The Effect of Rosiglitazone on Insulin Sensitivity, Beta Cell Function, Bone Mineral Density, and Body Composition in HIV-positive Patients on Highly-active Antiretroviral Therapy (HAART)

Abstract

Highly active antiretroviral therapy (HAART) leads to lipodystrophy and is associated with detrimental changes in glucose and lipid metabolism. This study investigated the impact of rosiglitazone on insulin sensitivity, beta cell function, bone mineral density, and body composition in HIV+ nondiabetic subjects under HAART. In this randomized, double blind, placebo controlled parallel group study, 40 HIV+ subjects were treated with rosiglitazone 4 mg/day (R, n=23) or placebo (P, n=17) for 6 months. Glucose, insulin and C peptide concentrations were analyzed for assessing insulin sensitivity and secretion. Adiponectin and leptin were evaluated. Body fluid compartments were measured with bioelectrical impedance spectroscopy, and bone mineral density and body composition with Dual X Ray absorptiometry. Rosiglitazone improved peripheral insulin sensitivity (+36.7±15.7 ml/min/m², p=0.03, means±SEM), while no change was observed in P (+4.5±19.5 ml/min/m², p=0.55). Liver insulin resistance, beta cell activity, and hepatic insulin clearance did not change. Plasma adiponectin increased (R: +2.47±0.86 μg/ml, p=0.01 vs. P: +0.45±0.60, p=0.28). Rosiglitazone had no influence on body composition, fat distribution and bone mineral density but expanded extra-cellular fluid volume in HIV infected persons (R: +0.50±0.21 l, p=0.02 vs. P: 0.10±0.25 l, p=0.32). Lipid metabolism in P remained unchanged, in R total cholesterol and LDL cholesterol levels increased significantly (p<0.05). Rosiglitazone treatment resulted in improved peripheral insulin sensitivity with increased circulating adiponectin in HIV patients under HAART. No effect was seen on body fat distribution, bone mineral density, and weight. These side effects and their potential for cardiac risk must be weighed against the beneficial effects on glucose metabolism.

