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

IF 6.3 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2026-01-01 Epub Date: 2025-10-18 DOI:10.1016/j.molmet.2025.102274

Talía Boronat-Belda , Hilda Ferrero , Sergi Soriano , Elena Ribes-García , Rubén Betoret-Gustems , Daniel Martínez-Bañón , Mónica Serrano-Selva , Juan Martínez-Pinna , Ángel Nadal , Iván Quesada , Paloma Alonso-Magdalena

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引用次数: 0

Abstract

Background

Gestational diabetes mellitus (GDM) is the most common metabolic disease during pregnancy and increases the prevalence of type 2 diabetes in both mothers and children. GDM management provides an opportunity to prevent and lower the global burden of diabetes across life. Molecular mechanisms underlying GDM are not completely understood. In this study, we explore the role of transforming growth factor beta (TGF-β) signaling in GDM, as this pathway reportedly affects pancreatic β-cell development, function, and proliferation.

Methods

We developed a GDM animal model. Serum circulating levels of TGF-β family ligands were measured in mice and human GDM. Pancreatic TGF-β signaling was investigated via gene and protein expression.

Results

Our GDM animal model recapitulates the main pathophysiological features of human GDM, including glucose intolerance, decreased insulin sensitivity and pancreatic β-cell malfunction. Islets from GDM mice showed impaired insulin secretion and content, altered ion channel activity, and decreased β-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-β/Activin-Smad2 signaling in mouse pancreatic islets resulted in improved pancreatic β-cell function and regeneration capacity.

Conclusions

Our data suggest that disruption of the 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 may represent a putative therapeutic target for GDM.

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TGF-β/激活素- smad2信号的增加与妊娠期糖尿病胰腺β细胞功能障碍和葡萄糖耐受不良有关。

背景：妊娠期糖尿病（GDM）是妊娠期最常见的代谢性疾病，增加了母亲和儿童2型糖尿病的患病率。糖尿病管理为预防和降低终生糖尿病的全球负担提供了机会。GDM的分子机制尚不完全清楚。在本研究中，我们探讨了转化生长因子β (TGF-β)信号在GDM中的作用，因为据报道该途径影响胰腺β细胞的发育、功能和增殖。方法：建立GDM动物模型。测定小鼠和人GDM血清中TGF-β家族配体的循环水平。通过基因和蛋白表达研究胰腺TGF-β信号通路。结果：我们的GDM动物模型概括了人类GDM的主要病理生理特征，包括葡萄糖耐受不良、胰岛素敏感性降低和胰腺β细胞功能障碍。GDM小鼠胰岛胰岛素分泌和含量受损，离子通道活性改变，β细胞复制率降低。这伴随着Smad2信号激活的增加。在小鼠和人GDM中发现血清激活素- a和抑制素水平升高，表明它们是胰腺Smad2激活的上游信号转导。药理抑制小鼠胰岛TGF-β/激活素- smad2信号传导可改善胰腺β细胞功能和再生能力。结论：我们的数据表明，胰腺Smad2通路的破坏在GDM的发病机制中起着关键作用，导致葡萄糖稳态异常和胰岛素分泌不足。这种信号通路的衰减可能是GDM的一个假定的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.