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

Journal article
Authors J. G. Knudsen
A. Hamilton
R. Ramracheya
A. I. Tarasov
M. Brereton
E. Haythorne
M. V. Chibalina
P. Spegel
H. Mulder
Q. Zhang
F. M. Ashcroft
J. Adam
Patrik Rorsman
Published in Cell Metabolism
Volume 29
Issue 2
Pages 430-+
ISSN 1550-4131
Publication year 2019
Published at Institute of Neuroscience and Physiology
Pages 430-+
Language en
Keywords pancreatic beta-cells, fumarate hydratase, alpha, dehydrogenase, succination, inhibition, metabolism, ph, inactivation, transport, Cell Biology
Subject categories Endocrinology


Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their beta cells (Fh1 beta KO 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 alpha cells from hyperglycemic Fh1 beta KO and beta-V59M gain-of-function K-ATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1 beta KO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.

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