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Resistin Levels in Human Immunodeficiency Virus-Infected Patients with Lipoatrophy Decrease in Response to Rosiglitazone

Program in Nutritional Metabolism (D.K., C.H., S.M., S.G.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and Division of Endocrinology, Diabetes, and Metabolism (M.L., M.A.L.), Department of Medicine and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Colleen Hadigan, M.D., M.P.H., Program in Nutritional Metabolism, Massachusetts General Hospital, 55 Fruit Street, LON 207, Boston, Massachusetts 02114. E-mail: chadigan{at}partners.org.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Resistin is a recently recognized adipocytokine thought to contribute to insulin resistance. We determined resistin levels and metabolic parameters in 24 HIV-infected men and women with lipoatrophy and hyperinsulinemia and studied the effect of 12 wk of the peroxisome proliferator-activated receptor- agonist rosiglitazone (4–8 mg/d) on resistin in these subjects. Participants completed metabolic testing before and after rosiglitazone including fasting determination of resistin, adiponectin, and leptin levels, serum inflammatory markers, and hyperinsulinemic euglycemic clamp testing. Resistin concentration decreased significantly after rosiglitazone (12.17 ± 1.15 ng/ml to 10.23 ± 1.05 ng/ml; P = 0.02), in conjunction with significant increases in adiponectin- (P < 0.001) and insulin- stimulated glucose disposal (P = 0.004). Leptin levels, as well as TNF-, did not change with rosiglitazone. In summary, among HIV-infected subjects with insulin resistance and lipoatrophy, resistin levels decreased significantly after rosiglitazone. Further investigation into the physiological role of this peroxisome proliferator-activated receptor--responsive adipocytokine in the metabolic abnormalities associated with HIV is warranted.

	Introduction

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HIV LIPODYSTROPHY IS a constellation of metabolic abnormalities associated with antiretroviral therapy, characterized by insulin resistance, dyslipidemia, and abnormal fat distribution (1). The underlying pathophysiology of insulin resistance in such patients may include direct drug toxicity (2), as well as abnormal fat distribution (3).

Resistin is an adipocytokine highly expressed in murine adipose tissue (4). In animals, resistin is believed to function through effects on glucose flux into muscle (5) and hepatic glucose production (6). Currently, human physiology of resistin remains unclear (7). Diabetic and insulin-resistant subjects have elevated resistin in some studies (8, 9) but not others (10, 11). In vitro studies have not convincingly isolated resistin from cultured human adipocytes (12, 13), whereas macrophages may elaborate the bulk of circulating resistin in humans (14, 15).

Here, we characterize resistin concentrations in HIV- infected adults with lipoatrophy and hyperinsulinemia. In a recent study (16), we showed benefits of rosiglitazone on insulin sensitivity and sc fat in this population, and we now demonstrate that rosiglitazone reduced circulating resistin.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Twenty-eight HIV-infected men and women with lipoatrophy (fat loss in the arms, face, hips, or legs determined by self-assessment and physician examination) with documented hyperinsulinemia [fasting insulin > 15 µIU/ml (>104 pmol/liter) or 2-h insulin > 75 µIU/ml (>521 pmol/liter) after 75-g oral glucose challenge] received rosiglitazone (4 mg) or placebo daily for 12 wk in a randomized double-blind, placebo-controlled trial assessing glucose metabolism and body composition (16). Exclusion criteria were antiretroviral regimen change in the past 3 months, diagnosis of diabetes mellitus, aminotransferases more than 2 times the upper limit of normal, hemoglobin less than 9 g/dl, or known allergies to thiazolidinediones. Sixteen subjects received 4 mg/d for 12 wk during the double-blind phase of the study, and eight subjects initially randomized to placebo subsequently received open-label rosiglitazone 4 mg/d for 2 wk followed by 8 mg daily for 10 wk after completion of the randomized portion of the study. Therefore, 24 subjects completed 3 months of rosiglitazone treatment.

Subjects completed a comprehensive assessment of insulin sensitivity, as well as measurement of adipocytokines and inflammatory markers, before and at completion of both the 12-wk placebo-controlled and open-label portions of the study. Blood samples were obtained after a 12-h overnight fast and stored at –80 C until analyzed. Testing included determination of adiponectin, resistin, leptin, plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), C reactive protein (CRP), TNF-, soluble TNF- receptor 1 (sTNF-Rc1), and soluble TNF- receptor 2 (sTNF-Rc2), as well as CD4 T-cell count and HIV viral load. Insulin sensitivity was determined by hyperinsulinemic euglycemic clamp testing, which consisted of a 2-h primed infusion of regular insulin at 40 mU/m²·min and variable-rate glucose to maintain blood sugar at 90 mg/dl. The effects of rosiglitazone on insulin sensitivity, lipid profile, and body composition during the 12-wk randomized controlled study were published previously (16). Written informed consent was obtained from each subject, and the protocol was approved by the Massachusetts General Hospital and the Massachusetts Institute of Technology institutional review boards.

