Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production

Jakob G. Knudsen, Alexander Hamilton, Reshma Ramracheya, Andrei I. Tarasov, Melissa Brereton, Elizabeth Haythorne, Margarita V. Chibalina, Peter Spégel, Hindrik Mulder, Quan Zhang, Frances M. Ashcroft, Julie Adam, Patrik Rorsman

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Abstract

Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their β cells (Fh1βKO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in α cells from hyperglycemic Fh1βKO and β-V59M gain-of-function KATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1βKO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.
Original languageEnglish
Pages (from-to)430-442.e4
Number of pages13
JournalCell Metabolism
Volume29
Issue number2
Early online date8 Nov 2018
DOIs
Publication statusPublished (in print/issue) - 5 Feb 2019

Keywords

  • glucagon
  • Fh1
  • succination
  • sodium-glucose co-transport
  • diabetes

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