Abstract

Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β’s chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.

Details

Title
Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling
Author
Ji-Hyeon, Lee 1 ; Mellado-Gil, Jose Manuel 2 ; Bahn, Young Jae 1 ; Pathy Sushrut M 1 ; Zhang, Ying E 3   VIAFID ORCID Logo  ; Rane, Sushil G 1 

 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch, Bethesda, USA (GRID:grid.419635.c) (ISNI:0000 0001 2203 7304) 
 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch, Bethesda, USA (GRID:grid.419635.c) (ISNI:0000 0001 2203 7304); Jerez University Hospital, Biomedical Research and Innovation Institute of Cádiz (INiBiCA) Research Unit, Cádiz, Spain (GRID:grid.419635.c) 
 Center for Cancer Research, National Cancer Institute, National Institutes of Health, Laboratory of Cellular and Molecular Biology, Bethesda, USA (GRID:grid.417768.b) (ISNI:0000 0004 0483 9129) 
Publication year
2020
Publication date
Mar 2020
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2376945780
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.