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

基本信息

批准号：
6682519
负责人：
Mary E Patti
金额：
$ 39.37万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
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

项目摘要

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）都会融合以影响基因和蛋白质表达水平的细胞功能，因此我们假设，nondiabetic个体中基因表达的变化是，nondiabetic senterry in Nondiabetic sentery for高风险糖尿病（“糖尿病前”）介导了这种风险。在我们最近对墨西哥裔美国人骨骼肌中差异基因表达的阵列研究中，我们确定了多个核呼吸因子（NRF）调节的氧化代谢和线粒体功能中胰岛素抵抗和糖尿病性受试者中氧化代谢和线粒体功能的调节基因的坐标模式。我们现在已经确定了这些变化的潜在分子机制：PGC-1的表达降低，PGC-1的表达是NRF和PPARGAMMA依赖性转录的共激活因子，与线粒体生物发生和功能有关。定量RT-PCR表明，在胰岛素和糖尿病患者中降低了PGC-1的表达，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代谢变化特征中起着重要作用，包括调节脂质氧化，内部脂质内脂质的积累，脂质内脂质的积累，，脂质内脂质的氧化不足。并进一步胰岛素抵抗。我们将在糖尿病高风险的另外两个人群中检验这一假设：具有糖尿病和非裔美国人种族家族史的受试者。此外，我们将测试通过降低PGC-1和NRF依赖性基因表达的肥胖症和不活动的特定假设，并评估体重减轻和体育锻炼是否可以增加PGC-1表达和反向代谢基因的反向异常模式与提高的胰岛素敏感性并联表达。最后，由于很难剖析单个代谢风险因素对人类PGC-1表达降低的贡献，因此我们将利用培养的细胞来测试营养过量和/或胰岛素抵抗是否可以直接降低PGC-1的表达，并确定并确定PGC-1表达的实验降低是否可以直接诱导细胞内甘油三酸酯的积累和/或胰岛素抵抗。