Glucokinase Gene Locus Transgenic Mice Are Resistant to the Development of Obesity-Induced Type 2 Diabetes

Glucokinase Gene Locus Transgenic Mice Are Resistant to the Development of Obesity-Induced Type 2 Diabetes Masakazu Shiota 1 , Catherine Postic 1 , Yuka Fujimoto 1 , Thomas L. Jetton 1 , Kathryn Dixon 1 , Danhua Pan 1 , Joseph Grimsby 2 , Joseph F. Grippo 2 , Mark A. Magnuson 1 and Alan D. Cherrington 1 1 Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, Tennessee 2 Department of Metabolic Disease, Hoffmann-La Roche Inc., Nutley, New Jersey Abstract Transgenic mice that overexpress the entire glucokinase (GK) gene locus have been previously shown to be mildly hypoglycemic and to have improved tolerance to glucose. To determine whether increased GK might also prevent or diminish diabetes in diet-induced obese animals, we examined the effect of feeding these mice a high-fat high–simple carbohydrate low-fiber diet (HF diet) 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 concentration 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 transgenic mice rose to only 9.7 ± 1.2 mmol/l at the 15th week, after which it returned to 7.6 ± 1.0 mmol/l by the 30th week. The plasma insulin concentration 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 levels dramatically lessen the development of both hyperglycemia and hyperinsulinemia associated with the feeding of an HF diet. ANOVA, analysis of variance DTT, dithioerythritol G6Pase, glucose-6-phosphatase GK, glucokinase GKRP, GK regulatory protein HF diet, high-fat high–simple carbohydrate low-fiber diet NEFA, nonesterified fatty acid Footnotes Address correspondence and reprint requests to Masakazu Shiota, DVM, Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 710 Medical Research Bldg. 1, Nashville, TN 37232-0615. E-mail: masakazu.shiota{at}mcmail.vanderbilt.edu . Received for publication 21 January 2000 and accepted in revised form 6 December 2000. A.D.C. and M.A.M. are on an advisory panel of OSI Pharmaceuticals.