BETA-CELL LIPOTOXICITY IN MA: PROT 1: EFFECT OF GLUCOSE TOXICITY ON B-CELL FUNCT

MA 中的 β 细胞脂毒性：PROT 1：葡萄糖毒性对 B 细胞功能的影响

• 批准号: 7627483
• 负责人: KENNETH CUSI
• 金额: $ 10.51万
• 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/7627483
• 关键词: Animals; Area; Beta Cell; Cell physiology; Cells; Clinical Research; Complex; Computer Retrieval of Information on Scientific Projects Database; Defect; Development; Elevation; Epidemic; Ethnic group; Failure; Family history of; Funding; Future; Genetic; Glucose; Grant; High Prevalence; Human; Hyperglycemia; Hyperinsulinism; In Vitro; Individual; Infusion procedures; Institution; Insulin; Insulin Resistance; Intravenous; K-Series Research Career Programs; Knowledge; Lead; Lipids; Liver; Magnetic Resonance Spectroscopy; Mexican Americans; Muscle; 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; Scanning; Source; Structure of beta Cell of islet; Toxic effect; United States National Institutes of Health; Vertebral column; acipimox; 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. 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. 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 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 has a "lipotoxic" effect on insulin secretion in non-diabetic subjects predisposed to develop T2DM. This observation in humans confirmed 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 toward 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 on insulin secretion in MxAm subjects genetically predisposed to T2DM. We plan to expand these findings in the following areas: (1) 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; (2) 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 (3) 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. In summary, 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. Subjects will receive liver and muscle MRS scans.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 众所周知，2型糖尿病（T2 DM）是一个主要的公共卫生问题，在不久的将来只会变得更糟。 2型糖尿病（T2 DM）的发病机制的特征在于胰岛素分泌和胰岛素作用的缺陷。 在最近的研究中，我们已经表明，在遗传上易患T2 DM的墨西哥裔美国人（MxAm）非糖尿病受试者中，高胰岛素血症和胰岛素抵抗早在高血糖症发生之前就已存在，即父母中有两个T2 DM的个体是种族群体中T2 DM患病率最高的个体之一（约50%）。 在职业发展奖的支持下，我们最近证明，在MxAMFH+中，4天静脉脂质输注（Lyposyn III）可导致血浆FFA浓度生理性升高（约500-700 mU/ml），显著损害胰岛素分泌。 相比之下，在没有T2 DM家族史（FH-）的匹配对照组中，相同的脂质输注增强了β细胞功能。 这是第一项临床研究，表明血浆FFA浓度升高对易患T2 DM的非糖尿病受试者的胰岛素分泌具有“脂毒性”作用。 在人体中的这一观察结果证实了早期在体外和动物体内的报告，即长时间的FFA暴露可能对β细胞功能有害。 这一新的发现代表了理解脂毒性在MxAmFH+胰腺β细胞衰竭发展中的潜在作用的第一步。 然而，β细胞脂毒性与其他因素（即，葡萄糖毒性、胰岛素抵抗等）在T2 DM发病机制中的作用需要更仔细地表征。 没有研究关注在遗传上易患T2 DM的MxAm受试者中血浆FFA水平升高、高血糖症和胰岛素抵抗对胰岛素分泌的复杂相互作用。 我们计划在以下领域扩展这些发现：（1）血浆FFA升高损害FH+受试者中β细胞功能的机制，特别是脂毒性如何与其他因素相互作用，如葡萄糖毒性和胰岛素抵抗;（2）β细胞脂毒性在多大程度上取决于FH+受试者的遗传结构与胰岛素作用的获得性缺陷（即，肥胖和/或胰岛素抵抗）;和（3）是否通过显著降低血浆FFA来改善β-细胞脂毒性（即，与阿昔莫司（一种抗脂解剂）联合使用可以改善倾向于β-细胞衰竭的受试者（例如MxAm FH+受试者）的胰岛素分泌。 总之，T2 DM的流行程度需要更好地了解导致β细胞衰竭的机制以及如何预防T2 DM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T2 DM的因素的理解的重要空白。 所获得的知识将作为T2 DM高风险受试者预防计划的基础。 受试者将接受肝脏和肌肉MRS扫描。