Marshall B A, Hansen P A, Ensor N J, Ogden M A, Mueckler M
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Am J Physiol. 1999 Feb;276(2):E390-400. doi: 10.1152/ajpendo.1999.276.2.E390.
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. 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 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. kg-1. min-1 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.
2型糖尿病患者的胰岛素刺激的葡萄糖摄取存在缺陷。为了确定肌肉中转基因葡萄糖转运体的过表达是否能预防高脂高糖饮食诱导的糖尿病，将单转基因（GLUT-1、GLUT-4）和双转基因（GLUT-1和-4）小鼠置于高脂高糖饮食或标准饲料饮食中。在高脂高糖饮食中，野生型小鼠而非转基因小鼠出现空腹高血糖和葡萄糖不耐受（高脂高糖饮食组中，野生型小鼠的血糖峰值为337±19mg/dl，而转基因小鼠为185 - 209mg/dl；在标准饲料饮食中，野生型小鼠血糖峰值为293±13mg/dl，转基因小鼠为166 - 194mg/dl）。高胰岛素钳夹试验表明，在标准饲料饮食中，转运体过表达提高了胰岛素刺激的葡萄糖利用（给予20mU·kg⁻¹·min⁻¹胰岛素时，野生型小鼠的葡萄糖利用率为49±4mg·kg⁻¹·min⁻¹，而GLUT-1、GLUT-4以及GLUT-1和-4转基因小鼠分别为61±4、67±5和63±6mg·kg⁻¹·min⁻¹；给予60 - 80mU·kg⁻¹·min⁻¹胰岛素时，野生型、GLUT-1和GLUT-4小鼠的葡萄糖利用率分别为54±7、85±4和98±11mg·kg⁻¹·min⁻¹）。在高脂高糖饮食中，野生型和GLUT-1小鼠出现明显的胰岛素抵抗，但GLUT-4和GLUT-1和-4小鼠受到一定程度的保护（高胰岛素钳夹试验期间，野生型、GLUT-1、GLUT-4、GLUT-1和-4小鼠的葡萄糖利用率分别为28.5±3.4、42.4±5.9、51.2±8.1和55.9±4.9mg·kg⁻¹·min⁻¹）。这些数据表明，GLUT-1和/或GLUT-4的过表达增强了全身葡萄糖利用，并预防了高脂高糖饮食诱导的空腹高血糖和葡萄糖不耐受的发生。GLUT-4的过表达改善了由该饮食诱导的胰岛素抵抗。我们得出结论，上调骨骼肌中的葡萄糖转运体可能是治疗人类2型糖尿病的一种有效治疗方法。
