In this study, a two-stage euglycemic hyperinsulinemic clamp, with infusion of stable isotopically labeled tracers, was used to evaluate insulin action in skeletal muscle, liver, and adipose tissue in HIV-infected men with dyslipidemia (HIV-DL; plasma triglyceride Ͼ250 mg/dl and HDL Ͻ45mg/dl; n ϭ 12), HIV-infected men without dyslipidemia (HIV w/o DL; n ϭ 12), and healthy men (n ϭ 6). Basal rates of glucose production (glucose R a), glucose disposal (glucose R d), and lipolysis (palmitate Ra) were similar between groups. The relative suppression of glucose R a (63 Ϯ 4, 77 Ϯ 2, and 78 Ϯ 3%, P ϭ 0.008) and palmitate R a (49 Ϯ 4, 63 Ϯ 3, and 68 Ϯ 3%, P ϭ 0.005) during low-dose insulin infusion (plasma insulin ϳ30 U/ml), and the relative stimulation of glucose R d (214 Ϯ 21, 390 Ϯ 25, and 393 Ϯ 46%, P ϭ 0.001) during high-dose insulin infusion (plasma insulin ϳ75 U/ml) were lower in HIV-DL than in HIV w/o DL and healthy volunteers, respectively. Suppression of basal glucose R a correlated with plasma adiponectin (r ϭ 0.44, P ϭ 0.02) and inversely with plasma IL-6 (r ϭ Ϫ0.49, P Ͻ 0.001). Stimulation of glucose R d correlated directly with adiponectin (r ϭ 0.48, P Ͻ 0.01) and inversely with IL-6 (r ϭ Ϫ0.49, P ϭ 0.02). We conclude that dyslipidemia in HIV-infected men is indicative of multiorgan insulin resistance, and circulating adipokines may be important in the pathogenesis of impaired insulin action. insulin resistance; adipokine; hepatic steatosis THE INTRODUCTION of highly active antiretroviral therapy (HAART) has led to a marked increase in survival of patients with human immunodeficiency virus (HIV) infection. The beneficial effect on survival has been tempered by the potential effect of treatment on increased risk of coronary heart disease (CHD) mortality (15) and by metabolic abnormalities that are risk factors for CHD, including hypertriglyceridemia, low plasma HDL-cholesterol concentration, impaired glucose tolerance, type 2 diabetes, and increased abdominal fat mass (6,8,9). Dyslipidemia (i.e., high plasma triglyceride and low HDLcholesterol concentrations) is a common complication of HIV infection and occurs in Ն50% of patients receiving HAART (2, 3). In patients who do not have HIV infection, dyslipidemia is often associated with insulin-resistant glucose metabolism (12,34). Therefore, the presence of dyslipidemia could identify patients with HIV infection, who are at particularly high risk for developing CHD because of concomitant risk factors. However, it is controversial whether dyslipidemia in patients with HIV infection is associated with abnormalities in insulin action (26,27,42).The purpose of the present study was to evaluate insulin action in liver [glucose rate of appearance (R a )], muscle [glucose rate of disposal (R d )] and adipose tissue (fatty acid R a ), and specific factors (i.e., plasma adipokine concentrations and fat distribution) that may be involved in the pathogenesis of insulin resistance in men who have HIV infection and dyslipidemia (HIV-DL). A two-stage euglycemic hyperinsuli...

Carper MJ, Cade WT, Cam M, Zhang S, Shalev A, Yarasheski KE, Ramanadham S. HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus.

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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.

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