Alterations in liver, muscle, and adipose tissue insulin sensitivity in men with HIV infection and dyslipidemia

Abstract

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...

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

“…In agreement with others, we found that fasting FFAs and liver lipid content were elevated and positively correlated in HIVϩIGT subjects (11,13,35). The correlations between FFA levels, glucose, and leucine kinetics in HIVϩIGT subjects raise the possibility that elevated FFA flux and their byproducts can accumulate in insulinsensitive tissues and disrupt normal insulin signaling pathways.…”

“…IGT was defined as fasting glucose 100 -126 mg/dl or glucose 140 -200 mg/dl 2 h after ingesting a 75-g glucose beverage (American Diabetes Association criteria). Glucose and fatty acid kinetics for 30 of these 47 subjects were reported previously in a study of men with HIV dyslipidemia (11).…”

“…This is contrasted with glucose regulation in HIVϩIGT subjects, where absolute basal glucose R a and R d (micromoles per kilogram FFM per hour) were similar among the groups, but insulin action on glucose R a and R d was blunted in HIVϩIGT subjects during insulin infusion. Taken together, these findings indicate that dysregulated fasting leucine and protein metabolism, along with impairments in glucose and fatty acid metabolism (9,11,(13)(14)(15)(16)18), may be integrated and represent metabolic syndromes associated with HIV infection and HAART.…”

“…The mechanism is multifactorial and likely comprises the effects of chronic viral infection, host response, anti-HIV medications, genetics, lifestyle/behavioral factors on intracellular signaling pathways, and substrate partitioning and sensing (9,10). Several groups have reported that HIV-associated insulin resistance is characterized by perturbations in glucose and lipid metabolism, which are common to type 2 diabetes (11)(12)(13)(14)(15)(16)(17)(18)(19). Whether HIV-associated insulin resistance is associated with defects in amino acid and protein metabolism has not been addressed.…”

Peroxisome Proliferator-Activated Receptor γ 2 Modulates Late-Pregnancy Homeostatic Metabolic Adaptations

“…In situations of hypoadiponectinemia in humans, redistribution of fat in different depots or in other tissues determines the existence of low levels of adiponectin, especially when the fat is deposited in visceral depots, liver or muscle (32)(33)(34). Furthermore, we speculate that the lack of insulin stimulation observed in muscle from PPγ2KO-P mice could be related to alterations in WAT, and could also contribute to the higher degree of peripheral IR found in these animals.…”