Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Knudsen, Jakob G ; Hamilton, Alexander LU ; Ramracheya, Reshma ; Tarasov, Andrei I ; Brereton, Melissa ; Haythorne, Elizabeth ; Chibalina, Margarita V ; Spégel, Peter LU ; Mulder, Hindrik LU orcid and Zhang, Quan , et al. (2019) In Cell Metabolism 29(2). p.4-442
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Metabolism
volume
29
issue
2
pages
4 - 442
publisher
Cell Press
external identifiers
  • pmid:30415925
  • scopus:85059061884
ISSN
1550-4131
DOI
10.1016/j.cmet.2018.10.003
language
English
LU publication?
yes
id
c90f8f20-aba2-433c-b3f2-4ee17698f725
date added to LUP
2019-01-21 08:04:24
date last changed
2023-04-09 01:31:27
@article{c90f8f20-aba2-433c-b3f2-4ee17698f725,
  abstract     = {{<p>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.</p>}},
  author       = {{Knudsen, Jakob G and Hamilton, Alexander and Ramracheya, Reshma and Tarasov, Andrei I and Brereton, Melissa and Haythorne, Elizabeth and Chibalina, Margarita V and Spégel, Peter and Mulder, Hindrik and Zhang, Quan and Ashcroft, Frances M and Adam, Julie and Rorsman, Patrik}},
  issn         = {{1550-4131}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{4--442}},
  publisher    = {{Cell Press}},
  series       = {{Cell Metabolism}},
  title        = {{Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production}},
  url          = {{http://dx.doi.org/10.1016/j.cmet.2018.10.003}},
  doi          = {{10.1016/j.cmet.2018.10.003}},
  volume       = {{29}},
  year         = {{2019}},
}