β-cell Smad2 null mice have improved β-cell function and are protected from diet-induced hyperglycemia
| Autor: | Nada Mohamed, Ting Zhang, Justin Molitoris, Krishna Prasadan, Mohamed Saleh, Yan Wang, Anuradha Sehrawat, Ranjeet Kalsi, Madison Thomas, George K. Gittes |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
insulin secretion
HFD high-fat diet medicine.medical_treatment glucose metabolism Smad2 Protein Carbohydrate metabolism Diet High-Fat SMAD transcription factor TGF-β transforming growth factor-beta Biochemistry transforming growth factor beta (TGF-β) BrdU bromodeoxyuridine ER endoplasmic reticulum GSIS glucose-stimulated insulin secretion Mice Downregulation and upregulation PPX partial pancreatectomy Diabetes mellitus Insulin-Secreting Cells medicine Animals Molecular Biology IPITT intraperitoneal insulin tolerance testing Mice Knockout biology Chemistry Cell growth smad2-βKO deletion of smad2 protein in ins1cre smad2fx/fx Insulin RIP rat insulin promoter Type 2 Diabetes Mellitus Cell Biology Transforming growth factor beta T2DM type 2 diabetes mellitus medicine.disease β-cell Cell biology Hyperglycemia HOMA-IR homeostatic model assessment–estimated insulin resistance biology.protein Signal transduction HbA1c glycated hemoglobin RT-PCR real-time PCR IHC immunohistochemistry Signal Transduction Research Article |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | Understanding signaling pathways that regulate pancreatic β-cell function to produce, store, and release insulin, as well as pathways that control β-cell proliferation, is vital to find new treatments for diabetes mellitus. Transforming growth factor-beta (TGF-β) signaling is involved in a broad range of β-cell functions. The canonical TGF-β signaling pathway functions through intracellular smads, including smad2 and smad3, to regulate cell development, proliferation, differentiation, and function in many organs. Here, we demonstrate the role of TGF-β/smad2 signaling in regulating mature β-cell proliferation and function using β-cell-specific smad2 null mutant mice. β-cell-specific smad2-deficient mice exhibited improved glucose clearance as demonstrated by glucose tolerance testing, enhanced in vivo and ex vivo glucose-stimulated insulin secretion, and increased β-cell mass and proliferation. Furthermore, when these mice were fed a high-fat diet to induce hyperglycemia, they again showed improved glucose tolerance, insulin secretion, and insulin sensitivity. In addition, ex vivo analysis of smad2-deficient islets showed that they displayed increased glucose-stimulated insulin secretion and upregulation of genes involved in insulin synthesis and insulin secretion. Thus, we conclude that smad2 could represent an attractive therapeutic target for type 2 diabetes mellitus. |
| Databáze: | OpenAIRE |
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