An examination of the contribution of visceral adiposity to insulin resistance in humans.

2型糖尿病的全球流行与主要的营养和活动变化有关，这些变化与遗传易感性相互作用。2型糖尿病的两个关键缺陷是对胰岛素的反应降低（胰岛素抵抗）和胰岛素产生的相对失败。胰岛素抵抗是最早的缺陷，与心血管风险密切相关。肥胖会产生胰岛素抵抗，但腹内（内脏）脂肪特别重要。内脏脂肪细胞与其他脂肪细胞不同;它们代谢非常活跃，并且不加选择地“溢出”脂肪酸，从而导致肝脏和肌肉中的胰岛素抵抗;它们还产生可能改变胰岛素作用的激素。我们将研究接受腹部手术的人。受试者将为（1）正常体重且对胰岛素敏感，（2）腹部超重且胰岛素抵抗，（3）胰岛素抵抗伴2型糖尿病。我们将记录腹部脂肪、循环脂质和激素水平以及胰岛素作用。在手术中，将从（a）腹腔内，（B）腹部皮肤下的脂肪层和（c）腹部脂肪中获得脂肪活检。将使用DNA阵列在8名受试者中评估脂肪组织中大量基因的活性（第1组和第2组各4名）。然后，根据内脏脂肪和脂肪的不同活性，以及胰岛素敏感和胰岛素抵抗人群之间的不同活性，选择少量基因。将在3组的所有受试者中测定这些基因的活性。我们预计将确定一些（也许3个）基因的活性与胰岛素抵抗密切相关，并将在一系列动物和细胞研究中检查它们阻断胰岛素作用的能力。这些研究应该确定内脏脂肪产生胰岛素抵抗的具体机制。这将是预防和改善2型糖尿病药物治疗的重要一步。

The worldwide epidemic of Type 2 diabetes is related to major nutritional and activity changes interacting with a genetic predisposition. The two key defects in Type 2 diabetes are a reduced response to insulin (insulin resistance) and relative failure of insulin production. Insulin resistance is the earliest defect and is closely associated with cardiovascular risk. Obesity generates insulin resistance, but intraabdominal (visceral) fat has particular importance. Visceral fat cells are different to other fat cells; they are very metabolically active and 'spill out' fatty acids indiscriminately contributing to insulin resistance in liver and muscle; they also produce hormones which may modify the action of insulin. We will study people undergoing abdominal surgery. Participants will be (1) normal weight and sensitive to insulin, (2) abdominally overweight and insulin resistant, (3) insulin resistant with Type 2 diabetes. We will document abdominal fat, circulating lipid and hormone levels and insulin action. At surgery fat biopsies will be obtained from (a) inside the abdominal cavity, (b) the fat layer under the abdominal skin and (c) fat in the buttock. The activity of a large number of genes in the fat tissue will be assessed in 8 subjects using DNA array (4 each from Groups 1 and 2). Then a small number of genes will be selected on the basis of different activity in visceral fat from buttock fat, and between insulin sensitive and insulin resistant people. The activity of these genes will be determined in all subjects in the 3 groups. We anticipate identifying a few (perhaps 3) genes whose activity is closely associated with insulin resistance and will examine their capability to block insulin action in a series of animal and cellular studies. These studies should identify specific mechanisms by which visceral fat creates insulin resistance. This would be an important step towards prevention and improved medication for Type 2 diabetes.