Effect of high-fat diet on glucose homeostasis and gene expression in glucokinase knockout mice
2008
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.
We have generated a heterozygous glucokinase knockout mouse (gkdel/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 gkdel/wtmouse islets. Male gkdel/wtand gkwt/wtmice 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. gkdel/wtmice 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 gkdel/wtmice were less than half that of gkwt/wtmice, although they were equivalent to gkwt/wtmice on CD. While gkwt/wtmice maintained moderate hyperglycaemia, gkdel/wtmice became overtly diabetic, with worsened glucose tolerance. A GKA (GKA50) increased GSIS, at 10 mM glucose, in gkdel/wtmice to an extent at least as great as that seen in gkwt/wtmice on both CD and HFD. gkdel/wtmice showed only a small number of changes in gene expression compared with gkwt/wtmice. We propose the high fat-fed gkdel/wtmouse as a model of type 2 diabetes and report retained efficacy of a GKA on in vitro GSIS.
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