Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production.
Cell Metab
; 29(2): 430-442.e4, 2019 02 05.
Article
en En
| MEDLINE
| ID: mdl-30415925
ABSTRACT
Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their ß cells (Fh1ßKO 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 Fh1ßKO and ß-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 Fh1ßKO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Glucagón
/
Adenosina Trifosfato
/
Diabetes Mellitus Tipo 2
/
Células Secretoras de Glucagón
/
Células Secretoras de Insulina
/
Hiperglucemia
/
Insulina
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Cell Metab
Asunto de la revista:
METABOLISMO
Año:
2019
Tipo del documento:
Article
País de afiliación:
Reino Unido