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Diabetologia. 2014 Jan;57(1):148-56. doi: 10.1007/s00125-013-3079-6. Epub 2013 Oct 17.

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

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1
Department of Neuroscience, Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Berzelius vag 35, B3 Box 285, SE-171 77, Stockholm, Sweden.

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.

PMID:
24132781
DOI:
10.1007/s00125-013-3079-6
[Indexed for MEDLINE]
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