Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes

• Published in: Cell reports (Cambridge) Vol. 20; no. 13; pp. 3135 - 3148
• Main Authors: Adam, Julie, Ramracheya, Reshma, Chibalina, Margarita V., Ternette, Nicola, Hamilton, Alexander, Tarasov, Andrei I., Zhang, Quan, Rebelato, Eduardo, Rorsman, Nils J.G., Martín-del-Río, Rafael, Lewis, Amy, Özkan, Gizem, Do, Hyun Woong, Spégel, Peter, Saitoh, Kaori, Kato, Keiko, Igarashi, Kaori, Kessler, Benedikt M., Pugh, Christopher W., Tamarit-Rodriguez, Jorge, Mulder, Hindrik, Clark, Anne, Frizzell, Norma, Soga, Tomoyoshi, Ashcroft, Frances M., Silver, Andrew, Pollard, Patrick J., Rorsman, Patrik
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.09.2017; Cell Press; Elsevier
• Subjects: Animals; biomarker; Cell Biology; chemical-modification; Clinical Medicine; dehydrogenase; diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; fumarate; fumarate hydratase; Fumarate Hydratase - deficiency; Fysiologi; glucose metabolism; glucose-homeostasis; Humans; hyperglycemia; insulin; Insulin-Secreting Cells - metabolism; insulin-secretion; islets; Islets of Langerhans - metabolism; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; metabolism; Mice; mitochondrial stress; mouse model; pathway; Physiology; succination; β cell; hyperglycemia; insulin; mouse model; fumarate hydratase; succination; pH; β cell; diabetes; glucose metabolism; fumarate
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.08.093

We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic β cells (Fh1βKO 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 Hif1α or Nrf2. Progressive hyperglycemia in Fh1βKO mice led to dysregulated metabolism in β cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca2+]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 Fh1βKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D. [Display omitted] •Fh1 loss in β cells causes progressive Hif1α-independent diabetes•Fh1 loss in β cells impairs ATP generation, electrical activity, and GSIS•Elevated fumarate is a feature of diabetic murine and human islets•“Normoglycemia” restores GSIS in Fh1βKO islets Adam et al. have shown that progressive diabetes develops if fumarate hydratase is deleted in mouse pancreatic β cells. Such β cells exhibit elevated fumarate and protein succination and show progressively reduced ATP production and insulin secretion. The depleted insulin response to glucose recovers when diabetic islets are cultured in reduced glucose.