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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。目的：众所周知，2型糖尿病（T2DM）是一个重大的公共卫生问题，在不久的将来只会变得更糟。这对于美国所有退伍军人事务部的医疗机构来说尤其如此，因为他们照顾的是老龄化人口。2型糖尿病（T2DM）的发病机制以胰岛素分泌和胰岛素作用缺陷为特征。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(即父母均为2型糖尿病的个体（MxAmFH+）中，高胰岛素血症和胰岛素抵抗早在高血糖发生之前就存在。MxAmFH+是T2DM患病率最高的族群之一（~ 50%）。在职业发展奖的支持下，我们最近证明，在MxAmFH+中，4天静脉输注脂质（Lyposyn III）导致血浆FFA浓度（~ 500-700 mU/ml）的生理性升高，显著损害胰岛素分泌。相反，在没有2型糖尿病家族史的对照组中，同样的脂质输注增强了β细胞功能。这是首次临床研究表明血浆游离脂肪酸浓度升高对易患2型糖尿病的非糖尿病受试者的胰岛素分泌具有“脂毒性”作用。这一观察结果证实了早期在体外和动物体内对人类的报道，即长期暴露于FFA可能对β细胞功能有害。这一新发现是了解脂肪毒性在MxAmFH+胰腺β细胞衰竭发展中的潜在作用的第一步。然而，β细胞脂肪毒性与其他因素（即葡萄糖毒性、胰岛素抵抗等）在T2DM发病机制中的确切作用需要更仔细地表征。目前还没有研究关注MxAm遗传易感T2DM患者血浆游离脂肪酸水平升高、高血糖和胰岛素抵抗在胰岛素分泌中的复杂相互作用。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升高损害FH+受试者β细胞功能的机制，特别是脂肪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；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的获得性缺陷（即肥胖和/或胰岛素抵抗），后者可能导致胰岛素分泌储备耗尽；iii)通过药理学降低血浆FFA（即使用抗脂药阿昔莫司）改善β细胞脂肪毒性是否可以改善β细胞衰竭患者（如MxAm FH+患者）的胰岛素分泌。临床相关性：2型糖尿病的流行程度需要更好地了解导致β细胞衰竭的机制和预防2型糖尿病的新策略。这一建议将填补我们对导致MxAm人群中β细胞衰竭和2型糖尿病的因素的理解的重要空白。所获得的知识将作为发展高风险科目的预防项目的支柱

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