DIETARY DM

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。 脂肪底物的增加，特别是血浆非酯化游离脂肪酸和细胞内甘油三酯储存的增加与胰岛素抵抗综合征的许多方面有关，包括肥胖、血脂异常和2型糖尿病。流行病学和动物数据表明，饱和脂肪在诱导胰岛素抵抗以及它们对胰岛β细胞功能的影响(包括刺激和抑制)方面具有不同的作用，特别是与不饱和植物脂肪和海洋油脂相比。目前的医学指南建议限制脂肪，特别是饱和脂肪的摄入量。令人惊讶的是，考虑到饮食脂肪摄入对公众健康的潜在影响，在这一领域几乎没有针对人类受试者的直接实验数据。因此，这些研究的目的是利用体内稳定同位素多肽药代动力学的新方法，直接检验这一假说，即与不饱和脂肪相比，饮食饱和脂肪酸具有时间依赖性地刺激更多的胰岛素分泌，从而防止长期暴露于不饱和脂肪的代偿性胰岛素高分泌。随着NEFA暴露时间的延长，β细胞功能亢进的程度逐渐减轻，与胰岛素抵抗程度相匹配的高胰岛素血症将通过降低全身和肝脏的胰岛素清除率来维持。我们还将测试这一假设，即与正常对照组相比，2型糖尿病高危人群对饱和物的影响更敏感。最后，我们假设，作为一个整体，胰岛素作用、胰岛素清除和最终的β细胞分泌功能的缺陷将与磁共振质子谱无创监测的多种组织中细胞内甘油三酯的积累密切相关，包括肝细胞和骨骼肌细胞内的甘油三酯积累，这为胰岛素抵抗综合征中系统性器官功能障碍和脂代谢异常提供了统一的联系。作为这项研究的一部分，参与研究的受试者将接受以下程序：磁共振扫描、静脉注射脂肪乳剂、输注或肝素、稳定同位素标记的葡萄糖、脂质和C-肽、低剂量的胰岛素(猪、门冬氨酸胰岛素、胰岛素-精氨酸)。

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. 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 pancreatic beta cell function, particularly in comparison to unsaturated vegetable and marine oil 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. The goal of these studies therefore, is to directly test the hypothesis that dietary saturated fatty acids time dependently both stimulate the insulin secretion more and then prevent compensatory insulin hypersecretion with prolonged exposure as compared to unsaturated fats using the novel method of in vivo stable isotope peptide pharmacokinetics. As beta cell hyperfunction decreases 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 hypothesis 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 closely 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. Participating subjects will undergo the following procedures as part of this study: magnetic resonance scans, infusion of lipid emulsions i.v., infusion or heparin, stable isotope labeled glucose, lipids and C-peptide, insulins at low doses (porcine, insulin aspart, insulin-arginine).