Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling

• Published in: Cell death & disease Vol. 11; no. 3; p. 184
• Main Authors: Lee, Ji-Hyeon, Mellado-Gil, Jose Manuel, Bahn, Young Jae, Pathy, Sushrut M., Zhang, Ying E., Rane, Sushil G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.03.2020; Springer Nature B.V
• Subjects: 13/2; 14/19; 631/80/82/23; 64/110; 692/699/2743/137/773; 82/51; Animals; Antibodies; Apoptosis; Apoptosis - genetics; Autocrine signalling; B-Lymphocytes - metabolism; Beta cells; Biochemistry; Biomedical and Life Sciences; Cell activation; Cell Biology; Cell Culture; Cell Proliferation; Diabetes; Diabetes mellitus (non-insulin dependent); Disease Models, Animal; FOXO1 protein; Glucose tolerance; Humans; Hyperglycemia; Immunology; Insulin; Intolerance; Life Sciences; Mice; Pancreas; Phosphorylation; Signal Transduction; Smad3 protein; Smad3 Protein - antagonists & inhibitors; Smad3 Protein - genetics; Transforming Growth Factor beta1 - antagonists & inhibitors; Transforming Growth Factor beta1 - genetics; Transforming growth factor-b1
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2365-8

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.