ROLE OF ENPP1 IN INSULIN RESISTANCE WITHOUT OBESITY

ENPP1 在无肥胖的胰岛素抵抗中的作用

• 批准号: 7724111
• 负责人: Nicola Abate
• 金额: $ 1.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7724111
• 关键词: Accounting; Adipose tissue; Asian Indian; Biological Markers; Body fat; Cardiovascular system; Caucasians; Caucasoid Race; Computer Retrieval of Information on Scientific Projects Database; Condition; Data; Diabetes Mellitus; Environmental Risk Factor; Esterified Fatty Acids; Ethnic Origin; Ethnic group; Evaluation; Fasting; Fatty acid glycerol esters; Foundations; Functional disorder; Funding; Genetic; Goals; Grant; Hepatic; Individual; Institution; Insulin; Insulin Resistance; International; Intervention; Leptin; Metabolic; Metabolism; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Numbers; Obesity; Pilot Projects; Plasma; Play; Predisposition; Prevention; Recruitment Activity; Research; Research Personnel; Resources; Role; Source; South Asian; Techniques; Testing; United States National Institutes of Health; Work; abdominal fat; adiponectin; base; ethnic difference; ethnic minority population; glucose production; metabolic abnormality assessment; non-diabetic; oxidation; stable isotope; volunteer; waist circumference

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. The central goal of this project is to assess the mechanisms of adipose tissue insulin resistance. In this R01, we will examine ex vivo adipose tissue metabolism among non-obese individuals of all ethnicities. Whole-body metabolic assessments including euglycemic - hyperinsulinemic clamps are central to this project. As a consequence of this work and observations in other labs, it is becoming increasingly evident that there are significant ethnic differences in susceptibility to metabolic complications of obesity, particularly type 2 diabetes. For example, we have shown that Asian Indians have significantly higher insulin resistance compared to Caucasians for similar BMI, body fat and lower waist circumference, even below the cutoffs suggested by the International diabetes foundation. We have established that Asian Indians with increased insulin resistance compared to Caucasians do not have increased abdominal fat contrary to popular misconception among investigators. More recently, we have found that the plasma concentration of adipose tissue metabolites leptin and non-esterified fatty acids (NEFAs) were higher and that of adiponectin were lower in insulin resistant healthy Asian Indians compared to more insulin sensitive Caucasians. Again, these differences in biomarkers of adipose tissue metabolism are not explained by degree of adiposity or by fat distribution. Taken together, these studies support the notion that adipose tissue metabolism is dysfunctional in Asian Indians susceptible to insulin resistance evening the absence of obesity. However, the role of hepatic glucose production and hepatic contribution to increased plasma free fatty acid in ethnic differences in NEFA is still not understood. We therefore propose to extend our lab's current work on ENPP1 and adipose tissue, and to compare hepatic b oxidation and hepatic glucose production by stable isotope technique in healthy young Asian Indians and Caucasians matched for total body fat. The overall hypothesis of the project is that ethnic minorities will have defective hepatic beta oxidation which will explain increased plasma NEFA and insulin resistance independent of obesity. The long term goal of our proposal is to determine the mechanisms whereby hepatic beta oxidation and adipose tissue dysfunction account for susceptibility to insulin resistance in all US ethnic minorities. However, this proposal will focus on comparing South Asians with Caucasians for a variety of reasons, including the rapidly growing number of South Asians in the US, the presence of established susceptibility to insulin resistance in South Asians, the need for extensive metabolic studies and the limited duration of this grant mechanism and our track record of effectively recruiting these subjects. The specific aim and hypothesis to be tested are: To compare hepatic glucose production and hepatic beta oxidation in non-diabetic volunteers of Caucasian and South Asian descent. The hypothesis for this specific aim is that South Asians will have increased hepatic glucose production and decreased beta oxidation compared to Caucasians, independent of total and abdominal fat content. The result form this study will establish if defective hepatic beta oxidation plays a role in ethnic susceptibility to higher NEFA and insulin resistance, especially in South Asians. If confirmed, the data from this study will set the bases for further evaluation of the genetic/ environmental factors that are mechanistically responsible for adipose tissue dysfunction, and for identifying biomarkers and possible targets of intervention for more effective prevention of type 2 diabetes and related cardiovascular complications in all US ethnic groups. To accomplish this aim we will study 20 South Asian and 20 Caucasians as pilot study who are non-obese and non diabetic. We will study them in fasting condition.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目的中心目标是评估脂肪组织胰岛素抵抗的机制。 在本 R01 中，我们将检查所有种族非肥胖个体的离体脂肪组织代谢。 全身代谢评估（包括正常血糖-高胰岛素钳夹）是该项目的核心。这项工作和其他实验室的观察结果表明，肥胖代谢并发症（尤其是 2 型糖尿病）的易感性存在显着的种族差异，这一点变得越来越明显。例如，我们发现，在体重指数、体脂和腰围相似的情况下，亚裔印度人的胰岛素抵抗明显高于白人，甚至低于国际糖尿病基金会建议的临界值。我们已经确定，与白种人相比，胰岛素抵抗较高的亚洲印度人的腹部脂肪并未增加，这与研究人员普遍的误解相反。最近，我们发现，与胰岛素敏感的白种人相比，胰岛素抵抗的健康亚洲印度人的脂肪组织代谢物瘦素和非酯化脂肪酸（NEFA）的血浆浓度较高，而脂联素的血浆浓度较低。同样，脂肪组织代谢生物标志物的这些差异不能用肥胖程度或脂肪分布来解释。总而言之，这些研究支持这样的观点：即使没有肥胖，亚洲印度人的脂肪组织代谢也存在功能障碍，容易产生胰岛素抵抗。然而，在 NEFA 种族差异中，肝脏葡萄糖生成和肝脏对血浆游离脂肪酸增加的贡献仍不清楚。 因此，我们建议扩展我们实验室目前在 ENPP1 和脂肪组织方面的工作，并通过稳定同位素技术在与全身脂肪匹配的健康年轻亚洲印度人和白种人中比较肝 b 氧化和肝葡萄糖产生。该项目的总体假设是，少数族裔的肝脏β氧化存在缺陷，这可以解释血浆NEFA和胰岛素抵抗的增加，而与肥胖无关。我们提案的长期目标是确定肝脏β氧化和脂肪组织功能障碍导致美国所有少数民族对胰岛素抵抗的易感性的机制。然而，出于多种原因，该提案将侧重于将南亚人和白人进行比较，包括美国南亚人数量的迅速增长、南亚人对胰岛素抵抗的易感性、广泛代谢研究的需要以及该资助机制的期限有限，以及我们有效招募这些受试者的记录。要测试的具体目标和假设是： 比较白种人和南亚裔非糖尿病志愿者的肝脏葡萄糖产生和肝脏β氧化。这一具体目标的假设是，与白种人相比，南亚人的肝脏葡萄糖生成量增加，β 氧化减少，与总脂肪和腹部脂肪含量无关。 这项研究的结果将确定肝脏 β 氧化缺陷是否在种族易感性较高的 NEFA 和胰岛素抵抗中发挥作用，特别是在南亚人中。如果得到证实，这项研究的数据将为进一步评估导致脂肪组织功能障碍的遗传/环境因素奠定基础，并为识别生物标志物和可能的干预目标奠定基础，以更有效地预防 2 型糖尿病和相关心血管疾病美国所有族裔的并发症。为了实现这一目标，我们将对 20 名非肥胖且非糖尿病的南亚人和 20 名白种人进行试点研究。我们将在禁食条件下研究它们。