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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

pancreatic beta-cells

fumarate hydratase

alpha

dehydrogenase

succination

inhibition

metabolism

ph

inactivation

transport

Cell Biology

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)