPRETATION: We found BMP4 treatment to markedly inhibit GSIS from rodent pancreatic islets in a calbindin1-dependent manner. Calbindin1 is suggested to mediate the effect of BMP4 by buffering Ca2+ and decreasing Ca2+ channel activity, resulting in diminished insulin exocytosis. Both BMP4 and calbindin1 are potential pharmacological targets for the treatment of beta cell dysfunction.