ROLE OF ENPP1 IN INSULIN RESISTANCE WITHOUT OBESITY

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。 该项目的中心目标是评估脂肪组织胰岛素抵抗的机制。在这个R01中，我们将检查所有种族的非肥胖者的体外脂肪组织代谢。包括正常血糖-高胰岛素钳夹在内的全身代谢评估是该项目的核心。作为这项工作和在其他实验室观察到的结果，越来越明显的是，肥胖，特别是2型糖尿病的代谢并发症的易感性存在显著的种族差异。例如，我们已经表明，与高加索人相比，亚裔印度人的胰岛素抵抗明显更高，他们的BMI、体脂和腰围相似，甚至低于国际糖尿病基金会建议的临界值。我们已经证实，与高加索人相比，胰岛素抵抗增加的亚裔印度人并没有增加腹部脂肪，这与研究人员普遍存在的误解相反。最近，我们发现，与胰岛素敏感的高加索人相比，胰岛素抵抗的健康亚裔印度人的脂肪组织代谢物瘦素和非酯化脂肪酸(NEFAs)的血浆浓度较高，而脂联素的浓度较低。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。综上所述，这些研究支持这样一种观点，即在没有肥胖的情况下，易患胰岛素抵抗的亚裔印度人的脂肪组织代谢紊乱。然而，在NEFA中，肝脏葡萄糖产生和肝脏对血浆游离脂肪酸升高的贡献在种族差异中的作用仍然不清楚。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比较健康的年轻亚裔印度人和高加索人的肝脏b氧化和肝脏葡萄糖产生。该项目的总体假设是，少数民族将有缺陷的肝脏β氧化，这将解释血浆NEFA和胰岛素抵抗增加，而不是肥胖。我们建议的长期目标是确定肝脏β氧化和脂肪组织功能障碍在所有美国少数民族中导致胰岛素抵抗易感性的机制。然而，这项建议将集中于比较南亚人和高加索人，原因有很多，包括美国南亚人的数量迅速增加、南亚人对胰岛素抵抗的易感性、需要广泛的新陈代谢研究、这一资助机制的有限期限以及我们有效招募这些对象的过往记录。测试的具体目标和假设是：比较高加索血统和南亚血统的非糖尿病志愿者的肝脏葡萄糖生成和肝脏β氧化。这一特定目的的假设是，与高加索人相比，南亚人的肝脏葡萄糖产量增加，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对较高的NEFA和胰岛素抵抗的易感性中起作用，特别是在南亚人。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，并确定生物标志物和可能的干预目标，以便在美国所有种族中更有效地预防2型糖尿病和相关的心血管并发症。为了实现这一目标，我们将研究20名南亚人和20名高加索人作为先导研究，他们是非肥胖者和非糖尿病人。我们将在禁食条件下对它们进行研究。

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.