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Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

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

Author

  • 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

Summary, in English

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.

Department/s

  • Centre for Analysis and Synthesis
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • Diabetes - Molecular Metabolism

Publishing year

2019

Language

English

Pages

4-442

Publication/Series

Cell Metabolism

Volume

29

Issue

2

Document type

Journal article

Publisher

Cell Press

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Molecular Metabolism

ISBN/ISSN/Other

  • ISSN: 1550-4131