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: 7718686
• 负责人: RALPH A DEFRONZO
• 金额: $ 0.21万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7718686
• 关键词: Address; Adipose tissue; Affect; American; Amino Acids; Arts; Biopsy; Caucasians; Caucasoid Race; Computer Retrieval of Information on Scientific Projects Database; DNA; DNA Sequence; Defect; Development; Disease; Enzymes; Ethnic group; Fasting; Frequencies; Funding; GLUT 4 protein; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Gluconeogenesis; Glucose; Glucose Intolerance; Glycogen; Glycogen (Starch) Synthase; Glycolysis; Grant; Harvest; Healthcare Systems; Hepatic; Hexokinase 2; Hyperglycemia; Immunoblotting; Impairment; In Vitro; Inherited; Institution; Insulin; Insulin Resistance; Investigation; Laboratories; Leukocytes; Life; Liver; Maps; Measurement; Measures; Messenger RNA; Metabolic; Metabolic Diseases; Methodology; Mexican Americans; Molecular; Molecular Abnormality; Molecular Epidemiology; Muscle; Natural History; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Parents; Pathogenesis; Pathway interactions; Patients; Peripheral; Phosphorylation; Plasma; Population; RNase protection assay; Rate; Regulation; Research; Research Personnel; Resources; Risk; SLC2A1 gene; Source; Staging; Susceptibility Gene; Therapeutic; Tissues; Translations; United States National Institutes of Health; Whole Blood; anaerobic glycolysis; base; clinically relevant; glucose disposal; glucose metabolism; glucose production; glucose transport; health care delivery; in vivo; insulin receptor tyrosine kinase; insulin secretion; oxidation; pyruvate dehydrogenase

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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：非胰岛素依赖型糖尿病(NIDDM)是一种常见的代谢性疾病，影响着约1000万美国人，在墨西哥裔美国人中发病率增加。这种疾病和相关并发症的治疗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研究，但导致糖耐量异常的主要代谢和分子异常仍不清楚。有明显空腹高血糖的NIDDM患者的特点是存在无数涉及胰岛素分泌和胰岛素作用的缺陷。胰岛素抵抗已被证明影响所有的胰岛素靶组织，包括肌肉、脂肪组织和肝脏，并涉及已检测的所有葡萄糖代谢途径。胰岛素受体酪氨酸激酶、葡萄糖转运、糖原合成、总糖酵解、厌氧糖酵解、葡萄糖氧化、肝脏葡萄糖生成和糖异生的紊乱已被描述。然而，在NIDDM自然历史的后期阶段，很难确定哪些缺陷是原发的，因此是遗传的，哪些缺陷是继发于失代偿代谢状态(即高血糖、胰岛素减少、血浆游离脂肪酸/氨基酸水平和氧化率升高)。 为了解决这个问题，我们将采用全面的代谢/分子方法来研究两位患有NIDDM的墨西哥裔美国父母的正常糖耐量后代。我们已经证明，后代在胰岛素作用方面有明显的损害，并且可能携带胰岛素抵抗基因(S)，该基因容易在以后的生活中发展为非胰岛素依赖型糖尿病。将从全血和白细胞中提取DNA，以研究DNA多态性和胰岛素抵抗的标记基因，并开发NIDDM的遗传图谱。 研究计划和方法：我们的研究将采用本实验室开发的最先进的方法学，在体内从整体和肌肉水平定量检测以下各项：葡萄糖转运、葡萄糖磷酸化、总糖酵解、厌氧糖酵解、葡萄糖氧化和糖原合成。这些体内测量将与体外定量关键肌肉酶(己糖激酶II、糖原合成酶、丙酮酸脱氢酶、磷酸果糖激酶)的活性相关，这些酶参与通过葡萄糖处置的主要途径调节通量。己糖激酶II、糖原合成酶和GLUT 4转运蛋白基因将从从外周血白细胞中提取的DNA中测序。分别采用免疫印迹和核糖核酸酶保护试验，检测股外侧肌活检组织中己糖激酶II/糖原合成酶/GLUT 4蛋白和mRNA的含量。通过将转录、翻译和酶活性的定量测量与正常糖耐量、胰岛素抵抗高危人群体内的通量相结合，我们希望能够确定导致墨西哥裔美国人II型糖尿病发病的早期代谢和分子缺陷(S)。 临床相关性：从质量的角度来看，墨西哥裔美国人的NIDDM的代谢缺陷与高加索人的相似，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)，仅在这一种族中定义NIDDM的原因就具有重大的科学、治疗和医疗保健意义。