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JAIDS Journal of Acquired Immune Deficiency Syndromes:
Letters to the Editor

HIV Protease Inhibitors Increase Adiponectin Levels in HIV-Negative Men

Lee, Grace A. MD*†; Mafong, Derek D. MD‡; Noor, Mustafa A. MD*†**; Lo, Joan C. MD†§; Mulligan, Kathleen PhD†§; Schwarz, Jean-Marc PhD*§¶; Schambelan, Morris MD†§; Grunfeld, Carl MD, PhD*†

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*Metabolism and Endocrine Sections, San Francisco Department of Veterans Affairs Medical Center, CA †Department of Medicine, University of California, CA ‡Department of Medicine, University Hospitals of Cleveland, OH §Division of Endocrinology, San Francisco General Hospital, CA ¶Department of Nutritional Sciences, University of California, Berkeley

**Current address: Bristol-Myers Squibb Company, Princeton, NJ.

Drs. Lee and Mafong contributed equally.

Supported by the National Institutes of Health (DK54615) and the University-wide Aids Research Project (ID02-SF-060, ID01-SF-014). All studies were conducted in the General Clinical Research Center at San Francisco General Hospital with support by the National Center for Research Resources, National Institutes of Health (RR00083). This work was also partially funded by Bristol Myers Squibb Co., who make a competitive product, atazanavir. The data were not reviewed in any way by Bristol Myers Squibb Co.

To the Editor:

Lower levels of adiponectin, a hormone secreted by adipose tissue, have been associated with insulin resistance and increased visceral adipose tissue. 1,2 Adiponectin has been shown to directly and rapidly decrease endogenous glucose production and improve glucose metabolism and fatty acid utilization in the liver and skeletal muscles in vivo. 3,4 The relation of adiponectin to insulin sensitivity is independent of changes in other known adipocytokines, including leptin. 5 Adiponectin is inversely associated with visceral and total adipose mass, as well as insulin sensitivity.

Both HIV-induced lipoatrophy and lipohypertrophy are associated with lower adiponectin levels, 5 but the cause is unknown. HIV protease inhibitors have been studied as a possible cause of lower adiponectin levels. Although preliminary data found that protease inhibitors caused decreased adiponectin expression in fat cells in vitro, 6 one group recently reported increased adiponectin levels during indinavir treatment in HIV-negative men in vivo. 7,8 They have postulated that indinavir induced the increase in adiponectin levels due to either induction of insulin resistance or endothelial dysfunction.

Previously, we reported that the protease inhibitors, indinavir and lopinavir/ritonavir, have different metabolic effects in HIV-negative men. 9,10 Whereas indinavir induced insulin resistance with no effect on lipid metabolism, lopinavir/ritonavir increased fasting triglycerides and free fatty acids but had little or no effect on insulin sensitivity during the euglycemic hyperinsulinemic clamp. Indinavir and other protease inhibitors can induce insulin resistance without changes in body fat. 9–11 Therefore to assess the effects of 2 different protease inhibitors on adiponectin levels in vivo, we measured adipocytokine levels in indinavir- and lopinavir/ritonavir-treated subjects.

As previously reported, HIV-negative men were treated with indinavir 800 mg 3 times daily 9 or lopinavir 400 mg/ritonavir 100 mg twice 10 daily. Fasting lipid and lipoprotein profiles, insulin sensitivity (euglycemic hyperinsulinemic clamp), and body composition were measured before and at the end of 4 weeks of treatment. Adiponectin and leptin levels were measured by radioimmunoassay (Linco Research, Inc., St. Charles, MO) in serum obtained after overnight fasting; serum samples were stored at −70°C. The data met normality assumptions and paired t tests were performed using Sigma Stat v. 2.03 (SPSS, Inc., San Rafael, CA). Data are presented as mean ± SEM. Two-tailed P value <0.05 was considered statistically significant.

Insulin-mediated glucose disposal per unit of insulin (M/I) decreased by 19% in response to indinavir with no change in lipid or lipoprotein profiles (Table 1). During lopinavir/ritonavir treatment, fasting triglycerides and free fatty acids increased with no change in insulin-mediated glucose disposal. Abdominal visceral and subcutaneous adipose tissue measured by CT scan as well as total, appendicular, or trunk fat by dual-energy x-ray absorptiometry did not change after either treatment.

Table 1
Table 1
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Adiponectin levels increased with indinavir and to an even greater extent with lopinavir/ritonavir. In contrast, leptin levels did not change after either treatment. There was no correlation between individual changes in body composition and changes in adiponectin levels.

