Glucokinase gene locus transgenic mice are resistant to the development ofobesity-induced type 2 diabetes

Transgenic mice that overexpress the entire glucokinase (GK) gene locus hav e been previously shown to be mildly hypoglycemic and to have improved tole rance to glucose. To determine whether increased GK might also prevent or d iminish diabetes in diet-induced obese animals, we examined the effect of f eeding these mice a high-fat high-simple carbohydrate low-fiber diet (HF di et) for 30 weeks. In response to this diet, both normal and transgenic mice became obese and had similar BMIs (5.3 +/- 0.1 and 5.0 +/- 0.1 kg/m(2) in transgenic and nontransgenic mice, respectively). The blood glucose concent ration of the control mice increased linearly with time and reached 17.0 +/ - 1.3 mmol/l at the 30th week. In contrast, the blood glucose of GK transge nic mice rose to only 9.7 +/- 1.2 mmol/l at the 15th week, after which it r eturned to 7.6 +/- 1.0 mmol/l by the 30th week. The plasma insulin concentr ation was also lower in the GK transgenic animals (232 +/- 79 pmol/l) than in the controls (595 +/- 77 pmol/l), but there was no difference in plasma glucagon concentrations. Together, these data indicate that increased GK le vels dramatically lessen the development of both hyperglycemia and hyperins ulinemia associated with the feeding of an HF diet.