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Departments of 1 Pediatrics, 2 Medicine, and 3 Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110
Insulin-stimulated glucose uptake is defective
in patients with type 2 diabetes. 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 hyperglycemia
and glucose intolerance (peak glucose of 337 ± 19 vs. 185-209
mg/dl in the same groups on the high-fat, high-sugar diet and 293 ± 13 vs. 166-194 mg/dl on standard chow). Hyperinsulinemic clamps
showed that transporter overexpression elevated insulin-stimulated
glucose utilization on standard chow (49 ± 4 mg · kg
1 · min1
in wild-type vs. 61 ± 4, 67 ± 5, and 63 ± 6 mg · kg1 · min1
in GLUT-1, GLUT-4, and GLUT-1 and -4 transgenic mice given 20 mU · kg1 · min1
insulin, and 54 ± 7, 85 ± 4, and 98 ± 11 in wild-type,
GLUT-1, and GLUT-4 mice given 60-80
mU · kg1 · min1
insulin). On the high-fat, high-sugar diet, wild-type and GLUT-1 mice
developed marked insulin resistance, but GLUT-4 and GLUT-1 and -4 mice
were somewhat 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 · kg1 · min1
in wild 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 utilization and prevents the development of fasting hyperglycemia and glucose intolerance induced by a high-fat, high-sugar diet. GLUT-4 overexpression improves the insulin resistance induced by the diet. We conclude that upregulation of glucose transporters in skeletal muscle may be an effective therapeutic approach to the treatment of human type 2 diabetes.
diabetes mellitus; obesity; transgenic mice; glucose clamp technique; glucose transport
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