EFFECT OF ACQUIRED INSULIN RESISTANCE (DEXAMETHASONE-INDUCED) ON INSULIN SECRETN

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。 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，我们发现高胰岛素血症和胰岛素抵抗在墨西哥裔美国人(MxAm)非糖尿病患者(即父母有两个T2 DM(MxAmFH+)的人)发生高血糖之前很久就已经存在。MxAmFH+是各民族中T2 DM患病率最高的人群之一(约50%)。在职业发展奖的支持下，我们最近证明，在MxAMFH+中，为期4天的静脉输注脂肪(Lyposyn III)会导致血浆FFA浓度生理性升高(约500-700 mU/ml)，显著抑制胰岛素分泌。相比之下，在没有T2 DM家族史(FM-)的匹配对照组中，同样的脂肪输注可以增强β细胞功能。这是第一项临床研究表明，血浆FFA浓度升高对非糖尿病易患T2 DM的受试者的胰岛素分泌有“脂毒性”影响。这一观察结果证实了早先在人体和动物体内的报告，即长期接触FFA可能对β细胞功能有害。 这一新的发现代表了理解脂肪毒性在MxAmFH+胰腺β细胞衰竭发展中的潜在作用的第一步。然而，β细胞脂毒性与其他因素(如葡萄糖毒性、胰岛素抵抗等)在T2 DM发病机制中的确切作用需要更仔细地描述。在遗传易感T2 DM的MxAM受试者中，尚无研究集中于血浆FFA水平升高、高血糖和胰岛素抵抗对胰岛素分泌的复杂交互作用。我们计划在以下方面扩展这些发现：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细胞脂毒性在多大程度上依赖于FH+受试者的遗传构建与可能导致胰岛素分泌储备耗竭的获得性胰岛素作用缺陷(即肥胖和/或胰岛素抵抗)；以及iii)通过药物降低血浆FFA(即使用抗脂剂acipimox)来改善β细胞脂毒性是否可以改善易发生β细胞衰竭的受试者的胰岛素分泌，例如MxAm FH+受试者。 总而言之，T2 DM流行的规模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的新战略。这一建议将填补我们对导致MxAM人群中β细胞衰竭和T2 DM的因素的理解的一个重要空白。所获得的知识将作为T2 DM高危人群预防计划的基础。

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 (MxAmFH+). MxAmFH+ have one of the highest prevalence rates of T2DM (approx 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 (approx 500-700 mU/ml) significantly impairs insulin secretion. In contrast, the same lipid infusion in matched controls without a family history of T2DM (FM-) 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 on insulin secretion in MxAM subjects genetically predisposed to T2DM. 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. 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.