We also compared mean fasting resistin with a reference group of nondiabetic adults from the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA; n = 879) (17). Subjects in SIRCA were healthy men aged 30–65 yr or women aged 35–70 yr with a family history of premature coronary artery disease [male SIRCA participants: median age 46 yr (41–52 interquartile range, IQR), body mass index 27.6 kg/m² (25.3–30.5 IQR), n = 471; female SIRCA participants: median age 50 yr (44–57 IQR), body mass index 25.7 kg/m² (22.8–30.4 IQR), n = 408].

Plasma resistin was measured by enzyme immunoassay (LINCO Research, Inc., St. Charles, MO). Average correlation coefficient for standards was 0.99. The average intraassay coefficient of variation was 1.2% for low and 0.83% for high resistin standards and 16.67% for fresh aliquots of pooled human plasma, included in duplicate on all plates. Results for plasma samples across different assay plates were standardized by using the ratio of individual plate pooled plasma to the average established pooled plasma value, which was used as a reference across multiple studies. The sensitivity based on the lowest standard for the assay was 0.16 ng/ml. Resistin determinations for this study and the SIRCA study were completed in a single laboratory by using the same assay and control standards.

CRP was measured by ELISA (Diagnostic Systems Laboratories, Webster, TX). PAI-1 and tPA antigens were determined by ELISA (Biopool, Umea, Sweden, distributed by Biopool International, Ventura, CA). Adiponectin and leptin were measured by using a RIA (LINCO Research, Inc.). Insulin was measured by using a RIA (Diagnostic Products Corp., Los Angeles, CA). TNF-, sTNF-R1, and sTNF-R2 were measured by quantitative sandwich enzyme immunoassay (R&D Systems, Minneapolis, MN).

CD4⁺ count was determined by flow cytometry (BD Biosciences, San Jose, CA) and HIV viral load by ultrasensitive assay (Amplicor HIV-1 Monitor Assay; Roche Molecular Systems, Branchburg, NJ).

Data analysis

We assessed the metabolic effects of rosiglitazone by comparing values obtained immediately before and after 12 wk of rosiglitazone therapy. We pooled data from subjects who initially received rosiglitazone (n = 16) during the randomized study with subjects who originally received placebo but subsequently received rosiglitazone (n = 8) for 12 wk to increase the power of the study. Paired t tests were performed to compare immediate prerosiglitazone baseline and posttreatment values for each variable. Linear correlation coefficients were generated to determine associations between adipocytokines and inflammatory markers. All data are presented as mean ± SE of the mean unless otherwise indicated. A two-level of 0.05 was used to determine statistical significance. Statistical analyses were performed by using SAS JMP software, version 4.04 (SAS Institute, Inc., Cary, NC).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Baseline clinical characteristics are summarized in Table 1. After 12 wk of rosiglitazone, mean resistin levels decreased significantly from a baseline of 12.17 ± 1.15 ng/ml to 10.23 ± 1.05 ng/ml (P = 0.02) (Table 2). There was no difference in the magnitude of reduction in resistin according to dose of rosiglitazone (mean change in resistin, 4 mg/d = –1.97 ng/ml vs. 8 mg/d = –1.87 ng/ml). Rosiglitazone also resulted in a marked increase in adiponectin; however, there was no effect on leptin.

There was no significant difference in baseline resistin according to protease inhibitor use (current protease use 11.36 ± 1.26 ng/ml vs. no protease inhibitor 13.29 ± 2.16 ng/ml, P = 0.42). Baseline markers of inflammation/coagulation (TNF-, sTNF-R1, sTNF-R2, CRP, fibrinogen, tPA, and PAI-1) did not correlate with baseline resistin (P > 0.05 for each). Similarly, change in inflammatory markers did not correlate with change in resistin. Neither baseline resistin, nor change in resistin with rosiglitazone, correlated with insulin sensitivity (r = 0.07, P = 0.8) or change in insulin sensitivity(r = 0.07, P = 0.7), respectively.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We assessed resistin concentrations and evaluated the effect of rosiglitazone among HIV-infected adults with lipodystrophy, a population characterized by significant insulin resistance and abnormal fat distribution. After 12 wk of rosiglitazone, resistin decreased in individuals with hyperinsulinemia and lipoatrophy associated with HIV.

