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

Summary 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.
Graphical Abstract
Highlights • Chronic hyperglycemia inhibits fumarase and glucagon secretion by α cells • Hyperglycemia causes SGLT-dependent reduction of cytoplasmic pH and ATP production • SGLT inhibitors normalize cytoplasmic pH, ATP production, and glucagon secretion • The Na-dependent mechanism may impair ATP production in other SGLT-expressing cells
In diabetes, glucagon secretion is dysregulated but the underlying mechanisms are not fully understood. Knudsen et al. report that hyperglycemia impairs glucagon secretion by SGLT-dependent elevation of intracellular Na+, leading to acidification, reduced ATP production, and dysregulated KATP channel activity in α cells. The SGLT mechanism may also impair heart and kidney cell ATP production.