WHOLE-BODY PROTEOLYSIS RATE IS ELEVATED IN HIV-ASSOCIATED INSULIN RESISTANCE

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。 2型糖尿病的特征是葡萄糖代谢受损(IGT)和胰岛素抵抗，但不是氨基酸代谢。我们检查了患有IGT的HIV感染者体内的亮氨酸和蛋白质代谢是否失调。测定了10例HIV血清阴性对照组、16例HIV+正常糖耐量受试者和21例HIV+IGT受试者在空腹胰岛素状态下和正常血糖高胰岛素血症时2H2-葡萄糖和13C-亮氨酸的动态变化。高胰岛素血症时，HIV+IGT组的血糖代谢率低于其他两组。在所有胰岛素水平下，HIV+IGT组的血浆亮氨酸绝对值和出现率(全身蛋白分解)均高于其他两组，但随着高胰岛素血症的出现，亮氨酸绝对值和出现率均下降。HIV+IGT组的内脏肥胖率、空腹血清IL-8和游离脂肪酸水平以及钳夹期间的脂质氧化率均高于其他两组。这些发现涉及胰岛素信号通路中的几个因素，这可能在HIV+IGT中进一步失调，并支持葡萄糖和亮氨酸代谢的胰岛素信号通路可能被促炎脂肪细胞因子(IL-8)增加和脂质氧化增加所破坏的观点。蛋白分解增加可能为糖异生提供氨基酸，从而加剧HIV的高血糖。

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. Type 2 diabetes is characterized by impaired glucose tolerance (IGT) and insulin resistance with respect to glucose metabolism but not amino acid metabolism. We examined whether whole-body leucine and protein metabolism are dysregulated in HIV-infected individuals with IGT. Glucose and leucine kinetics were measured under fasting insulin conditions and during euglycemic hyperinsulinemia using primed-constant infusions of 2H2-glucose and 13C-leucine in 10 HIV-seronegative control subjects, 16 HIV+ subjects with normal glucose tolerance, and 21 HIV+IGT subjects. Glucose disposal rate during hyperinsulinemia was lower in HIV+IGT than the other two groups. Absolute plasma leucine levels and rate of appearance (whole-body proteolysis) were higher in HIV+IGT at all insulin levels but declined in response to hyperinsulinemia in parallel to those in the other two groups. HIV+IGT had greater visceral adiposity, fasting serum interleukin (IL)-8 and free fatty acid levels, and higher lipid oxidation rates during the clamp than the other two groups. These findings implicate several factors in the insulin signaling pathway, which may be further dysregulated in HIV+IGT, and support the notion that insulin signaling pathways for glucose and leucine metabolism may be disrupted by increased proinflammatory adipocytokines (IL-8) and increased lipid oxidation. Increased proteolysis may provide amino acids for gluconeogenesis, exacerbating hyperglycemia in HIV.