MOLECULAR EPIDEMIOLOGY OF TYPE 2 DIABETES MELLITUS IN MEXICAN AMERICANS

墨西哥裔美国人 2 型糖尿病的分子流行病学

• 批准号: 7378140
• 负责人: RALPH A DEFRONZO
• 金额: $ 9.41万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378140
• 关键词: MOLECULAR; EPIDEMIOLOGY; TYPE; DIABETES; MELLITUS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: Non-insulin dependent diabetes mellitus (NIDDM) is a common metabolic disorder that affects approximately ten million Americans and occurs with increased frequency in Mexican-Americans. The treatment of this disorder and related complications presents a large financial burden on the health care system. Despite numerous investigations into the pathogenesis of NIDDM, the primary metabolic and molecular abnormalities responsible for the glucose intolerance remain unclear. NIDDM patients with overt fasting hyperglycemia are characterized by the myriad of defects involving both insulin secretion and insulin action. The insulin resistance has been shown to affect all insulin target tissues, including muscle, adipose tissue, and liver, and to involve all pathways of glucose metabolism that have been examined. Disturbances in insulin receptor tyrosine kinase, glucose transport, glycogen synthesis, total glycolysis, anaerobic glycolysis, glucose oxidation, hepatic glucose production, and gluconeogenesis have been described. However, at this late stage in the natural history of NIDDM it is difficult to establish which defects are primary, and therefore inherited, and which defects are acquired secondarily to the decompensated metabolic state (i.e., hyperglycemia, insulinopenia, elevated plasma free fatty acid/amino acid levels and oxidation rate). To address this issue we will employ a comprehensive metabolic/molecular approach to study the normal glucose tolerant offspring of two Mexican-American parents with NIDDM. We have shown that the offspring have a marked impairment in insulin action and presumably are carrying the insulin resistant gene(s) that predispose to development of NIDDM later in life. DNA will be isolated from whole blood and WBC's in order to study DNA polymorphisms and marker genes for insulin resistance and to develop inheritance maps for NIDDM. RESEARCH PLAN AND METHODS: Our studies will employ state-of-the-art methodology developed in our laboratory to quantitate in vivo at the whole body and muscle level the following: glucose transport, glucose phosphorylation, total glycolysis, anaerobic glycosysis, glucose oxidation, and glycogen synthesis. These in vivo measurements will be correlated with in vitro quantitation of the activity of the key muscle enzymes (hexokinase II, glycogen synthase, pyruvate dehydrogenase, phosphofructokinase) involved in the regulation of flux through the major pathways of glucose disposal. The hexokinase II, glycogen synthase, and GLUT 4 transporter genes will be sequenced from the DNA which is harvested from peripheral leukocytes. Using immunoblot and RNase protection assays, respectively, the amount of hexokinase II/glycogen synthase/GLUT 4 protein and mRNA will be determined in biopsies obtained from the vastus lateralis muscle. By combining quantitative measures of transcription, translation, and enzymatic activity with in vivo fluxes in a normal glucose tolerant, insulin resistant population at high risk to develop NIDDM, we hope to be able to define the early metabolic and molecular defect(s) responsible for the pathogenesis of type II diabetes in Mexican-Americans. CLINICAL RELEVANCE: From the qualitative standpoint, the metabolic defects that characterize NIDDM in Mexican-Americans are similar to those in Caucasians, we believe that our results will have generalized importance and will help to define the genetic basis of type II diabetes in other populations. Mexican-Americans comprise 5% (12 million) of the U.S. population and definition of the cause of NIDDM in this ethnic group alone would have major scientific, therapeutic and healthcare delivery significance.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。目的：非胰岛素依赖型糖尿病（NIDDM）是一种常见的代谢紊乱，影响约一千万美国人，并且在墨西哥裔美国人中发生频率增加。治疗这种疾病和相关并发症给卫生保健系统带来了巨大的财政负担。尽管对NIDDM的发病机制进行了大量的研究，但导致葡萄糖耐受不良的主要代谢和分子异常仍不清楚。具有明显空腹高血糖的NIDDM患者的特征在于涉及胰岛素分泌和胰岛素作用的无数缺陷。胰岛素抵抗已显示影响所有胰岛素靶组织，包括肌肉、脂肪组织和肝脏，并涉及已检查的所有葡萄糖代谢途径。已经描述了胰岛素受体酪氨酸激酶、葡萄糖转运、糖原合成、总糖酵解、无氧糖酵解、葡萄糖氧化、肝葡萄糖产生和肝异生中的紊乱。然而，在NIDDM自然史的这个晚期阶段，难以确定哪些缺陷是原发性的，因此是遗传的，以及哪些缺陷是继发于失代偿代谢状态（即，高血糖症、胰岛素减少、血浆游离脂肪酸/氨基酸水平和氧化速率升高）。 为了解决这个问题，我们将采用一个全面的代谢/分子方法来研究两个墨西哥裔美国人的父母与NIDDM正常的葡萄糖耐量的后代。我们已经证明，后代有一个明显的损害，胰岛素作用，并推测携带胰岛素抵抗基因（S），易患NIDDM的发展以后的生活。将从全血和WBC中分离DNA，以研究胰岛素抵抗的DNA多态性和标记基因，并开发NIDDM的遗传图谱。 研究方法：我们的研究将采用我们实验室开发的最先进的方法，在全身和肌肉水平对以下内容进行体内定量：葡萄糖转运、葡萄糖磷酸化、总糖酵解、无氧糖基化、葡萄糖氧化和糖原合成。这些体内测量将与参与通过葡萄糖处置的主要途径调节流量的关键肌肉酶（己糖激酶II、糖原合酶、丙酮酸脱氢酶、磷酸果糖激酶）的活性的体外定量相关。将从外周白细胞收获的DNA中对己糖激酶II、糖原合酶和GLUT 4转运蛋白基因进行测序。分别使用免疫印迹和RNA酶保护测定，在从股外侧肌获得的活检中测定己糖激酶II/糖原合酶/GLUT 4蛋白和mRNA的量。通过将转录、翻译和酶活性的定量测量与正常葡萄糖耐受、胰岛素抵抗人群中发生NIDDM的高风险体内通量相结合，我们希望能够确定墨西哥裔美国人II型糖尿病发病机制的早期代谢和分子缺陷。 临床相关性：从定性的角度来看，墨西哥裔美国人NIDDM的代谢缺陷特征与高加索人相似，我们相信我们的结果将具有普遍的重要性，并将有助于确定其他人群中II型糖尿病的遗传基础。墨西哥裔美国人占美国人口的5%（1200万），仅在这一种族群体中定义NIDDM的病因就具有重大的科学、治疗和医疗保健意义。