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Whole-Body Proteolysis Rate Is Elevated in HIV-Associated Insulin Resistance

From the Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri

Address correspondence and reprint requests to Kevin E. Yarasheski, PhD, Washington University School of Medicine, 660 South Euclid Ave., Endocrinology, Metabolism and Lipid Research, Campus Box 8127, St. Louis, MO 63110. E-mail: key{at}im.wustl.edu

Abbreviations: BCAA, branched-chain amino acid; FFA, free fatty acid; FFM, fat-free mass; GC-MS, gas chromatography–mass spectrometry; GCRC, General Clinical Research Center; HAART, highly active antiretroviral therapy; HOMA, homeostasis model assessment; IGT, impaired glucose tolerance; IL, interleukin; KIC, ketoisocaproic acid; NGT, normal glucose tolerance

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.

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