Transgenic mice overexpressing Glut1 glucose transporter in skeletal muscle and/or Glut4 glucose transporter in skeletal muscle, heart, and fat and nontransgenic littermates were placed on a high fat (36%)/ high simple carbohydrate (33%) diet which has been shown to induce obesity and diabetes mellitus in some strains of mouse. Prior to beginning the diet, body weight was similar in the nontransgenic littermate controls, and in the transgenic mice overexpressing Glut1, Glut4, or both transporters. The weight increased by ≈85% after 16 weeks on the diet in all groups. Blood glucose prior to beginning the diet was 188±4, 156±8, 159±3, and 160±14 mg/dl in the same groups of mice. Glucose tolerance testing after 5 months showed glucose intolerance in the wild type mice (peak glucose of 306 mg/dl 60 min after 1 mg/g of dextrose i.p.) while the transgenic mice showed normal glucose tolerance (peak glucose of 190±26, 132±10, and 122±9 mg/dl in the Glut1, Glut4, and Glut1 and Glut4 overexpressing mice, respectively). Hyperinsulinemic (20 mU/kg/min) clamp studies were carried out in groups of the same mice with pentobarbital anesthesia to assess insulin responsiveness. Blood glucose was clamped at 165±9 (n=5), 177(n=1), 173±10 (n=5) and 201±5 (n=2) in the wild type, Glut1, Glut4, and Glut 1 and Glut4 overexpressing mice, respectively. The rate of glucose utilization was 31.7±5.1, 63, 62.8±7.3, and 54.2±9.3 mg/kg/min in the same groups. Wild type mice subjected to the same clamp protocol after being on a normal rodent diet show glucose utilization of 47±5 mg/kg/min. In conclusion, overexpression of Glut1 or Glut4 in transgenic mice prevents the onset of glucose intolerance, insulin resistance but not obesity caused by a high fat/high sugar diet.