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Effect of high‐fat diet on glucose homeostasis and gene expression in glucokinase knockout mice
Author(s) -
Gorman T.,
Hope D. C. D.,
Brownlie R.,
Yu A.,
Gill D.,
Löfvenmark J.,
Wedin M.,
Mayers R. M.,
Snaith M. R.,
Smith D. M.
Publication year - 2008
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2007.00819.x
Subject(s) - glucokinase , medicine , endocrinology , islet , glucose homeostasis , insulin , triglyceride , knockout mouse , gene expression , chemistry , biology , insulin resistance , cholesterol , gene , biochemistry , receptor
Aim: We have generated a heterozygous glucokinase knockout mouse ( gk del/wt ), upon which we investigated the effect of high‐fat diet (HFD) with respect to metabolic control and both hepatic and β‐cell gene expression. We also investigated the in vitro efficacy of a glucokinase activator (GKA) on glucose‐stimulated insulin secretion (GSIS) in gk del/wt mouse islets. Methods: Male gk del/wt and gk wt/wt mice were grouped (n = 8–10) at 10 weeks of age and fed HFD or chow diet (CD) for 10 weeks. Multiple parameters including blood glucose, plasma insulin and glucose tolerance were assessed. Further animal groups were used for in vitro GSIS and islet and liver gene expression analysis. Results and Conclusions: gk del/wt mice showed early‐onset persistent hyperglycaemia, raised glycated haemoglobin levels, impaired GSIS and glucose tolerance but no change in plasma cholesterol, non‐esterified fatty acids or triglyceride levels. After HFD feeding, insulin levels of gk del/wt mice were less than half that of gk wt/wt mice, although they were equivalent to gk wt/wt mice on CD. While gk wt/wt mice maintained moderate hyperglycaemia, gk del/wt mice became overtly diabetic, with worsened glucose tolerance. A GKA (GKA50) increased GSIS, at 10 mM glucose, in gk del/wt mice to an extent at least as great as that seen in gk wt/wt mice on both CD and HFD. gk del/wt mice showed only a small number of changes in gene expression compared with gk wt/wt mice. We propose the high fat–fed gk del/wt mouse as a model of type 2 diabetes and report retained efficacy of a GKA on in vitro GSIS.