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Chronic glucokinase activation reduces glycaemia and improves glucose tolerance in high-fat diet fed mice.

Sörhede Winzell, Maria LU ; Coghlan, Matthew; Leighton, Brendan; Frangioudakis, Georgia; Smith, David M; Storlien, Leonard H and Ahrén, Bo LU (2011) In European Journal of Pharmacology 663. p.80-86
Abstract
Glucokinase (GK) plays a key role in maintaining glucose homeostasis by promoting insulin secretion from pancreatic beta cells and increasing hepatic glucose uptake. Here we investigate the effects of acute and chronic GK activation on glucose tolerance and insulin secretion in mice with diet-induced insulin resistance. In the acute study, a small molecule GK activator (GKA71) was administered to mice fed a high-fat diet for 8weeks. In the long-term study, GKA71 was provided in the diet for 4weeks to high-fat diet-fed mice. Glucose tolerance was measured after intravenous glucose administration, and insulin secretion was measured both in vivo and in vitro. Acute GK activation efficiently improved glucose tolerance in association with... (More)
Glucokinase (GK) plays a key role in maintaining glucose homeostasis by promoting insulin secretion from pancreatic beta cells and increasing hepatic glucose uptake. Here we investigate the effects of acute and chronic GK activation on glucose tolerance and insulin secretion in mice with diet-induced insulin resistance. In the acute study, a small molecule GK activator (GKA71) was administered to mice fed a high-fat diet for 8weeks. In the long-term study, GKA71 was provided in the diet for 4weeks to high-fat diet-fed mice. Glucose tolerance was measured after intravenous glucose administration, and insulin secretion was measured both in vivo and in vitro. Acute GK activation efficiently improved glucose tolerance in association with increased insulin secretion after intravenous glucose both in control and high-fat fed mice. Chronic GK activation significantly reduced basal plasma glucose and insulin, and improved glucose tolerance despite reduced insulin secretion after intravenous glucose, suggesting improved insulin sensitivity. Isolated islets from chronically GKA71-treated mice displayed augmented insulin secretion at 8.3mmol/l glucose, without affecting glucose oxidation. High-fat diet fed mice had reduced glycogen and increased triglyceride in liver compared to control mice, and these parameters were not altered by long-term GK activation. We conclude that GK activation in high-fat diet-fed mice potently reduces glycaemia and improves glucose tolerance, with combined effect both to stimulate insulin secretion from islets and improve insulin sensitivity. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
European Journal of Pharmacology
volume
663
pages
80 - 86
publisher
Elsevier
external identifiers
  • wos:000292431700010
  • pmid:21586282
  • scopus:79959308013
ISSN
1879-0712
DOI
10.1016/j.ejphar.2011.05.009
language
English
LU publication?
yes
id
fde441c9-3df9-4922-ae85-3b402bb8087a (old id 1972429)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21586282?dopt=Abstract
date added to LUP
2011-06-07 21:06:56
date last changed
2017-03-05 03:19:39
@article{fde441c9-3df9-4922-ae85-3b402bb8087a,
  abstract     = {Glucokinase (GK) plays a key role in maintaining glucose homeostasis by promoting insulin secretion from pancreatic beta cells and increasing hepatic glucose uptake. Here we investigate the effects of acute and chronic GK activation on glucose tolerance and insulin secretion in mice with diet-induced insulin resistance. In the acute study, a small molecule GK activator (GKA71) was administered to mice fed a high-fat diet for 8weeks. In the long-term study, GKA71 was provided in the diet for 4weeks to high-fat diet-fed mice. Glucose tolerance was measured after intravenous glucose administration, and insulin secretion was measured both in vivo and in vitro. Acute GK activation efficiently improved glucose tolerance in association with increased insulin secretion after intravenous glucose both in control and high-fat fed mice. Chronic GK activation significantly reduced basal plasma glucose and insulin, and improved glucose tolerance despite reduced insulin secretion after intravenous glucose, suggesting improved insulin sensitivity. Isolated islets from chronically GKA71-treated mice displayed augmented insulin secretion at 8.3mmol/l glucose, without affecting glucose oxidation. High-fat diet fed mice had reduced glycogen and increased triglyceride in liver compared to control mice, and these parameters were not altered by long-term GK activation. We conclude that GK activation in high-fat diet-fed mice potently reduces glycaemia and improves glucose tolerance, with combined effect both to stimulate insulin secretion from islets and improve insulin sensitivity.},
  author       = {Sörhede Winzell, Maria and Coghlan, Matthew and Leighton, Brendan and Frangioudakis, Georgia and Smith, David M and Storlien, Leonard H and Ahrén, Bo},
  issn         = {1879-0712},
  language     = {eng},
  pages        = {80--86},
  publisher    = {Elsevier},
  series       = {European Journal of Pharmacology},
  title        = {Chronic glucokinase activation reduces glycaemia and improves glucose tolerance in high-fat diet fed mice.},
  url          = {http://dx.doi.org/10.1016/j.ejphar.2011.05.009},
  volume       = {663},
  year         = {2011},
}