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

Abstract

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 2 H 2 -glucose and 13 C-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.

XIAP Reduces Muscle Proteolysis Induced by CKD

“…It occurs in chronic kidney disease (CKD), 3,4 sepsis, 5 cancer, 6 diabetes, 7,8 trauma, 9 burn injury, 10 AIDS, 11 and heart failure. 12,13 Regardless of the triggering event, common mechanisms contribute to the muscle-wasting process.…”

In vivo kinetic approach reveals slow SOD1 turnover in the CNS

“…Animal protocols were approved by the Institutional Animal Care and Use Committee at Washington University and conducted according to the NIH Guide for the Care and Use of Laboraprecipitated with 10% trichloroacetic acid overnight at 4°C, the protein pellet was retained for quantification of bound 13 C 6 -leucine, and the supernatant was removed after centrifugation at 21,000 g for 10 minutes. The supernatant was chemically derivatized to form the N-heptafluorobutyryl n-propyl esters of plasma-free amino acids, and 13 C 6 -leucine enrichment was quantified using capillary gas chromatography-negative chemical ionization-quadrupole mass spectrometry (GC-MS; Agilent 6890N Gas Chromatograph and Agilent 5973N Mass Selective Detector) with the m/z of 355 as compared with 349 as described previously (11,39). Protein-bound 13 C 6 -leucine abundance was quantified in the TCA-precipitated proteins after sonicating the pellet in a cold 10% TCA solution twice.…”

The role of protease inhibitors in the pathogenesis of HIV-associated insulin resistance: Cellular mechanisms and clinical implications

“…Elevated cytokines and inflammatory mediators such as interleukin-8 [76] or tumor necrosis factor-observed in chronic HIV infection also induce ceramide production and promote intracellular palmitoyl-CoA accumulation [73] with independent effects on promoting abnormal lipid metabolism. Once triggered, the system would no longer be able to confine dietary energy sources or excess lipid to the adipocytes specifically designed to store calories for long term (Fig.…”

“…At the cellular level, the initial signal is triggered by an induction of ER stress which triggers a response specific to the cell (ie, in inhibition of glucose uptake in the adipocytes and unregulated SREBP activity in the hepatocyte). As a consequence of alteration in the protein expression, the homeostasis in the oxidation of energy substrates is impaired with a shift towards increased lipolysis [76]. The resulting imbalance in the intracellular rate of lipogenesis versus lipolysis can affect the adipocyte and the hepatocyte with consequences for total body fat mass and distribution.…”