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

ABSTRACT: Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (?-cells) that involves increases in ?-cell function and ?-cell mass. However, the sustained metabolic stress eventually leads to ?-cell failure characterized by severe ?-cell dysfunction and progressive loss of ?-cell mass. Whereas, ?-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of ?-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased ?-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of ?-cell replication or neogenesis, strongly suggesting a role for apoptosis in ?-cell failure. Here, we describe a permissive role for TGF-?/Smad3 in ?-cell apoptosis. Human islets undergoing ?-cell apoptosis release increased levels of TGF-?1 ligand and phosphorylation levels of TGF-?'s chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-?/Smad3 signaling in ?-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing ?-cell apoptosis. In mice, ?-cell-specific activation of Smad3 promotes apoptosis and loss of ?-cell mass in association with ?-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves ?-cell mass while improving ?-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-?-dependent ?-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-?/Smad3 signals or knocking down Foxo1 protects from ?-cell apoptosis. These findings reveal the importance of TGF-?/Smad3 in promoting ?-cell apoptosis and demonstrate the therapeutic potential of TGF-?/Smad3 antagonism to restore ?-cell mass lost in diabetes.

SUBMITTER: Lee JH 

PROVIDER: S-EPMC7070087 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature