Fasting hyperinsulinemia in human immunodeficiency virus-infected men: Relationship to body composition, gonadal function, and protease inhibitor use

Fat redistribution in the setting of protease inhibitor use is increasingly common and is associated with insulin resistance in human immunodeficiency virus (HIV)-infected patients. However, little is known regarding the fact ors that may contribute to abnormal insulin regulation in this population. We assessed fasting insulin levels in HIV-infected men and determined the r elationship among insulin, body composition, endogenous gonadal steroid con centrations, and antiviral therapy in this population. We also determined t he effects of exogenous testosterone administration using the homeostatic m odel for insulin resistance (HOMA IR) in hypogonadal HIV-infected men with the acquired immunodeficiency syndrome wasting syndrome. Fifty HIV-infected men with acquired immunodeficiency syndrome wasting were com;pared with 20 age- and body mass index (BMI)-matched healthy control s ubjects. Insulin concentrations were significantly increased in HIV-infecte d patients compared to those in control patients (16.6 +/- 1.8 vs. 10.4 +/- 0.8 mu U/mL; P < 0.05) and were increased in nucleoside reverse transcript ase (NRTI)-treated patients who did not receive a protease inhibitor (PI; 2 1.7 +/- 4.3 us. 10.4 +/- 0.8 mu U/mL; P < 0.05). Insulin concentrations and HOMA IR were inversely correlated with the serum free testosterone concent ration (r = -0.36; P = 0.01 for insulin level; r = -0.30; P = 0.03 for HOMA ), but not to body composition parameters, age, or BMI. In a multivariate r egression analysis, free testosterone (P = 0.05), BMI(P < 0.01), and lean b ody mass (P = 0.04) were significant. Lower lean body mass and higher BMI p redicted increased insulin resistance. The HIV-infected patients demonstrated an increased trunk fat to total fat ratio (0.49 +/- 0.02 vs. 0.45 +/- 0.02; P < 0.05) and an increased trunk fa t to extremity fat ratio (1.27 +/- 0.09 us. 0.95 +/- 0.06, P = 0.01), but a reduced extremity fat to total fat ratio (0.44 +/- 0.01 us. 0.49 +/- 0.01; P = 0.02) and reduced overall total body fat (13.8 +/- 0.7 us. 17.2 +/- 0. 9 kg; P < 0.01) compared to the control subjects. Increased truncal fat and reduced extremity fat were seen among NRTI-treated patients, but this patt ern was most severe among patients receiving combined NRTI and PI therapy [ trunk fat to extremity ratio, 1.47 +/- 0.15 vs. 0.95 +/- 0.06 (P < 0.01); e xtremity fat to total fat ratio, 0.40 +/- 0.02 us. 0.49 +/- 0.01(P < 0.05)] . Insulin responses to testosterone administration were investigated among 52 HIV-infected men with hypogonadism and wasting (weight <90% ideal body wei ght and/or weight loss >10%) randomized to either testosterone (300 mg, im, every 3 weeks) or placebo for 6 months. Testosterone administration reduce d HOMA IR in the HIV-infected men(-0.6 +/- 0.7 vs. + 1.41 +/- 0.8, testoste rone vs, placebo, P = 0.05) in association with increased lean body mass (P = 0.02). These data demonstrate significant hyperinsulinemia in HIV-infected patient s, which can occur in the absence of PI use. In NRTI-treated patients not r eceiving PI, a precursor phenotype is apparent, with increased truncal fat, reduced extremity fat, and increased insulin concentrations. This phenotyp e is exaggerated in patients receiving PI therapy, with further increased t runcal fat and reduced extremity fat, although hyperinsulinemia per se is n ot worse. Endogenous gonadal steroid levels are inversely related to hyperi nsulinemia in HIV-infected men, but reduced lean body mass and increased we ight are the primary independent predictors of hyperinsulinemia. Indexes of insulin sensitivity improve in response to physiological androgen administ ration among hypogonadal HIV-infected patients, and this change is again re lated primarily to increased lean body mass in response to testosterone adm inistration.