Changes in fat distribution, including increased abdominal visceral fat and reduced subcutaneous fat are increasingly recognized in HIV-infected patients receiving highly active antiretroviral therapy. We have previously shown that the changes in fat distribution are associated with a metabolic syndrome, including insulin resistance and dyslipidemia, hypertension, impaired thrombosis and bone loss. We have recently demonstrated reduced mean GH concentrations, and GH pulse amplitude among patients with HIV lipodystrophy and significant visceral fat accumulation using detailed frequent sampling and pulse detection algorithms. Using standard stimulation testing with arginine and GHRH, up to one third of such patients may be GH deficient. GH deficiency is associated with insulin resistance, dyslipidemia, increased cardiovascular risk parameters, fat redistribution, and bone loss among non HIV infected patients, in whom GH replacements attenuates increased cardiovascular risk parameters and improves bone density. Novel preliminary data presented with this grant application suggest that cardiovascular risk markers are increased in association with GH deficiency in HIV-infected patients with lipodystrophy and that bone density is inversely related to mean overnight GH levels and peak GH responses to secretogogue testing in this population, suggesting the potential utility of physiologic GH administration in this population. To date, short-term studies using very high doses of GH have been performed, with the anticipated negative effects on glucose homeostasis. In contrast, physiologic GH administration has been shown to improve insulin sensitivity in non HIV-infected patients with abdominal obesity and to improve cardiovascular risk markers, bone density, and fat redistribution in non HIV-infected patients with GH deficiency. Importantly, studies investigating the pathophysiology of GH deficiency, strategies to increase physiologic GH secretion, and the use of long-term physiologic GH to improve insulin sensitivity, cardiovascular risk indices and bone density have not been performed in the large group of HIV-infected patients with reduced GH. In the proposed grant, we will: 1) investigate the pathophysiology of reduced growth hormone, 2) determine the novel short-term effects of a GH secretogogue, GHRH, to restore physiologic GH levels, and 3) determine the long-term effects of physiologic GH administration on bone and metabolic parameters in patients with HIV lipodystrophy and reduced GH. The studies outlined in this grant proposal will investigate a novel approach to the treatment and management of critical metabolic abnormalities in patients with HIV lipodystrophy. ? ?
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