Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production.
Cell Metab
; 29(2): 430-442.e4, 2019 02 05.
Article
in 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Glucagon
/
Adenosine Triphosphate
/
Diabetes Mellitus, Type 2
/
Glucagon-Secreting Cells
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Insulin-Secreting Cells
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Hyperglycemia
/
Insulin
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Cell Metab
Journal subject:
METABOLISMO
Year:
2019
Document type:
Article
Affiliation country:
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA