More than half of individuals treated for HIV-infection now demonstrate changes in body fat distribution, including increased visceral adiposity and peripheral fat atrophy. Along with these changes, HIV-infected patients are at increased risk for insulin resistance, diabetes, dyslipidemia, and cardiovascular disease. This grant proposal investigates a novel strategy to decrease abdominal fat and reduce metabolic risk in HIV- infection by augmenting endogenous growth hormone (GH) secretion through the use of growth hormone releasing hormone (GHRH1-44). The rationale for this strategy stems from data that HIV-infected patients with abdominal fat accumulation are relatively GH deficient, and from clinical observations that GH replacement in other populations with GH deficiency improves body composition and ameliorates cardiometabolic risk. The use of GHRH1-44 in this application, in contrast to the use of exogenous recombinant human GH (rhGH), is proposed in order to augment physiologic pituitary GH secretion rather than providing apulsatile exogenous replacement. Our preliminary data demonstrate that GHRH1-44 increases endogenous pulsatile growth hormone secretion, which we hypothesize will lead to greater efficacy and reduced side effects as compared to exogenous rhGH. Previous studies have demonstrated that GHRH1-44 reduces visceral fat accumulation and improves dyslipidemia. In this proposal we hypothesize that GHRH1-44 will also decrease ectopic fat in liver and muscle, potentially ameliorating insulin resistance. Two studies are proposed in this application - a short-term comparison of the effects of GHRH1-44 vs. rhGH on endogenous GH pulsatility and insulin sensitivity, and a 1 year randomized placebo-controlled trial measuring the effects of GHRH1-44 on lipolysis, insulin sensitivity, and ectopic fat accumulation. Together, data from these studies will characterize the metabolic effects GHRH1- 44 and, additionally, will explore the physiologic importance of GH pulsatility by contrasting the effects of GHRH1-44 vs. rhGH. With these goals, the proposed research will both enhance our understanding of GH physiology and contribute to the development of a potentially important new treatment strategy for metabolic complications of HIV. The candidate in this application, Dr. Takara Stanley, is a pediatric endocrinologist with clinical research experience in metabolic and endocrine complications of HIV-infection. Dr. Stanley's career goal is to perform patient-oriented research in an academic setting, focusing on the metabolic and endocrine aspects of body fat distribution. In the current proposal, Dr. Stanley will explore these themes through the model of HIV-lipodystrophy. As she progresses in her career, she plans to expand her field of investigation to pediatric conditions of abdominal obesity. The proposed studies will provide Dr. Stanley with experience and training in numerous methods of physiologic investigation, including techniques for analyzing hormone secretory dynamics, glucose homeostasis, and lipid metabolism. In addition, the proposed career development plan will provide Dr. Stanley will further training in statistics and drug development. The mentor in this proposal, Dr. Steven Grinspoon, is an internationally recognized expert in the field of HIV-associated endocrine and metabolic complications. In addition to being a well-established and well-funded clinical researcher, he is an accomplished mentor with the skills and infrastructure necessary to mentor Dr. Stanley and help her transition to independence. Along with the mentorship of Dr. Grinspoon, the career development plan proposed in this application will provide Dr. Stanley with the training and skills to become an independent clinical investigator.

Public Health Relevance

This project will determine the metabolic effects of a new therapy, growth hormone releasing hormone (GHRH1-44), to reduce abdominal fat and improve metabolism in patients with HIV-infection and increased belly size. The research will contribute to our knowledge of this important potential therapy for complications of HIV-infection, and will also increase our understanding of how growth hormone affects sugar and fat metabolism.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Hyde, James F
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Massachusetts General Hospital
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Stanley, Takara L; Feldpausch, Meghan N; Murphy, Caitlin A et al. (2014) Discordance of IGF-1 and GH stimulation testing for altered GH secretion in obesity. Growth Horm IGF Res 24:10-5
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
Stanley, Takara L; Chen, Minghua L; Goodman, Elizabeth (2014) The typology of metabolic syndrome in the transition to adulthood. J Clin Endocrinol Metab 99:1044-52
Sinha, Manasi; Stanley, Takara L; Webb, Jessica et al. (2013) Metabolic effects of Roux-en-Y gastric bypass in obese adolescents and young adults. J Pediatr Gastroenterol Nutr 56:528-31
Stanley, Takara (2012) Diagnosis of growth hormone deficiency in childhood. Curr Opin Endocrinol Diabetes Obes 19:47-52
Makimura, Hideo; Feldpausch, Meghan N; Stanley, Takara L et al. (2012) Reduced growth hormone secretion in obesity is associated with smaller LDL and HDL particle size. Clin Endocrinol (Oxf) 76:220-7
Stanley, Takara L; Falutz, Julian; Marsolais, Christian et al. (2012) Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin. Clin Infect Dis 54:1642-51
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
Fitch, Kathleen V; Stanley, Takara L; Looby, Sara E et al. (2011) Relationship between neck circumference and cardiometabolic parameters in HIV-infected and non-HIV-infected adults. Diabetes Care 34:1026-31
Stanley, Takara L; Zanni, Markella V; Johnsen, Stine et al. (2011) TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J Clin Endocrinol Metab 96:E146-50

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