Abstract
SummaryWe 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.
Highlights
The high levels of fumarate that accumulate in fumarate hydratase (FH)-deficient cells cause post-translational modification of cysteine residues in proteins to form S-(2-succino)-cysteine (2SC), a proce
Mice Lacking Fh1 in Pancreatic b Cells Exhibit Hif1a-Independent Glucose Intolerance We generated animals in which Fh1 was deleted in pancreatic b cells (Fh1fl/flRip2-Cre+/À; Fh1bKO mice) by intercrossing an Fh1 conditional knockout mouse (Pollard et al, 2007) with mice expressing Cre recombinase driven by the rat insulin promoter (Rip2-Cre mice; Herrera, 2000)
Distinct from the mouse model in which von Hippel-Lindau protein (Vhl) is deleted in b cells (Zehetner et al, 2008; Cantley et al, 2009), we found that the diabetes associated with Fh1 loss is Hif1a and Nrf2 independent
Summary
Adam et al have shown that progressive diabetes develops if fumarate hydratase is deleted in mouse pancreatic b cells. Such b 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. Highlights d Fh1 loss in b cells causes progressive Hif1a-independent diabetes d Fh1 loss in b cells impairs ATP generation, electrical activity, and GSIS d Elevated fumarate is a feature of diabetic murine and human islets d ‘‘Normoglycemia’’ restores GSIS in Fh1bKO islets. 2017, Cell Reports 20, 3135–3148 September 26, 2017 a 2017 The Author(s).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
