| First Author | Adam J | Year | 2017 |
| Journal | Cell Rep | Volume | 20 |
| Issue | 13 | Pages | 3135-3148 |
| PubMed ID | 28954230 | Mgi Jnum | J:254516 |
| Mgi Id | MGI:6103990 | Doi | 10.1016/j.celrep.2017.08.093 |
| Citation | Adam J, et al. (2017) Fumarate Hydratase Deletion in Pancreatic beta Cells Leads to Progressive Diabetes. Cell Rep 20(13):3135-3148 |
| abstractText | We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic beta cells (Fh1betaKO mice) appear normal for 6-8 weeks but then develop progressive glucose intolerance and diabetes. Glucose tolerance is rescued by expression of mitochondrial or cytosolic FH but not by deletion of Hif1alpha or Nrf2. Progressive hyperglycemia in Fh1betaKO mice led to dysregulated metabolism in beta cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca(2+)]i elevation, and GSIS. Fh1 loss resulted in elevated intracellular fumarate, promoting succination of critical cysteines in GAPDH, GMPR, and PARK 7/DJ-1 and cytoplasmic acidification. Intracellular fumarate levels were increased in islets exposed to high glucose and in islets from human donors with type 2 diabetes (T2D). The impaired GSIS in islets from diabetic Fh1betaKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D. |
