HIV-infected patients demonstrate changes in fat distribution and metabolic abnormalities which increase cardiovascular risk. GH secretion is reduced in inverse association with excess visceral adiposity in HIV- infected patients. Physiological studies have shown reduced GHRH as one mechanism in this regard. We have now shown significant effects of exogenous GHRH, to result in physiologic increases in GH. Recent data from a large, randomized, placebo-controlled multicenter trial with GHRH1-44 demonstrate highly significant effects to reduce VAT >15% with the achievement of physiologic IGF-I levels. In addition, GHRH1-44 improved lipid parameters significantly. GHRH1-44, in contrast to recently published reports of GH, was well tolerated, without effects on insulin or glucose, even among those with impaired glucose tolerance at baseline. Taken together, these data strongly suggest that HIV-infected patients with central fat accumulation will have reduced GH secretion that is in part a function of reduced GHRH. Physiologic augmentation with GHRH is thus logical and now shown to be highly efficacious. Despite significant recent advances shown in large trials utilizing GHRH to reduce visceral adiposity and improve lipids in the HIV population, much remains to be learned regarding the use of this novel strategy in the HIV population: For example, important questions of physiology remain: 1) does GHRH1-44 therapy normalize GH pulse secretion 2) why are the effects of GHRH1-44 on visceral fat so potent for a relatively modest effects on IGF-I? 3) do the effects of GHRH1-44 on VAT result, in part, from normalized endogenous GH secretion? In addition, critical effects of GHRH on other fat depots, including muscle and liver have yet to be characterized. Effects to reduce visceral fat may also actually improve insulin sensitivity in the long run, especially as the increase in GH secretion is physiologic, and filtered through the pituitary, which is subject to feedback inhibition by IGF-I and produces physiological increases in GH, which may be less directly antagonistic to insulin. Furthermore, the effects of GHRH1-44 on direct measures of insulin sensitivity have not been investigated using the sensitive euglycemic clamp procedure. Importantly, the effects of GHRH1-44 on clinical CV risk markers, including endpoints such as IMT have not been investigated.
The Aims proposed in the grant renewal will answer critical unanswered questions regarding the mechanisms of reduced GH secretion and potential clinical utility of GHRH1-44 in the HIV population.

Public Health Relevance

In this grant we will study how the secretion of growth hormone is regulated in HIV patients. We will also investigate whether the use of a secretory factor that induces the body to makes its own GH, growth hormone releasing hormone, will improve cardiovascular risk endpoints, including abdominal fat, insulin, and carotid IMT.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063639-10
Application #
8299121
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Malozowski, Saul N
Project Start
2003-04-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$451,961
Indirect Cost
$151,135
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Stanley, Takara L; Feldpausch, Meghan N; Oh, Jinhee et al. (2014) Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial. JAMA 312:380-9
Denny-Brown, S; Stanley, T L; Grinspoon, S K et al. (2012) The association of macro- and micronutrient intake with growth hormone secretion. Growth Horm IGF Res 22:102-7
Makimura, H; Stanley, T L; Chen, C Y et al. (2011) Relationship of adiponectin to endogenous GH pulse secretion parameters in response to stimulation with a growth hormone releasing factor. Growth Horm IGF Res 21:155-9
Stanley, Takara L; Chen, Cindy Y; Branch, Karen L et al. (2011) Effects of a growth hormone-releasing hormone analog on endogenous GH pulsatility and insulin sensitivity in healthy men. J Clin Endocrinol Metab 96:150-8
Lo, Janet; You, Sung Min; Liebau, James et al. (2010) Effects of low-dose growth hormone withdrawal in patients with HIV. JAMA 304:272-4
Stanley, Takara L; Grinspoon, Steven K (2009) GH/GHRH axis in HIV lipodystrophy. Pituitary 12:143-52
Lo, Janet; You, Sung Min; Canavan, Bridget et al. (2008) Low-dose physiological growth hormone in patients with HIV and abdominal fat accumulation: a randomized controlled trial. JAMA 300:509-19
Koutkia, Polyxeni; Eaton, Kristina; You, Sung Min et al. (2006) Growth hormone secretion among HIV infected patients: effects of gender, race and fat distribution. AIDS 20:855-62
Koutkia, Polyxeni; Canavan, Bridget; Breu, Jeff et al. (2005) Effects of growth hormone-releasing hormone on bone turnover in human immunodeficiency virus-infected men with fat accumulation. J Clin Endocrinol Metab 90:2154-60
Koutkia, Polyxeni; Canavan, Bridget; Breu, Jeff et al. (2005) Growth hormone (GH) responses to GH-releasing hormone-arginine testing in human immunodeficiency virus lipodystrophy. J Clin Endocrinol Metab 90:32-8

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