Inhibition of beta cell growth and function by bone morphogenetic proteins

Aims/hypothesis Impairment of beta cell mass and function is evident in both type 1 and type 2 diabetes. In healthy physiological conditions pancreatic beta cells adapt to the body's increasing insulin requirements by proliferation and improved function. We hypothesised that during the developm...

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Bibliographic Details
Published in:	Diabetologia Vol. 57; no. 12; pp. 2546 - 2554
Main Authors:	Bruun, Christine, Christensen, Gitte L., Jacobsen, Marie L. B., Kanstrup, Marianne B., Jensen, Pernille R., Fjordvang, Helle, Mandrup-Poulsen, Thomas, Billestrup, Nils
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2014 Springer Springer Nature B.V
Subjects:	Animals Apoptosis - drug effects Biological and medical sciences Bone Morphogenetic Protein 2 - pharmacology Bone Morphogenetic Protein 4 - pharmacology Cell cycle Cell growth Cell Proliferation - drug effects Cells, Cultured Cytokines Diabetes Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Gene Expression - drug effects Glucose Growth factors Human Physiology Insulin - metabolism Insulin resistance Insulin-Secreting Cells - drug effects Insulin-Secreting Cells - physiology Internal Medicine Kinases Medical sciences Medicin och hälsovetenskap Medicine Medicine & Public Health Metabolic Diseases Mice Proteins R&D Rats Research & development Rodents Signal Transduction - drug effects United Kingdom > UK Denmark Beta cell proliferation Glucose-stimulated insulin secretion Bone morphogenetic protein Inhibitor of DNA binding Cell cycle Endocrinopathy Cell proliferation Pancreatic hormone Growth Secretion Diabetes mellitus Langerhans islet Glucose Insulin DNA β Cell Inhibition Endocrine pancreas
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Summary:	Aims/hypothesis Impairment of beta cell mass and function is evident in both type 1 and type 2 diabetes. In healthy physiological conditions pancreatic beta cells adapt to the body's increasing insulin requirements by proliferation and improved function. We hypothesised that during the development of diabetes, there is an increase in the expression of inhibitory factors that prevent the beta cells from adapting to the increased need for insulin. We evaluated the effects of bone morphogenetic protein (BMP) 2 and -4 on beta cells. Methods The effects of BMP2 and -4 on beta cell proliferation, apoptosis, gene expression and insulin release were studied in isolated islets of Langerhans from rats, mice and humans. The expression of BMPs was analysed by immunocytochemistry and real-time PCR. The role of endogenous BMP was investigated using a soluble and neutralising form of the BMP receptor 1A. Results BMP2 and -4 were found to inhibit basal as well as growth factor-stimulated proliferation of primary beta cells from rats and mice. Bmp2 and Bmp4 mRNA and protein were expressed in islets and regulated by inflammatory cytokines. Neutralisation of endogenous BMP activity resulted in enhanced proliferation of rodent beta cells. The expression of Id mRNAs was induced by BMP4 in rat and human islets. Finally, glucose-induced insulin secretion was significantly impaired in rodent and human islets pre-treated with BMP4, and inhibition of BMP activity resulted in enhanced insulin release. Conclusions/interpretation These data show that BMP2 and -4 exert inhibitory actions on beta cells in vitro and suggest that BMPs exert regulatory roles of beta cell growth and function.
ISSN:	0012-186X 1432-0428 1432-0428
DOI:	10.1007/s00125-014-3384-8