GLUT-1 or GLUT-4 transgenes in obese mice improve glucose tolerance but donot prevent insulin resistance

Insulin-stimulated glucose uptake is defective in patients with type 2 diab etes. To determine whether transgenic glucose transporter overexpression in muscle can prevent diabetes induced by a high-fat, high-sugar diet, singly (GLUT-1, GLUT-4) and doubly (GLUT-1 and -4) transgenic mice were placed on a high-fat, high-sugar diet or a standard chow diet. On the high-fat, high -sugar diet, wild-type but not transgenic mice developed fasting hyperglyce mia and glucose intolerance (peak glucose of 337 +/- 19 vs. 185-209 mg/dl i n the same groups on the high-fat, high-sugar diet and 293 +/- 13 vs. 166-1 94 mg/dl on standard chow). Hyperinsulinemic clamps showed that transporter overexpression elevated insulin-stimulated glucose utilization on standard chow (49 +/- 4 mg.kg(-1).min(-1) in wild-type vs. 61 +/- 4, 67 +/- 5, and 63 +/- 6 mg.kg(-1).min(-1) in GLUT-1, GLUT-4, and GLUT-1 and -4 transgenic mice given 20 mU.kg(-1).min(-1) insulin, and 54 +/- 7, 85 +/- 4, and 98 +/- 11 in wild-type, GLUT-1, and GLUT-4 mice given 60-80 mU.kg(-1).min(-1) ins ulin). On the high-fat, high-sugar diet, wild-type and GLUT-1 mice develope d marked insulin resistance, but GLUT-4 and GLUT-1 and -4 mice were somewha t protected (glucose utilization during hyperinsulinemic clamp of 28.5 +/- 3.4 vs. 42.4 +/- 5.9, 51.2 +/- 8.1, and 55.9 +/- 4.9 mg.kg(-1).min(-1) in w ild type, GLUT-1, GLUT-4, GLUT-1 and -4 mice). These data demonstrate that overexpression of GLUT-1 and/or GLUT-4 enhances whole body glucose utilizat ion and prevents the development of fasting hyperglycemia and glucose intol erance induced by a high-fat, high-sugar diet. GLUT-4 overexpression improv es the insulin resistance induced by the diet. We conclude that upregulatio n of glucose transporters in skeletal muscle may be an effective therapeuti c approach to the treatment of human type 2 diabetes.