Some cross-sectional studies have found resistin is higher among diabetics (8, 9) and that resistin predicts glycemia (8) and homeostasis model assessment of insulin resistance (18). Other studies have come to nearly opposite conclusions, suggesting that resistin may correlate with adiposity but not with measures of glucose homeostasis (10). Here, we find no significant correlation between baseline fasting resistin and measures of glucose homeostasis. Heterogeneous findings may reflect population differences and/or relate to the sensitivity of individual assays (7).

In the present study of HIV-infected subjects, resistin was elevated compared with a reference population of nondiabetic adults of similar age and body weight (17); e.g. median resistin for HIV-infected women was 9.51 ng/ml (7.53–16.26 IQR) compared with 5.88 ng/ml (4.42–7.84 IQR) for female SIRCA participants and 10.87 ng/ml (8.98–13.00 IQR) for HIV-infected men compared with 5.20 ng/ml (3.87–6.90 IQR) for men in the SIRCA study (17). Here and in SIRCA, resistin was measured in the same laboratory by using the same assay and control standards, allowing direct comparability.

The physiological basis for elevated resistin in patients with insulin resistance is not yet known (7). Unlike in mice, in humans resistin is expressed in and elaborated by activated macrophages. In vitro experiments show resistin is regulated by inflammatory mediators (14), is elaborated in humans exposed to lipopolysaccharide (19), and is reduced when macrophages are exposed to peroxisome proliferator-activated receptor- (PPAR-) agonists (15). PPAR- expression is reduced in response to nuclear HIV-1 Nef protein (20), and this may uniquely contribute to elevated resistin expression in HIV-infected patients compared with the general population.

Our findings are consistent with initial observations that PPAR- agonists regulate resistin (4), but the physiological relevance of a reduction in resistin remains uncertain. In a recent study of obese type 2 diabetics, resistin, insulin resistance, and hepatic fat improved after 16 wk of pioglitazone (21). Similarly, we found resistin decreased and insulin sensitivity improved with rosiglitazone; however, in both studies resistin did not correlate with glucose disposal. The smaller effect size on resistin in our study, compared with the study of Bajaj et al. (21), may be related to differences in thiazolidinedione, severity of insulin resistance among groups, and potential ongoing effects of antiretroviral medication. Research suggests that resistin may be most influential with regard to hepatic insulin sensitivity (6, 22), which has been characterized as one component of insulin resistance in those with HIV lipodystrophy (23), and therefore resistin may be less closely related to peripheral insulin sensitivity.

Circulating markers of inflammation were no different after 3 months of rosiglitazone, nor were baseline markers of inflammation (e.g. TNF-) related to circulating resistin. Similarly, TNF- expression was not responsive to treatment with PPAR- agonists among subjects with obesity and type 2 diabetes (24). Although the relatively small sample size of this study may have limited our ability to detect such relationships, it is possible that for HIV-infected individuals, inflammatory markers such as TNF- are more closely linked to chronic viral or immune factors.

In summary, we show that HIV-positive subjects with lipodystrophy and insulin resistance have high circulating resistin and demonstrate that resistin levels decrease as a result of thiazolidinedione therapy in this population. We studied a relatively small group of HIV-infected individuals with significant abnormalities in fat distribution and hyperinsulinemia, and, therefore, our results regarding resistin levels may not be generalized to the overall population of HIV-infected individuals. Prospective studies in well- defined groups of both insulin-resistant and insulin-sensitive individuals are necessary to more clearly elucidate the mechanisms by which resistin may influence the development of insulin resistance in HIV patients.

	Acknowledgments

 
The investigators thank the nursing and bionutrition staffs at the Massachusetts Institute of Technology and the Brigham and Women’s General Clinical Research Center for their dedicated patient care.

	Footnotes

 
The General Clinical Research Centers are supported by M01-RR300088 and M01-RR02635. D.K. is supported by National Institute of Diabetes and Digestive and Kidney Diseases Training Grant T32-DK07477. C.H. is supported by National Institutes of Health (NIH) Grant K23 DK 02844. M.L. is supported by German Scientific Foundation (Deutsche Forschungsgemeinschaft) Grant LE 1350/1-1. M.A.L. is supported by NIH Grants RO1 DK 49780 and RO1 DK 49210 and an unrestricted Bristol Myers-Squibb Freedom to Discover Award for Metabolic Research. S.G. and this project were supported by NIH Grant RO1 DK 59535.

First Published Online March 1, 2005

Abbreviations: CRP, C reactive protein; IQR, interquartile range; PAI-1, plasminogen activator inhibitor 1; PPAR-, peroxisome proliferator-activated receptor ; SIRCA, Study of Inherited Risk of Coronary Atherosclerosis; sTNF-Rc, soluble TNF- receptor; tPA, tissue plasminogen activator.

