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01.01.2014 | Article

Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands

verfasst von: Haiya Wu, Karima Mezghenna, Patricia Marmol, Tingqing Guo, Annalena Moliner, Shao-Nian Yang, Per-Olof Berggren, Carlos F. Ibáñez

Erschienen in: Diabetologia | Ausgabe 1/2014

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Abstract

Aims/hypothesis

Glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells is regulated by paracrine factors, the identity and mechanisms of action of which are incompletely understood. Activins are expressed in pancreatic islets and have been implicated in the regulation of GSIS. Activins A and B signal through a common set of intracellular components, but it is unclear whether they display similar or distinct functions in glucose homeostasis.

Methods

We examined glucose homeostatic responses in mice lacking activin B and in pancreatic islets derived from these mutants. We compared the ability of activins A and B to regulate downstream signalling, ATP production and GSIS in islets and beta cells.

Results

Mice lacking activin B displayed elevated serum insulin levels and GSIS. Injection of a soluble activin B antagonist phenocopied these changes in wild-type mice. Isolated pancreatic islets from mutant mice showed enhanced GSIS, which could be rescued by exogenous activin B. Activin B negatively regulated GSIS and ATP production in wild-type islets, while activin A displayed the opposite effects. The downstream mediator Smad3 responded preferentially to activin B in pancreatic islets and beta cells, while Smad2 showed a preference for activin A, indicating distinct signalling effects of the two activins. In line with this, overexpression of Smad3, but not Smad2, decreased GSIS in pancreatic islets.

Conclusions/interpretation

These results reveal a tug-of-war between activin ligands in the regulation of insulin secretion by beta cells, and suggest that manipulation of activin signalling could be a useful strategy for the control of glucose homeostasis in diabetes and metabolic disease.

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Titel: Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands
verfasst von: Haiya Wu
Karima Mezghenna
Patricia Marmol
Tingqing Guo
Annalena Moliner
Shao-Nian Yang
Per-Olof Berggren
Carlos F. Ibáñez
Publikationsdatum: 01.01.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 1/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-013-3079-6

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