Lee, Ji-HyeonMellado-Gil, Jose ManuelBahn, Young JaePathy, Sushrut M.Zhang, Ying E.Rane, Sushil G.2022-08-032022-08-032020-03-13Lee JH, Mellado-Gil JM, Bahn YJ, Pathy SM, Zhang YE, Rane SG. Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling. Cell Death Dis. 2020 Mar 13;11(3):184http://hdl.handle.net/10668/3869Prevailing 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.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Apoptosisβ-cellGlucoseGlucose intolerancePancreasRoleDiabetesCélulas secretoras de insulinaGlucosaIntolerancia a la glucosaRolFactor de crecimiento transformador betaProteína smad3Medical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::ApoptosisMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell ProliferationMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animal::Disease Models, AnimalMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal TransductionMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::DNA-Binding Proteins::Smad Proteins::Smad Proteins, Receptor-Regulated::Smad3 ProteinMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intercellular Signaling Peptides and Proteins::Transforming Growth Factors::Transforming Growth Factor beta::Transforming Growth Factor beta1research article32170115open access10.1038/s41419-020-2365-82041-4889PMC7070087