ACQUIRED VS GENETIC DETERMINANTS OF BETA-CELL LIPOTOXICITY IN MEXICAN AMERIC

墨西哥裔美国人 β 细胞脂肪毒性的后天性与遗传性决定因素

• 批准号: 7627484
• 负责人: KENNETH CUSI
• 金额: $ 6.36万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627484
• 关键词: Animals; Area; Beta Cell; Caring; Cell physiology; Clinical Research; Complex; Computer Retrieval of Information on Scientific Projects Database; Defect; Development; Elevation; Epidemic; Ethnic group; Failure; Family history of; Funding; Future; Genetic; Genetic Determinism; Glucose; Grant; Health care facility; High Prevalence; Human; Hyperglycemia; Hyperinsulinism; In Vitro; Individual; Infusion procedures; Institution; Insulin; Insulin Resistance; Intravenous; K-Series Research Career Programs; Knowledge; Lead; Lipids; Mexican; Mexican Americans; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Parents; Pathogenesis; Personal Satisfaction; Physiological; Plasma; Population; Prevention program; Public Health; Rate; Reporting; Research; Research Personnel; Resources; Risk; Role; Source; Structure of beta Cell of islet; Toxic effect; United States; United States National Institutes of Health; Vertebral column; acipimox; aging population; clinically relevant; day; exhaust; improved; in vivo; insulin secretion; non-diabetic; novel; prevent

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: It is well known that Type 2 diabetes mellitus (T2DM) is a major public health problem that only will become worse in the near future. This is especially true for all VA Health Care facilities across the United States, given that they take care of an aging population. The pathogenesis of Type 2 diabetes (T2DM) is characterized by defects in insulin secretion and insulin action. In recent studies we have shown that hyperinsulinemia and insulin resistance are present long before the development of hyperglycemia in Mexican-American (MxAm) non-diabetic subjects genetically predisposed to T2DM, i.e. individuals with two T2DM parents (MxAmFH+). MxAmFH+ have one of the highest prevalence rates of T2DM (~ 50%) among ethnic groups. With support of a Career Development Award, we have recently demonstrated that in MxAmFH+, a 4-day intravenous lipid infusion (Lyposyn III) that causes a physiologic elevation in the plasma FFA concentration (~ 500-700 mU/ml) significantly impairs insulin secretion. In contrast, the same lipid infusion in matched controls without a family history of T2DM (FH-) enhanced beta-cell function. This is the first clinical study showing that elevated plasma FFA concentration have a "lipotoxic" effect on insulin secretion in non-diabetic subjects predisposed to develop T2DM. This observation confirmed in humans earlier reports in vitro and in vivo in animals that prolonged FFA exposure could be deleterious to beta-cell function. This novel finding represents a first step towards understanding the potential role of lipotoxicity in the development of pancreatic beta-cell failure in MxAmFH+. However, the precise role of beta cell lipotoxicity in relationship to other factors (i.e., glucose toxicity, insulin resistance, among others) in the pathogenesis of T2DM needs to be more carefully characterized. No studies have focused on the complex interaction between elevated plasma FFA levels, hyperglycemia, and insulin resistance in insulin secretion in MxAm subjects genetically predisposed to T2DM. RESEARCH PLAN AND METHODS: We plan to expand these findings in the following areas; i) the mechanisms by which an elevation in plasma FFA impairs beta-cell function in FH+ subjects, in particular how lipotoxicity interacts with other factors, such as glucose toxicity and insulin resistance; ii) to what degree beta-cell lipotoxicity is dependent upon the genetic build of FH+ subjects vs. acquired defects in insulin action (i.e., obesity and/or insulin resistance) that may contribute to exhaust insulin secretory reserve; and iii) whether ameliorating beta-cell lipotoxicity by pharmacologically lowering plasma FFA (i.e., with acipimox, an antilipolytic agent) can improve insulin secretion in subjects prone to beta-cell failure, such as MxAm FH+ subjects. CLINICAL RELEVANCE: The magnitude of the epidemic of T2DM requires a better understanding of the mechanisms that lead to beta cell failure and new strategies on how to prevent T2DM. This proposal will fill an important gap in our understanding of the factors that lead to beta-cell failure and T2DM in the MxAm population. The knowledge gained will serve as the backbone for prevention programs in subjects at high risk of developing T2DM.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 目的：众所周知，2型糖尿病（T2DM）是一个主要的公共卫生问题，在不久的将来只会变得更糟。 鉴于他们照顾老龄化的人口，美国所有VA医疗保健机构尤其如此。 2型糖尿病（T2DM）的发病机理的特征是胰岛素分泌和胰岛素作用缺陷。 在最近的研究中，我们已经表明，在墨西哥裔美国人（MXAM）非糖尿病受试者的高血糖发展之前，高胰岛素血症和胰岛素抵抗就存在于基因上，即具有两个T2DM父母（MXAMFH+）的个体。 MXAMFH+在族裔群体中的患病率最高（约50％）。 在获得职业发展奖的支持下，我们最近证明，在MXAMFH+中，为期4天的静脉注射脂质输注（Lyposyn III），导致血浆FFA浓度（〜500-700 MU/ML）的生理升高会显着损害胰岛素分泌。 相反，在没有T2DM（FH-）增强β细胞功能家族史的匹配对照中，相同的脂质输注。 这是第一项临床研究，表明血浆FFA浓度升高对易感性T2DM的非糖尿病受试者的胰岛素分泌具有“脂蛋白毒性”作用。 这种观察结果在人类早期的体外报道中证实，在动物的体内报告表明，长时间的FFA暴露可能对β细胞功能有害。 这一新发现是了解脂肪毒性在MXAMFH+中胰腺β细胞衰竭发展中潜在作用的第一步。 但是，β细胞脂肪毒性在与其他因素（即葡萄糖毒性，胰岛素抵抗等）之间的关系中的确切作用需要更仔细地表征T2DM的发病机理。 没有研究集中于血浆FFA水平升高，高血糖和胰岛素耐药性在MXAM受试者的胰岛素分泌中的复杂相互作用之间的相互作用。 研究计划和方法：我们计划在以下领域扩展这些发现； i）血浆FFA升高会损害FH+受试者中β细胞功能的机制，特别是脂肪毒性与其他因素相互作用，例如葡萄糖毒性和胰岛素抵抗； ii）β细胞脂肪毒性在多大程度上取决于FH+受试者的遗传构建与胰岛素作用中获得的缺陷（即肥胖和/或胰岛素抵抗），这可能有助于排气胰岛素分泌储备；和iii）通过药理学降低血浆FFA（即使用Acipimox，抗溶液剂）来改善β细胞脂肪毒性，是否可以改善容易发生β细胞衰竭的受试者的胰岛素分泌，例如MXAM FH+受试者。 临床相关性：T2DM流行的大小需要更好地了解导致β细胞衰竭的机制以及如何预防T2DM的新策略。 该提案将填补我们对导致MXAM人群中β细胞衰竭和T2DM的因素的理解的重要空白。 获得的知识将作为预防计划的骨干，以高风险发展T2DM。