The observation that serum adiponectin levels increased during treatment with both indinavir and lopinavir/riton-avir has several implications. First, the increased adiponectin levels induced by indinavir and lopinavir/ritonavir treatment cannot explain the lower levels of adiponectin found in patients with HIV-associated lipohypertrophy and lipoatrophy, although many were on protease inhibitors. These data raise the possibility that body composition changes per se may be the underlying cause of the decrease in adiponectin levels in HIV-associated lipodystrophy, although a role for drugs other than protease inhibitors cannot be ruled out. Secondly, the increase in adiponectin induced by these 2 protease inhibitors in vivo contrasts with the decrease in adiponectin expression in 3T3 adipocytes acutely treated in vitro with indinavir, ritonavir, saquinavir, nelfinavir, zidovudine, or stavudine. 6 Third, other protease inhibitors should be studied for their effects on adiponectin levels. Finally, because adiponectin levels are increased by both indinavir, which induces insulin resistance, and by lopinavir/ritonavir, which has little or no effect on insulin sensitivity, induction of insulin resistance is unlikely to explain the increased adiponectin levels seen with both protease inhibitors. Thus these data argue against the hypothesis that indinavir-induced insulin resistance is the cause of the increased adiponectin levels. 7

We cannot rule out the possibility that induction of adiponectin blunted the appearance of insulin resistance. We also found that the increase in adiponectin levels occurred in the absence of changes in subcutaneous or visceral fat or leptin. The induction of adiponectin independent of changes in body fat mass is interesting with regard to thiazolidinedione therapy for HIV lipoatrophy. Thiazolidinediones have been shown to increase adiponectin levels, raising the possibility that adiponectin mediates some of the effects of thiazolidinediones on glucose metabolism. Recent data 12 have indicated the thiazolidinediones also raise adiponectin levels in patients with HIV lipoatrophy and insulin resistance without major changes in body fat mass. The cause for increased adiponectin levels during protease inhibitor treatment remains to be elucidated. Whether protease inhibitors exert their action on adipose or endothelial cells is unclear. Further studies identifying the mechanism of protease inhibitor-induced adiponectin increase are needed.

Grace A. Lee, MD,*†

Derek D. Mafong, MD‡

Mustafa A. Noor, MD*†**

Joan C. Lo, MD†§

Kathleen Mulligan, PhD†§

Jean-Marc Schwarz, PhD*§

Morris Schambelan, MD†§

Carl Grunfeld, MD, PhD*†

*Metabolism and Endocrine Sections, San Francisco Department of Veterans Affairs Medical Center, CA †Department of Medicine, University of California, CA ‡Department of Medicine, University Hospitals of Cleveland, OH §Division of Endocrinology, San Francisco General Hospital, CA ¶Department of Nutritional Sciences, University of California, Berkeley

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REFERENCES

1. Staiger H, Tschritter O, Machann J, et al. Relationship of serum adiponectin and leptin concentrations with body fat distribution in humans. Obes Res. 2003;11:368–372.

2. Stefan N, Stumvoll M. Adiponectin: its role in metabolism and beyond. Horm Metab Res. 2002;34:469–474.

3. Berg AH, Combs TP, Du X, et al. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7:947–953.

4. Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941–946.

5. Addy CL, Gavrila A, Tsiodras S, et al. Hypo-adiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy. J Clin Endocrinol Metab. 2003;88:627–636.

6. Jones S, Janneh O, Waitte C, Back D, et al. Altered adipocytokine gene expression in murine 3T3-F442A adipocytes treated with PIs and NRTIs. Paper presented at: 5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2003; Paris, France.

7. Shankar SS, Degawa-Yamauchi M, Considine R,V Dube MP, et al. Indinavir increases serum a d i p o n e c t i n in healthy HIV-negative men. Paper presented at: 63rd Scientific Sessions of the American Diabetes Association; 2003; New Orleans, LA.

8. Shankar SS D-YM, Considine RV, Steinberg HO, et al. Indinavir-associated endothelial dysfunction is associated with increased plasma adiponectin levels. Paper presented at: 5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2003; Paris, France.

9. Noor MA, Lo JC, Mulligan K, et al. Metabolic effects of indinavir in healthy HIV-sero-negative men. AIDS. 2001;15:F11–F18.

10. Lee G, Seneviratne T, Noor M, Lo J, et al. The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS. In press.

11. Mulligan K, Grunfeld C, Tai VW, et al. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Defic Syndr. 2000;23:35–43.

12. Hadigan C, Yawetz S, Thomas A, Havers F, et al. A randomized, double-blind, placebo-controlled study of rosiglitazone for patients with HIV lipodystrophy. Paper presented at: 5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV; 2003; Paris, France.

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