Ranheim T, Dumke C, Schueler K L, Cartee G D, Attie A D
Department of Biochemistry and Comparative Biosciences, University of Wisconsin-Madison 53706, USA.
Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):3286-93. doi: 10.1161/01.atv.17.11.3286.
Insulin resistance is a common syndrome that often precedes the development of noninsulin-dependent diabetes mellitus (NIDDM). Both diet and genetic factors are associated with insulin resistance. BTBR and C57BL/6J (B6) mice have normal insulin responsiveness and normal fasting plasma insulin levels. However, a cross between these two strains yielded male offspring with severe insulin resistance. Surprisingly, on a basal diet (6.5% fat), the insulin resistance was not associated with fasting hyperinsulinemia. However, a 15% fat diet produced significant hyperinsulinemia in the male mice (twofold at 10 weeks; P < .05). At 10 weeks of age, visceral fat contributed approximately 4.3% of the total body weight in the males versus 1.8% in females. In the males, levels of plasma triacylglycerol and total cholesterol increased 40% and 30%, respectively, compared to females. Plasma free fatty acid concentrations were unchanged. Oral glucose tolerance tests revealed significant levels of hyperglycemia and hyperinsulinemia 15 to 90 minutes after oral glucose administration in the male mice. This was particularly dramatic in males on a 15% fat diet. Glucose transport was examined in skeletal muscles in (BTBR x B6)F1 mice. In the nonhyperinsulinemic animals (females), insulin stimulated 2-deoxyglucose transport 3.5-fold in the soleus and 2.8-fold in the extensor digitorum longus muscles. By contrast, glucose transport was not stimulated in the hyperinsulinemic male mice. Hypoxia stimulates glucose transport through an insulin-independent mechanism. This is known to involve the translocation of GLUT4 from an intracellular pool to the plasma membrane. In the insulin-resistant male mice, hypoxia induced glucose transport as effectively as it did in the insulin-responsive mice. Thus, defective glucose transport in the (BTBR x B6)F1 mice is specific for insulin-stimulated glucose transport. This is similar to what has been observed in muscles taken from obese NIDDM patients. These animals represent an excellent genetic model for studying insulin resistance and investigating the transition from insulin resistance in the absence of hyperinsulinemia to insulin resistance with hyperinsulinemia.
胰岛素抵抗是一种常见综合征，常先于非胰岛素依赖型糖尿病（NIDDM）的发生。饮食和遗传因素均与胰岛素抵抗有关。BTBR和C57BL/6J（B6）小鼠具有正常的胰岛素反应性和正常的空腹血浆胰岛素水平。然而，这两个品系之间的杂交产生了具有严重胰岛素抵抗的雄性后代。令人惊讶的是，在基础饮食（6.5%脂肪）情况下，胰岛素抵抗与空腹高胰岛素血症无关。然而，15%脂肪饮食使雄性小鼠出现显著的高胰岛素血症（10周时增加两倍；P < 0.05）。在10周龄时，雄性小鼠的内脏脂肪占总体重的约4.3%，而雌性为1.8%。与雌性相比，雄性小鼠的血浆三酰甘油和总胆固醇水平分别升高了40%和30%。血浆游离脂肪酸浓度未改变。口服葡萄糖耐量试验显示，雄性小鼠口服葡萄糖后15至90分钟出现显著的高血糖和高胰岛素血症。在15%脂肪饮食的雄性小鼠中尤为明显。对（BTBR×B6）F1小鼠的骨骼肌葡萄糖转运进行了检测。在非高胰岛素血症动物（雌性）中，胰岛素刺激比目鱼肌中2-脱氧葡萄糖转运增加3.5倍，趾长伸肌中增加2.8倍。相比之下，高胰岛素血症雄性小鼠的葡萄糖转运未受刺激。缺氧通过一种不依赖胰岛素的机制刺激葡萄糖转运。已知这涉及GLUT4从细胞内池转位到质膜。在胰岛素抵抗的雄性小鼠中，缺氧诱导葡萄糖转运的效果与胰岛素反应性小鼠相同。因此，（BTBR×B6）F1小鼠中葡萄糖转运缺陷是胰岛素刺激的葡萄糖转运所特有的。这与肥胖NIDDM患者肌肉中观察到的情况相似。这些动物是研究胰岛素抵抗以及探究从无高胰岛素血症时的胰岛素抵抗到伴有高胰岛素血症时的胰岛素抵抗转变的优良遗传模型。
