Biology subjects

Alonso-Magdalena, P.

Publications and source records attributed to Alonso-Magdalena, P..

2 recordsLinked to original sources

bioRxiv2025

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

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

physiology↗

bioRxiv2022

SCREENING OF RELEVANT METABOLISM-DISRUPTING CHEMICALS ON PANCREATIC β-CELLS: EVALUATION OF MURINE AND HUMAN IN VITRO MODELS

Endocrine-disrupting chemicals (EDCs) are chemical substances that can interfere with the normal function of the endocrine system. EDCs are ubiquitous and can be found in a variety of consumer products such as food packaging materials, personal care and household products, plastic additives, and flame retardants. Over the last decade, the impact of EDCs on human health has been widely acknowledged as they have been associated with different endocrine diseases. Among them, a subset called metabolism-disrupting chemicals (MDCs) are able to promote metabolic changes that can lead to the development of metabolic disorders such as diabetes, obesity, hepatic steatosis, and metabolic syndrome, among others. Despite this, today, there are still no definitive and standardized in vitro tools to support the metabolic risk assessment of existing and emerging MDCs for regulatory purposes. Here, we evaluated two different pancreatic cell-based in vitro systems, the murine pancreatic {beta}-cell line MIN6 as well as the human pancreatic {beta}-cell line EndoC- {beta}H1. Both were challenged with a range of relevant concentrations of seven well-known EDCs (bisphenol-A (BPA), bisphenol-S (BPS), bisphenol-F (BPF), perfluorooctanesulfonic acid (PFOS), di(2-ethylhexyl) phthalate (DEHP), cadmium chloride (CdCl2) and dichlorodiphenyldichloroethylene (DDE)). The screening revealed that most of the tested chemicals have detectable deleterious effects on glucose-stimulated insulin release, insulin content, electrical activity, gene expression, and/or viability. Our data provide new molecular information on the direct effects of the selected chemicals on key aspects of pancreatic {beta}-cell function such as the stimulus-secretion coupling and ion channel activity. In addition, we found that, in general, the sensitivity and responses were comparable to those from other in vivo studies reported in the literature. Overall, our results suggest that both systems can serve as effective tools for rapid screening of potential MDC effects on pancreatic {beta}-cell physiology as well for deciphering and better understanding the molecular mechanisms that underlie their action.

pharmacology and toxicology↗