Increased TGFβ /Activin-Smad2 signaling is associated with pancreatic β-cell dysfunction and glucose intolerance in gestational diabetes mellitus

Abstract

BackgroundGestational diabetes mellitus (GDM) is the most common metabolic disease during pregnancy and increases the prevalence of type 2 diabetes in both mothers and offspring. GDM management provides a window of opportunity to prevent and lower the global burden of diabetes across life. Molecular mechanisms underlying GDM are poorly defined. In this study, we explore the potential involvement of transforming growth factor beta (TGF-{beta}) signaling in GDM as this pathway has been reported to affect pancreatic {beta}-cell development, proliferation and identity. MethodsWe developed a GDM animal model. Serum circulating levels of TGF{beta} family ligands were measured in mice and human GDM. Pancreatic TGF{beta} signaling was investigated at the level of gene and protein expression. ResultsOur GDM animal model recapitulates the main pathophysiological features of human GDM including glucose intolerance, decreased insulin sensitivity and pancreatic {beta}-cell malfunction. Islets from GDM mice showed impaired insulin secretion and content, altered ion channel activity, and decreased {beta}-cell replication rate. This was accompanied by increased Smad2 signaling activation. Elevated serum activin-A and inhibin levels were found in mice and human GDM, suggesting their role as upstream signaling transducers of pancreatic Smad2 activation. Pharmacological inhibition of TGF{beta}/Activin-Smad2 signaling in mouse pancreatic islets resulted in improved pancreatic {beta}-cell function and regeneration capacity of {beta}-cells. ConclusionsOur data disclose that disruption of pancreatic Smad2 pathway plays a critical role in the pathogenesis of GDM, contributing to abnormal glucose homeostasis and inadequate insulin secretion. Attenuation of this signaling pathway could represent a putative therapeutic target for GDM. HighlightsO_LIHigh fat diet just before and during pregnancy leads to gestational diabetes in mice. C_LIO_LIActivin and inhibin serum levels are increased in human and mice gestational diabetes. C_LIO_LIEnhanced pancreatic Smad2 signaling contributes to inadequate insulin secretion in gestational diabetes. C_LIO_LIInhibition of Smad2 signaling improves pancreatic {beta}-cell function and proliferation. C_LI