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: 7600845
• 负责人: Nicola Abate
• 金额: $ 1.51万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600845
• 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 labs 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。 该项目的核心目标是评估脂肪组织胰岛素抵抗的机制。 在此R01中，我们将研究所有种族的非肥胖个体中的体内脂肪组织代谢。 全身代谢评估在内，包括高糖症 - 高胰岛素夹是该项目的核心。由于这项工作和其他实验室的观察结果，越来越明显的是，肥胖代谢并发症的易感性存在很大的种族差异，尤其是2型糖尿病。例如，我们已经表明，与高加索人相比，亚洲印第安人的胰岛素抵抗力明显高于类似的BMI，体内脂肪和较低的腰围，甚至低于国际糖尿病基金会建议的截止。我们已经确定，与高加索人相比，胰岛素抵抗性增加的亚洲印第安人并没有增加腹部脂肪，这与研究人员之间的普遍误解相反。最近，我们发现脂肪组织代谢物瘦素的血浆浓度和非层化脂肪酸（NEFA）较高，与更胰岛素敏感的高加索人相比，胰岛素抵抗健康的亚洲印第安人的脂联素浓度较低。同样，脂肪组织代谢的生物标志物上的这些差异不能通过肥胖程度或脂肪分布来解释。综上所述，这些研究支持这样的观念，即在亚洲印第安人易受胰岛素抵抗的夜晚，脂肪组织代谢功能失调。然而，仍然尚不清楚肝葡萄糖产生和肝贡献对增加血浆脂肪酸在NEFA种族差异中的作用。 因此，我们建议扩展实验室在ENPP1和脂肪组织上的当前工作，并通过在健康的年轻亚洲印度人中通过稳定的同位素技术和与总体内脂肪相匹配的肝B氧化和肝葡萄糖产生。该项目的总体假设是，少数族裔将具有有缺陷的肝β氧化，这将解释血浆NEFA的增加和胰岛素抵抗，而与肥胖无关。我们建议的长期目标是确定肝β氧化和脂肪组织功能障碍的机制，解释了所有美国少数族裔胰岛素抵抗的易感性。但是，由于各种原因，该提案将着重于将南亚人与高加索人进行比较，包括在美国迅速增长的南亚人，南亚人对胰岛素抵抗的既定能力，对广泛的代谢研究的需求以及对这种赠款机制有限的持久性以及我们有效地招募这些主题的记录。要测试的具体目的和假设是：比较高加索和南亚血统的非糖尿病志愿者中的肝葡萄糖产生和肝β氧化。与高加索人相比，这种特定目的的假设是，与高加索人相比，南亚人将增加肝葡萄糖产生，并减少β氧化，而与总脂肪和腹部脂肪含量无关。 该研究的结果表格将确定有缺陷的肝β氧化是否在对更高NEFA和胰岛素抵抗的种族敏感性中，尤其是在南亚人中起作用。如果得到证实，这项研究的数据将设定基础，以进一步评估机械责任脂肪组织功能障碍的遗传/环境因素，并确定生物标志物和可能更有效预防2型糖尿病和所有族裔的相关心血管复杂性的生物标志物和可能的靶标。为了实现这一目标，我们将研究20个南亚和20名高加索人作为非肥胖和非糖尿病的试点研究。我们将在禁食条件下研究它们。