Key words

lipodystrophy - adiponectin - leptin

References

• 1 Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study.  Lancet. 1999;  353 2093-2099
• 2 Hadigan C, Meigs JB, Corcoran C, Rietschel P, Piecuch S, Basgoz N, Davis B, Sax P, Stanley T, Wilson PW, D’Agostino RB, Grinspoon S. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy.  Clin Infect Dis. 2001;  32 130-139
• 3 Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy.  J Biol Chem. 2000;  275 20251-20254
• 4 Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations.  AIDS. 2002;  16 859-863
• 5 Hadigan C, Borgonha S, Rabe J, Young V, Grinspoon S. Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy.  Metabolism. 2002;  51 1143-1147
• 6 Boden G, Chen X, Ruiz J, White JV, Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake.  J Clin Invest. 1994;  93 2438-2446
• 7 Olefsky JM. Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists.  J Clin Invest. 2000;  106 467-472
• 8 Carey DG, Cowin GJ, Galloway GJ, Jones NP, Richards JC, Biswas N, Doddrell DM. Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients.  Obes Res. 2002;  10 1008-1015
• 9 Krzyzanowska K, Mittermayer F, Krugluger W, Roden M, Schernthaner G, Wolzt M. Adiponectin concentrations increase during acute FFA elevation in humans treated with rosiglitazone.  Horm Metab Res. 2007;  39 769-772
• 10 Gelato MC, Mynarcik DC, Quick JL, Steigbigel RT, Fuhrer J, Brathwaite CE, Brebbia JS, Wax MR, MacNurlan MA. Improved insulin sensitivity and body fat distribution in HIV-infected patients treated with rosiglitazone: a pilot study.  J Acquir Immune Defic Syndr. 2002;  31 163-170
• 11 Hadigan C, Yawetz S, Thomas A, Havers F, Sax PE, Grinspoon S. Metabolic effects of rosiglitazone in HIV lipodystrophy: a randomized, controlled trial.  Ann Intern Med. 2004;  140 786-794
• 12 Sutinen J, Hakkinen AM, Westerbacka J, Seppala-Lindroos A, Vehkavaara S, Halavaara J, Jarvinen A, Ristola M, Yki-Jarvinen H. Rosiglitazone in the treatment of HAART-associated lipodystrophy – a randomized double-blind placebo-controlled study.  Antivir Ther. 2003;  8 199-207
• 13 Carr A, Workman C, Carey D, Rogers G, Martin A, Baker D, Wand H, Law M, Samaras K, Emery S, Cooper DA. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial.  Lancet. 2004;  363 429-438
• 14 Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, Reid IR. The peroxisome proliferator-activated receptor-{gamma} agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: A randomized, controlled trial.  J Clin Endocrinol Metab. 2007;  92 1305-1310
• 15 Yaturu S, Bryant B, Jain SK. Thiazolidinedione treatment decreases bone mineral density in type 2 diabetic men.  Diabetes Care. 2007;  30 1574-1576
• 16 Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR, Strotmeyer ES, Resnick HE, Carbone L, Beamer BA, Park SW, Lane NE, Harris TB, Cummings SR. Thiazolidinedione use and bone loss in older diabetic adults.  J Clin Endocrinol Metab. 2006;  91 3349-3354
• 17 Landay AL, Muirhead KA. Procedural guidelines for performing immunophenotyping by flow cytometry.  Clin Immunol Immunopathol. 1989;  52 48-60
• 18 Kautzky-Willer A, Pacini G, Tura A, Bieglmayer C, Schneider B, Ludvik B, Prager R, Waldhausl W. Increased plasma leptin in gestational diabetes.  Diabetologia. 2001;  44 164-172
• 19 Pernerstorfer-Schön H, Schindler K, Parschalk B, Schindl A, Thoeny-Lampert S, Wunderer K, Elmadfa I, Tschachler E, Jilma B. Beneficial effects of protease inhibitors on body composition and energy expenditure: a comparison between HIV-infected and AIDS patients.  AIDS. 1999;  13 2389-2396
• 20 Kyle UG, Genton L, Slosman DO, Pichard C. Fat-free and fat mass percentiles in 5 225 healthy subjects aged 15 to 98 years.  Nutrition. 2001;  17 534-541
• 21 Thomaseth K, Kautzky-Willer A, Ludvik B, Prager R, Pacini G. Integrated mathematical model to assess beta-cell activity during the oral glucose test.  Am J Physiol. 1996;  270 E522-E531
• 22 Tura A, Ludvik B, Nolan JJ, Pacini G, Thomaseth K. Insulin and C-peptide secretion and kinetics in humans: direct and model-based measurements during OGTT.  Am J Physiol Endocrinol Metab. 2001;  281 E966-E974
• 23 Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test.  Diabetes Care. 2001;  24 539-548
• 24 Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study.  Diabetes. 2006;  55 1430-1435
• 25 Pacini G, Mari A. Methods for clinical assessment of insulin sensitivity and beta-cell function.  Best Pract Res Clin Endocrinol Metab. 2003;  17 305-322
• 26 Ahren B, Pacini G, Foley JE, Schweizer A. Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year.  Diabetes Care. 2005;  28 1936-1940
• 27 Kosmiski L, Kuritzkes D, Lichtenstein K, Eckel R. Adipocyte-derived hormone levels in HIV lipodystrophy.  Antivir Ther. 2003;  8 9-15
• 28 Vigouroux C, Maachi M, Nguyen TH, Coussieu C, Gharakhanian S, Funahashi T, Matsuzawa Y, Shimomura I, Rozenbaum W, Capeau J, Bastard JP. Serum adipocytokines are related to lipodystrophy and metabolic disorders in HIV-infected men under antiretroviral therapy.  AIDS. 2003;  17 1503-1511
• 29 Mynarcik DC, Combs T, McNurlan MA, Scherer PE, Komaroff E, Gelato MC. Adiponectin and leptin levels in HIV-infected subjects with insulin resistance and body fat redistribution.  J Acquir Immune Defic Syndr. 2002;  31 514-520
• 30 Combs TP, Wagner JA, Berger J, Doebber T, Wang WJ, Zhang BB, Tanen M, Berg AH, O’Rahilly S, Savage DB, Chatterjee K, Weiss S, Larson PJ, Gottesdiener KM, Gertz BJ, Charron MJ, Scherer PE, Moller DE. Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization.  Endocrinology. 2002;  143 998-1007
• 31 Ohmura E, Hosaka D, Yazawa M, Tsuchida A, Tokunaga M, Ishida H, Minagawa S, Matsuda A, Imai Y, Kawazu S, Sato T. Association of free fatty acids (FFA) and tumor necrosis factor-alpha (TNF-alpha) and insulin-resistant metabolic disorder.  Horm Metab Res. 2007;  39 212-217
• 32 Kamin D, Hadigan C, Lehrke M, Mazza S, Lazar MA, Grinspoon S. Resistin levels in human immunodeficiency virus-infected patients with lipoatrophy decrease in response to rosiglitazone.  J Clin Endocrinol Metab. 2005;  90 3423-3426
• 33 Schwartz AV, Sellmeyer DE, Ensrud KE, Cauley JA, Tabor HK, Schreiner PJ, Jamal SA, Black DM, Cummings SR. Older women with diabetes have an increased risk of fracture: A prospective study.  J Clin Endocrinol Metab. 2001;  86 32-38
• 34 Deeg MA, Buse JB, Goldberg RB, Kendall DM, Zagar AJ, Jacober SJ, Khan MA, Perez AT, Tan MH. on behalf of the GSI . Pioglitazone and rosiglitazone have different effects on serum lipoprotein particle concentrations and sizes in patients with type 2 diabetes and dyslipidemia.  Diabetes Care. 2007;  30 2458-2464
• 35 Hadigan C, Mazza S, Crum D, Grinspoon S. Rosiglitazone increases small dense low-density lipoprotein concentration and decreases high-density lipoprotein particle size in HIV-infected patients.  AIDS. 2007;  21 2543-2546
• 36 Berria R, Glass L, Mahankali A, Miyazaki Y, Monroy A, De Filippis E, Cusi K, Cersosimo E, Defronzo RA, Gastaldelli A. Reduction in hematocrit and hemoglobin following pioglitazone treatment is not hemodilutional in Type II diabetes mellitus.  Clin Pharmacol Ther. 2007;  82 275-281

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