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Insulin Resistance in AIDS

Research within MGH Program in Nutritional Metabolism is directed toward better understanding the pathogenesis and treatment of metabolic dysfunction in over and undernutrition. One model that we have concentrated on is that of the lipodystrophic changes in fat, among HIV-infected patients treated with highly active antiretroviral therapy. In this regard, we have demonstrated a high prevalence of insulin resistance, and explored the role of excess free fatty acids derived from increased lipolysis in mediating insulin resistance in this population. We have demonstrated increased muscular adiposity and the potential utility of treatment strategies that reduce intramuscular adiposity and shift fat toward the subcutaneous depots. In collaboration with Gokhan Hotamisligil at the Harvard School of Public Health, we have demonstrated abnormal regulation of adiponectin in relationship to excess visceral fat. We have furthermore collaborated with the Framingham Study to determine excess cardiovascular risk attributable to the excess visceral adiposity and loss of subcutaneous fat seen in this syndrome. In two treatment studies, we have examined the potential utility of insulin sensitizing agents in this population. In particular, we have shown recently that use of TZD’s can decrease lipolysis and increase subcutaneous fat, while improving adiponectin and insulin sensitivity. This strategy affords potentially great benefit to a lipodystrophic population and will be followed up with studies of combined PPAR agonists to further modulate insulin sensitivity, adipose partitioning and lipid regulation in this population.

References:

1. Hadigan C, Meigs JB, Rabe J, et al. Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance. J Clin Endocrinol Metab 2001;86(2):939-43.

2. Hadigan C, Rabe J, Meininger G, Aliabadi N, Breu J, Grinspoon S. Inhibition of lipolysis improves insulin sensitivity in protease inhibitor-treated HIV-infected men with fat redistribution. Am J Clin Nutr 2003;77:490-4.

3. Hadigan C, Meigs JB, Wilson PW, et al. Prediction of coronary heart disease risk in HIV-infected patients with fat redistribution. Clin Infect Dis 2003;36(7):909-16.

4. Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome: A randomized controlled trial. JAMA 2000;284(4):472-7.

5. Driscoll SD, Meininger GE, Ljunquist K, et al. Differential effects of metformin and exercise on muscle adiposity and metabolic indices in human Immunodeficiecy virus-infected patients. J Clin Endocrinol Metab 2004;In Press.

6. Tong Q, Sankale JL, Hadigan CM, et al. Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices. J Clin Endocrinol Metab 2003;88(4):1559-64.

7. Hadigan C, Yawetz S, Thomas A, Havers F, Sax PE, Grinspoon S. Metabolic effects of rosiglitazone in HIV lipodystrophy: A randomized controlled trial. Annals of Internal Medicine 2004;140(10):786-94.


	Steven Grinspoon, M.D. Insulin Resistance in AIDS Research within MGH Program in Nutritional Metabolism is directed toward better understanding the pathogenesis and treatment of metabolic dysfunction in over and undernutrition. One model that we have concentrated on is that of the lipodystrophic changes in fat, among HIV-infected patients treated with highly active antiretroviral therapy. In this regard, we have demonstrated a high prevalence of insulin resistance, and explored the role of excess free fatty acids derived from increased lipolysis in mediating insulin resistance in this population. We have demonstrated increased muscular adiposity and the potential utility of treatment strategies that reduce intramuscular adiposity and shift fat toward the subcutaneous depots. In collaboration with Gokhan Hotamisligil at the Harvard School of Public Health, we have demonstrated abnormal regulation of adiponectin in relationship to excess visceral fat. We have furthermore collaborated with the Framingham Study to determine excess cardiovascular risk attributable to the excess visceral adiposity and loss of subcutaneous fat seen in this syndrome. In two treatment studies, we have examined the potential utility of insulin sensitizing agents in this population. In particular, we have shown recently that use of TZD’s can decrease lipolysis and increase subcutaneous fat, while improving adiponectin and insulin sensitivity. This strategy affords potentially great benefit to a lipodystrophic population and will be followed up with studies of combined PPAR agonists to further modulate insulin sensitivity, adipose partitioning and lipid regulation in this population. References: 1. Hadigan C, Meigs JB, Rabe J, et al. Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance. J Clin Endocrinol Metab 2001;86(2):939-43. 2. Hadigan C, Rabe J, Meininger G, Aliabadi N, Breu J, Grinspoon S. Inhibition of lipolysis improves insulin sensitivity in protease inhibitor-treated HIV-infected men with fat redistribution. Am J Clin Nutr 2003;77:490-4. 3. Hadigan C, Meigs JB, Wilson PW, et al. Prediction of coronary heart disease risk in HIV-infected patients with fat redistribution. Clin Infect Dis 2003;36(7):909-16. 4. Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome: A randomized controlled trial. JAMA 2000;284(4):472-7. 5. Driscoll SD, Meininger GE, Ljunquist K, et al. Differential effects of metformin and exercise on muscle adiposity and metabolic indices in human Immunodeficiecy virus-infected patients. J Clin Endocrinol Metab 2004;In Press. 6. Tong Q, Sankale JL, Hadigan CM, et al. Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices. J Clin Endocrinol Metab 2003;88(4):1559-64. 7. Hadigan C, Yawetz S, Thomas A, Havers F, Sax PE, Grinspoon S. Metabolic effects of rosiglitazone in HIV lipodystrophy: A randomized controlled trial. Annals of Internal Medicine 2004;140(10):786-94.