Gene Expression in Prediabetes: Potential Role of PGC-1

糖尿病前期的基因表达：PGC-1 的潜在作用

• 批准号: 6790652
• 负责人: Mary E Patti
• 金额: $ 30.41万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790652
• 关键词: African American; aerobiosis; body composition; clinical research; exercise; family genetics; gene expression; glucose tolerance test; human subject; insulin sensitivity /resistance; noninsulin dependent diabetes mellitus; obesity; peroxisome proliferator activated receptor; photon absorptiometry; polymerase chain reaction; prediabetic state; tissue /cell culture; triglycerides; weight loss

DESCRIPTION (provided by applicant): Since both genotype and environmental risk factors for diabetes, including obesity and inactivity, converge to influence cellular function at the level of gene and protein expression, we hypothesize that alterations in gene expression in nondiabetic individuals at high risk for developing diabetes ("prediabetes") mediate this risk. In our recent array studies of differential gene expression in skeletal muscle from Mexican-American subjects, we identified a pattern of coordinate reduction in expression of multiple nuclear respiratory factor (NRF)-regulated genes of oxidative metabolism and mitochondrial function in insulin resistant and diabetic subjects. We have now identified a potential molecular mechanism for these changes: decreased expression of PGC-1, a coactivator of both NRF and PPARgamma-dependent transcription linked to mitochondrial biogenesis and function. Quantitative RT-PCR demonstrates that PGC-1 expression is reduced in insulin resistant and diabetic subjects and correlates with obesity, insulin resistance, and free fatty acid levels. Taken together, these data form the basis of our hypothesis that reductions in PGC-1 and NRF-dependent metabolic gene transcription play an important role in metabolic changes characteristic of insulin resistance and diabetes progression, including inabililty to modulate lipid oxidation, intramuscular lipid accumulation, and further insulin resistance. We will test this hypothesis in 2 additional populations at high risk for diabetes: subjects with a family history of diabetes and African-American ethnicity. Moreover, we will test the specific hypotheses that obesity and inactivity mediate risk in prediabetes via reduction in PGC-1 and NRF-dependent gene expression, and evaluate whether weight loss and physical training can increase PGC-1 expression and reverse abnormal patterns of metabolic gene expression in parallel with improved insulin sensitivity. Finally, since it is difficult to dissect the contribution of individual metabolic risk factors to reductions in PGC-1 expression in humans, we will utilize cultured cells to test whether nutrient excess and/or insulin resistance can directly reduce PGC-1 expression, and determine whether experimental reductions in PGC-1 expression can directly induce intracellular triglyceride accumulation and/or insulin resistance.

描述（由申请人提供）：由于糖尿病的基因型和环境风险因素，包括肥胖和不活动，在基因和蛋白质表达水平上影响细胞功能，我们假设非糖尿病个体中基因表达的改变介导了糖尿病（“前驱糖尿病”）的高风险。在我们最近对墨西哥裔美国人骨骼肌差异基因表达的阵列研究中，我们确定了一种模式，即在胰岛素抵抗和糖尿病受试者中，多个核呼吸因子（NRF）调节的氧化代谢和线粒体功能基因的表达协调减少。我们现在已经确定了这些变化的潜在分子机制：PGC-1的表达减少，PGC-1是与线粒体生物发生和功能相关的NRF和PPARgamma依赖性转录的共激活因子。定量RT-PCR证实PGC-1表达在胰岛素抵抗和糖尿病受试者中降低，并且与肥胖、胰岛素抵抗和游离脂肪酸水平相关。综上所述，这些数据构成了我们假设的基础，即PGC-1和NRF依赖性代谢基因转录的减少在胰岛素抵抗和糖尿病进展的特征性代谢变化中起重要作用，包括不能调节脂质氧化、肌内脂质蓄积和进一步的胰岛素抵抗。我们将在另外2个糖尿病高危人群中检验这一假设：有糖尿病家族史和非裔美国人。此外，我们将测试特定的假设，肥胖和不活动介导的风险，在糖尿病前期通过减少PGC-1和NRF依赖的基因表达，并评估是否减肥和体育锻炼可以增加PGC-1的表达和逆转异常模式的代谢基因表达与改善胰岛素敏感性。最后，由于很难剖析个体代谢危险因素对人类PGC-1表达降低的贡献，我们将利用培养的细胞来测试营养过剩和/或胰岛素抵抗是否可以直接降低PGC-1表达，并确定PGC-1表达的实验性降低是否可以直接诱导细胞内甘油三酯积累和/或胰岛素抵抗。