Fat Cell Size, Muscle Lipid and Insulin Resistance

脂肪细胞大小、肌肉脂质和胰岛素抵抗

• 批准号: 6409439
• 负责人: Eric Ravussin
• 金额: $ 61.33万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6409439
• 关键词: adipocytes; cell differentiation; cell proliferation; clinical research; computed axial tomography; diabetes mellitus genetics; gender difference; gene expression; human subject; insulin sensitivity /resistance; lipid disorder; lipid metabolism; liver metabolism; muscle metabolism; noninsulin dependent diabetes mellitus; obesity; polymerase chain reaction; striated muscles; weight loss

DESCRIPTION (provided by applicant): There is growing evidence that the development of Type 2 diabetes is precipitated by alterations in the partitioning of fat between the adipose tissue vs. muscle, liver and pancreas. Intracellular accumulation of triglyceride and fatty acid metabolites leads to acquired insulin signaling defect and insulin resistance. One can, therefore, hypothesize that the inability of the adipose organ to expand to accommodate excess calories results in adipose tissue hypertrophy and Type 2 diabetes in predisposed obese subject. Such a hypothesis is now clearly supported by the following data: 1) Pima Indians with larger abdominal fat cells are more likely to develop diabetes than obesity-matched subjects with smaller fat cells; 2) thiazolidinediones improve insulin sensitivity by inducing adipocyte differentiation; 3) subjects with acquired total lipodystrophy (like fatless mice) are severely diabetic; 4) insulin sensitivity is inversely proportional to the triglyceride content of the muscle. In this application, we want to test the following hypotheses: 1) muscle lipid content correlates positively with abdominal subcutaneous adipocyte size in Type 2 diabetics and obesity-, sex-, and age-matched nondiabetics; 2) larger adipocytes are associated with greater weight loss and better improvement in insulin sensitivity after one year of intensive lifestyle treatment; 3) expression of genes involved in adipocyte proliferation and differentiation correlates negatively with adipocyte size in Type 2 diabetic and obesity matched non-diabetics. In response to weight loss, the expression of these genes will increase. To test these hypotheses we will perform the following studies: 1) determine the relationship between abdominal subcutaneous fat cell size (biopsy) and muscle fat infiltration (CT scan) in 100 subjects from Look AHEAD Trial and 50 non-diabetic matched for sex, race, age and BMI; 2) identify the effect of abdominal fat cell size on weight loss and improvement in insulin sensitivity (hyperglycemic clamp) after one year of intensive lifestyle treatment in the 100 subjects from the Look AHEAD Trial; 3) quantify in subcutaneous abdominal adipose tissue the expression of genes involved in adipocyte proliferation/differentiation in 100 Type 2 diabetic subjects and 50 non-diabetic subjects. Gene expression will also be measured in Type 2 diabetics after one year of intensive lifestyle changes.

描述(由申请人提供)： 越来越多的证据表明，2型糖尿病的发展是 由脂肪在脂肪之间分配的变化引起的 组织与肌肉、肝脏和胰腺。在细胞内积累的 甘油三酯和脂肪酸代谢产物导致获得性胰岛素信号转导 缺陷和胰岛素抵抗。因此，人们可以假设， 脂肪器官不能膨胀以容纳过量卡路里的结果 肥胖易感人群中脂肪组织肥大与2型糖尿病的关系 这样的假设现在明显得到了以下数据的支持：1)PIMA 腹部脂肪细胞较大的印度人更容易患糖尿病 比肥胖匹配的受试者脂肪细胞小；2)噻唑烷二酮 通过诱导脂肪细胞分化改善胰岛素敏感性；3)受试者 获得性全脂营养不良(如无脂小鼠)患有严重糖尿病；4) 胰岛素敏感性与甘油三酯含量成反比。 肌肉。 在这个应用中，我们想要检验以下假设：1)肌肉脂肪 脂肪含量与腹部皮下脂肪细胞大小呈正相关 2型糖尿病患者和肥胖、性别和年龄匹配的非糖尿病患者；2)更大 脂肪细胞与更大的体重减轻和更好的改善 生活方式强化治疗一年后的胰岛素敏感性；3) 脂肪细胞增殖分化相关基因的表达 2型糖尿病和肥胖者的脂肪细胞大小呈负相关 匹配的非糖尿病患者。作为对减肥的反应，这些表达 基因将会增加。为了验证这些假设，我们将执行以下操作 研究：1)确定腹部皮下脂肪细胞与 100例受试者的大小(活检)和肌肉脂肪渗透(CT扫描) 预先试验和50名在性别、种族、年龄和BMI方面匹配的非糖尿病患者；2)确定 腹部脂肪细胞大小对体重减轻和胰岛素改善的影响 高强度生活方式一年后的敏感性(高血糖钳) 来自前瞻性试验的100名受试者的治疗；3)量化 腹部皮下脂肪组织中相关基因的表达 100例2型糖尿病患者和50例2型糖尿病患者的脂肪细胞增殖/分化 非糖尿病受试者。基因表达也将在II型中进行测量 糖尿病患者经过一年密集的生活方式改变。