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

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 2型糖尿病的特征在于葡萄糖耐量受损（IGT）和关于葡萄糖代谢而不是氨基酸代谢的胰岛素抵抗。我们研究了是否全身亮氨酸和蛋白质代谢失调的HIV感染个体IGT。在空腹胰岛素条件下和正常血糖高胰岛素血症期间，在10名HIV-血清阴性对照受试者、16名HIV+葡萄糖耐量正常受试者和21名HIV+IGT受试者中使用2 H2-葡萄糖和13 C-亮氨酸的预充恒定输注测量葡萄糖和亮氨酸动力学。HIV+IGT组高胰岛素血症时葡萄糖代谢率低于其他两组。HIV+IGT患者在所有胰岛素水平下的绝对血浆亮氨酸水平和出现率（全身蛋白水解）均高于其他两组，但在高胰岛素血症时与其他两组平行下降。HIV+IGT组的内脏肥胖、空腹血清白细胞介素（IL）-8和游离脂肪酸水平以及钳夹过程中的脂质氧化率均高于其他两组。这些发现暗示了胰岛素信号通路中的几个因素，这些因素可能在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性脂肪细胞因子（IL-8）增加和脂质氧化增加破坏的观点。增加的蛋白质水解可能为HIV的新生提供氨基酸，从而加重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.