A new and poorly understood syndrome that may include central body fat redistribution, hyperlipidemia, and hyperglycemia has recently been recognized in individuals receiving highly active antiretroviral therapy (HAART) for HIV infection. It is likely that these metabolic changes, which resemble those seen in Cushing's syndrome, will significantly increase the risk for premature coronary artery disease in treated individuals. Although overt Cushing's syndrome has been excluded in affected individuals, there have been no reported studies based on actual measurement of cortisol production rates or tissue sensitivity to glucocorticoids in subjects receiving HAART. Similarly, it is not known whether HAART regimens may directly stimulate growth of abdominal adipocytes through an effect on PPAR gamma, a key transcriptional activator of preadipocyte differentiation. In this study, 180 HIV-infected individuals about to begin protease inhibitor therapy and 50 uninfected control subjects will be followed for one year with sensitive measurements of regional body composition, lipid and glucose metabolism, cortisol production, and adipocyte gene expression.
The Specific Aims of this study are twofold: First, a case definition of the metabolic syndrome will be formulated based on identification of predisposing clinical factors and a comparison of changes in body composition, lipoprotein levels, ans glucose metabolism occurring in subjects over the course of the study. The atherogenicity of the hyperlipidemia associated with HAART will be fully defined by a detailed analysis of lipoprotein subfractions.
The second aim of the study will be to test the hypotheses that (a) physiological hypercortisolemia + increased cortisol receptor expression, or (b) increased expression or activation of PPAR gamma is abdominal preadipocytes predict the subsequent development of metabolic abnormalities in subjects receiving HAART. The decision of investigate these two hypotheses was based on both the biological plausibility of the underlying mechanisms and the availability of drugs that might be used to specifically block glucococorticoid action (RU-486) or increase the activation of PPAR gamma in peripheral relative to abdominal preadipocytes (thiazolidenediones). Future trials of these medications, along with a great deal more basic research, are clearly justified by the increasing and sustained use of HAART to deal with the worldwide epidemic of HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055460-05
Application #
6626975
Study Section
Special Emphasis Panel (ZRG5-AARR-6 (01))
Program Officer
Teff, Karen L
Project Start
1999-01-15
Project End
2003-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
5
Fiscal Year
2003
Total Cost
$392,635
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Araneta, Maria Rosario G; Kanaya, Alka M; Hsu, William C et al. (2015) Optimum BMI cut points to screen asian americans for type 2 diabetes. Diabetes Care 38:814-20
Kratz, Mario; Weigle, David S; Breen, Patricia A et al. (2010) Exchanging carbohydrate or protein for fat improves lipid-related cardiovascular risk profile in overweight men and women when consumed ad libitum. J Investig Med 58:711-9
Gerchman, Fernando; Tong, Jenny; Utzschneider, Kristina M et al. (2009) Body mass index is associated with increased creatinine clearance by a mechanism independent of body fat distribution. J Clin Endocrinol Metab 94:3781-8
Kratz, Mario; Purnell, Jonathan Q; Breen, Patricia A et al. (2008) Reduced adipogenic gene expression in thigh adipose tissue precedes human immunodeficiency virus-associated lipoatrophy. J Clin Endocrinol Metab 93:959-66
Purnell, J Q; Cummings, D; Weigle, D S (2007) Changes in 24-h area-under-the-curve ghrelin values following diet-induced weight loss are associated with loss of fat-free mass, but not with changes in fat mass, insulin levels or insulin sensitivity. Int J Obes (Lond) 31:385-9
Koren, Mikhail S; Purnell, Jonathan Q; Breen, Patricia A et al. (2007) Changes in plasma amino Acid levels do not predict satiety and weight loss on diets with modified macronutrient composition. Ann Nutr Metab 51:182-7
Tong, J; Boyko, E J; Utzschneider, K M et al. (2007) Intra-abdominal fat accumulation predicts the development of the metabolic syndrome in non-diabetic Japanese-Americans. Diabetologia 50:1156-60
Koren, Mikhail S; Purnell, Jonathan Q; Breen, Patricia A et al. (2006) Plasma C-reactive protein concentration is not affected by isocaloric dietary fat reduction. Nutrition 22:444-8
Tong, Jenny; Fujimoto, Wilfred Y; Kahn, Steven E et al. (2005) Insulin, C-peptide, and leptin concentrations predict increased visceral adiposity at 5- and 10-year follow-ups in nondiabetic Japanese Americans. Diabetes 54:985-90
Weigle, David S; Breen, Patricia A; Matthys, Colleen C et al. (2005) A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin and ghrelin concentrations. Am J Clin Nutr 82:41-8

Showing the most recent 10 out of 18 publications