Received February 9, 2005.

Accepted February 23, 2005.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA 1999 Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 353:2093–2099[CrossRef][Medline]
2. Noor MA, Lo JC, Mulligan K, Schwarz JM, Halvorsen RA, Schambelan M, Grunfeld C 2001 Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS 15:F11–F18
3. Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC 2000 Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr 25:312–321
4. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA 2001 The hormone resistin links obesity to diabetes. Nature 409:307–312[CrossRef][Medline]
5. Moon B, Kwan JJ, Duddy N, Sweeney G, Begum N 2003 Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation. Am J Physiol Endocrinol Metab 285:E106–E115
6. Rajala MW, Obici S, Scherer PE, Rossetti L 2003 Adipose-derived resistin and gut-derived resistin-like molecule-ß selectively impair insulin action on glucose production. J Clin Invest 111:225–230[CrossRef][Medline]
7. Steppan CM, Lazar MA 2004 The current biology of resistin. J Intern Med 255:439–447[CrossRef][Medline]
8. Youn BS, Yu KY, Park HJ, Lee NS, Min SS, Youn MY, Cho YM, Park YJ, Kim SY, Lee HK, Park KS 2004 Plasma resistin concentrations measured by EMSA using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. J Clin Endocrinol Metab 89:150–156[Abstract/Free Full Text]
9. Fujinami A, Obayashi H, Ohta K, Ichimura T, Nishimura M, Matsui H, Kawahara Y, Yamazaki M, Ogata M, Hasegawa G, Nakamura N, Yoshikawa T, Nakano K, Ohta M 2004 Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes. Clin Chim Acta 339:57–63[CrossRef][Medline]
10. Volarova de Courten B, Degawa-Yamauchi M, Considine RV, Tataranni PA 2004 High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians. Diabetes 53:1279–1284[Abstract/Free Full Text]
11. Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS 2003 Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab 88:4848–4856[Abstract/Free Full Text]
12. Fain JN, Cheema PS, Bahouth SW, Lloyd Hiler M 2003 Resistin release by human adipose tissue explants in primary culture. Biochem Biophys Res Commun 300:674–678[CrossRef][Medline]
13. Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O’Rahilly S 2001 Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor- action in humans. Diabetes 50:2199–2202[Abstract/Free Full Text]
14. Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR 2003 Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun 309:286–290[CrossRef][Medline]
15. Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, Plumpton C, Macphee CH, Smith SA 2003 Resistin is expressed in human macrophages and directly regulated by PPAR activators. Biochem Biophys Res Commun 300:472–476[CrossRef][Medline]
16. Hadigan C, Yawetz S, Thomas A, Havers F, Sax PE, Grinspoon S 2004 Metabolic effects of rosiglitazone in HIV lipodystrophy: a randomized controlled trial. Ann Intern Med 140:786–794[Abstract/Free Full Text]
17. Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ 2005 Resistin in an inflammatory marker of atherosclerosis in human. Circulation 111:932–939[Abstract/Free Full Text]
18. Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ 2003 Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol 149:331–335[Abstract]
19. Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ, Lazar MA 30 November 2004 An inflammatory cascade leading to hyperresistinemia in humans. PLoS Med 1:e45
20. Otake K, Omoto S, Yamamoto T, Okuyama H, Okada H, Okada N, Kawai M, Saksena NK, Fujii YR 2004 HIV-1 Nef protein in the nucleus influences adipogenesis as well as viral transcription through the peroxisome proliferator-activated receptors. AIDS 18:189–198[CrossRef][Medline]
21. Bajaj M, Suraamornkul S, Hardies LJ, Pratipanawatr T, DeFronzo R 2004 Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type 2 diabetic patients. Int J Obes 28:783–789
22. Bajaj M, Suraamornkul S, Piper P, Hardies LJ, Glass L, Cersosimo E, Pratipanawatr T, Miyazaki Y, DeFronzo RA 2004 Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab 89:200–206[Abstract/Free Full Text]
23. van der Valk M, Bisschop PH, Romijn JA, Ackermans MT, Lange JM, Endert E, Reiss P, Sauerwein HP 2001 Lipodystrophy in HIV-1-positive patients is associated with insulin resistance in multiple metabolic pathways. AIDS 15:2093–2100[CrossRef][Medline]
24. Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P 2004 Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab 89:2728–2735[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) All Versions of this Article: 90/6/3423    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kamin, D. Articles by Grinspoon, S. Search for Related Content PubMed PubMed Citation Articles by Kamin, D. Articles by Grinspoon, S. Related Collections Diabetes and Insulin Metabolism