DIETARY DM

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。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，饱和脂肪对胰岛素抵抗的诱导以及对胰腺β细胞功能的影响（刺激和抑制）具有不同的作用，特别是与不饱和植物和海洋油脂相比。目前的医学指南建议限制脂肪，特别是饱和脂肪的摄入。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。因此，这些研究的目的是使用体内稳定同位素肽药代动力学的新方法，直接检验以下假设：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，然后防止代偿性胰岛素分泌过多。由于β细胞功能亢进随着长期NEFA暴露而降低，因此与胰岛素抵抗程度匹配的高胰岛素血症将通过全身和肝脏胰岛素清除率降低来维持。我们还将检验以下假设：与正常对照组相比，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，胰岛素清除和最后β细胞分泌功能将密切受到细胞内甘油三酯在多种组织中的积累的影响，包括在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作为本研究的一部分，参与受试者将接受以下程序：磁共振扫描、静脉输注脂肪乳剂，输注或肝素、稳定同位素标记的葡萄糖、脂质和C肽、低剂量胰岛素（猪胰岛素、门冬胰岛素、精氨酸胰岛素）。

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).