Role of Free Fatty Acids in Human Insulin Metabolism

游离脂肪酸在人体胰岛素代谢中的作用

• 批准号: 6755036
• 负责人: DANIEL T STEIN
• 金额: $ 31.31万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6755036
• 关键词: clearance rate; clinical research; dietary lipid; free fatty acids; glucose clamp technique; glucose tolerance; hormone metabolism; human subject; hyperinsulinism; insulin; insulin sensitivity /resistance; lipid metabolism; liver cells; muscle cells; noninsulin dependent diabetes mellitus; noninvasive diagnosis; nuclear magnetic resonance spectroscopy; nutrition related tag; pancreatic islet function; saturated fatty acids; stable isotope; triglycerides; unsaturated fatty acids

Increased availability of lipid substrates, particularly plasma non-esterified free fatty acids and intracellular triglyceride stores have been linked to many aspects of the insulin resistance syndrome including obesity, dyslipidemia and Type 2 diabetes. Epidemiologic and animal data suggest that saturated fats have differential effects on the induction of insulin resistance as well as their effects (both stimulatory and inhibitory) on beta cell function compared to unsaturated fats. Current medical guidelines suggest limiting fat, particularly saturated fat intake. Surprisingly, considering the potential public health implications of dietary fat intake, little direct experimental data exists for human subjects in this area, and available data is contradictory. The goal of these studies, therefore, is to explore the effect of lipids on normal beta cell physiology and then to directly test the hypothesis that dietary saturated fatty acids time dependently stimulate insulin secretion more and then induce greater degrees of insulin secretory dysfunction with prolonged exposure as compared to unsaturated fats using the novel method of in vivo stable isotope peptide pharmacokinetics. As beta cell function deteriorates with prolonged NEFA exposure, hyperinsulinemia matching the degree of insulin resistance will be maintained by decreases in systemic and hepatic insulin clearance. We will also test the proposition that subjects at risk for Type 2 diabetes will be more sensitive to the effects of saturates compared to normal controls. Lastly we hypothesize that for the group as a whole, defects in insulin action, insulin clearance and finally beta cell secretory function will be exactly paralleled by accumulations of intracellular triglycerides in multiple tissues including within hepatocytes and skeletal myocytes as monitored non-invasively by magnetic resonance proton spectroscopy and that this provides the unifying link to systemic organ dysfunction with abnormal lipid metabolism in the insulin resistance syndromes. Preliminary data support the feasibility of our approach as well as our hypothesis. An improved understanding of beta cell - lipid interactions should provide evidence for future dietary recommendations to prevent type 2 diabetes.

脂质底物，特别是血浆非酯化游离脂肪酸和细胞内甘油三酯储存的可用性增加与胰岛素抵抗综合征的许多方面有关，包括肥胖症、血脂异常和2型糖尿病。 流行病学和动物数据表明，与不饱和脂肪相比，饱和脂肪对胰岛素抵抗的诱导以及对β细胞功能的影响（刺激和抑制）具有不同的作用。目前的医学指南建议限制脂肪，特别是饱和脂肪的摄入。 令人惊讶的是，考虑到膳食脂肪摄入的潜在公共卫生影响，在这方面几乎没有直接的实验数据存在于人类受试者，现有的数据是矛盾的。 因此，这些研究的目的是探索脂质对正常β细胞生理学的影响，然后使用体内稳定同位素肽药代动力学的新方法，直接测试以下假设：与不饱和脂肪相比，膳食饱和脂肪酸时间依赖性地刺激胰岛素分泌更多，然后诱导更大程度的胰岛素分泌功能障碍。 由于β细胞功能随着长期NEFA暴露而恶化，与胰岛素抵抗程度相匹配的高胰岛素血症将通过全身和肝脏胰岛素清除率的降低来维持。 我们还将测试这样的命题，即与正常对照相比，有2型糖尿病风险的受试者对饱和物的影响更敏感。 最后，我们假设，对于整个组，胰岛素作用的缺陷，胰岛素清除和最终β细胞分泌功能将被细胞内甘油三酯在多种组织中的积累精确地抑制，所述组织包括肝细胞和骨骼肌细胞内，如监测的非并且这提供了与胰岛素中脂质代谢异常的全身器官功能障碍的统一联系抵抗综合征 初步数据支持我们的方法的可行性以及我们的假设。 对β细胞-脂质相互作用的更好理解应该为未来预防2型糖尿病的饮食建议提供证据。