Effect of high-fat diet on glucose homeostasis and gene expression in glucokinase knockout mice.
OBJECTIVE
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 beta-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.


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.
Diabetes & Obesity Drug Discovery, AstraZeneca, Macclesfield, Cheshire, UK. tracy.gorman@astrazeneca.com
T
T
Gorman
D C D
DC
Hope
R
R
Brownlie
A
A
Yu
D
D
Gill
J
J
Löfvenmark
M
M
Wedin
R M
RM
Mayers
M R
MR
Snaith
D M
DM
Smith
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D005941:Glucokinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006579:Heterozygote; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D011725:Pyridines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D007328:Insulin; D011725:Pyridines; D014280:Triglycerides; C520311:glucokinase activator compound 50; D005941:Glucokinase; D005947:Glucose