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

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