The Lundberg Laboratory for Diabetes Research, Center of Excellence for Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SE-413 45, Sweden.
Diabetol Metab Syndr. 2012 Sep 19;4(1):42. doi: 10.1186/1758-5996-4-42.
Obesity contributes to Type 2 diabetes by promoting systemic insulin resistance. Obesity causes features of metabolic dysfunction in the adipose tissue that may contribute to later impairments of insulin action in skeletal muscle and liver; these include reduced insulin-stimulated glucose transport, reduced expression of GLUT4, altered expression of adipokines, and adipocyte hypertrophy. Animal studies have shown that expansion of adipose tissue alone is not sufficient to cause systemic insulin resistance in the absence of adipose tissue metabolic dysfunction. To determine if this holds true for humans, we studied the relationship between insulin resistance and markers of adipose tissue dysfunction in non-obese individuals.
32 non-obese first-degree relatives of Type 2 diabetic patients were recruited. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was measured with the hyperinsulinaemic-euglycaemic clamp. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene/protein expression and adipocyte cell size measurements.
Our findings show that also in non-obese individuals low insulin sensitivity is associated with signs of adipose tissue metabolic dysfunction characterized by low expression of GLUT4, altered adipokine profile and enlarged adipocyte cell size. In this group, insulin sensitivity is positively correlated to GLUT4 mRNA (R = 0.49, p = 0.011) and protein (R = 0.51, p = 0.004) expression, as well as with circulating adiponectin levels (R = 0.46, 0 = 0.009). In addition, insulin sensitivity is inversely correlated to circulating RBP4 (R = -0.61, 0 = 0.003) and adipocyte cell size (R = -0.40, p = 0.022). Furthermore, these features are inter-correlated and also associated with other clinical features of the metabolic syndrome in the absence of obesity. No association could be found between the hypertrophy-associated adipocyte dysregulation and HIF-1alpha in this group of non-obese individuals.
In conclusion, these findings support the concept that it is not obesity per se, but rather metabolic dysfunction of adipose tissue that is associated with systemic insulin resistance and the metabolic syndrome.
肥胖通过促进全身胰岛素抵抗导致 2 型糖尿病。肥胖导致脂肪组织代谢功能障碍的特征，可能导致随后骨骼肌和肝脏胰岛素作用受损；这些特征包括胰岛素刺激的葡萄糖转运减少、GLUT4 表达减少、 adipokine 表达改变和脂肪细胞肥大。动物研究表明，在没有脂肪组织代谢功能障碍的情况下，仅仅扩张脂肪组织不足以导致全身胰岛素抵抗。为了确定这在人类中是否成立，我们研究了非肥胖个体中胰岛素抵抗与脂肪组织功能障碍标志物之间的关系。
招募了 32 名 2 型糖尿病患者的非肥胖一级亲属。通过口服葡萄糖耐量试验确定葡萄糖耐量，并用高胰岛素-正常血糖钳夹法测量胰岛素敏感性。采集血样并获取皮下腹部脂肪组织活检，用于基因/蛋白表达和脂肪细胞大小测量。
我们的发现表明，在非肥胖个体中，低胰岛素敏感性也与脂肪组织代谢功能障碍的迹象相关，其特征是 GLUT4 表达降低、 adipokine 谱改变和脂肪细胞增大。在该组中，胰岛素敏感性与 GLUT4 mRNA（R=0.49，p=0.011）和蛋白（R=0.51，p=0.004）表达以及循环 adiponectin 水平呈正相关（R=0.46，p=0.009）。此外，胰岛素敏感性与循环 RBP4（R=-0.61，p=0.003）和脂肪细胞大小（R=-0.40，p=0.022）呈负相关。此外，这些特征相互关联，并且与肥胖缺失的代谢综合征的其他临床特征相关。在该组非肥胖个体中，未发现与肥大相关的脂肪细胞失调与 HIF-1alpha 之间存在关联。
总之，这些发现支持这样的概念，即与全身胰岛素抵抗和代谢综合征相关的不是肥胖本身，而是脂肪组织的代谢功能障碍。
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