This project aims to further understand the adverse consequences of hypercortisolemia by investigatingpro- inflammatory markers, the GH/IGF-1 axis, and gastrointestinal appetite hormones in patients with chronic glucocorticoid excess. For this, we plan to follow patients with Cushing's Disease, due to an ACTH-secreting pituitary tumor, over time before and after surgical treatment.
The specific aims of the research proposal are to: 1) determine whether patients with Cushing's Disease have elevated serum pro-inflammatorymarkers compared to obese BMI- matched and lean controls;2) follow GH/IGF-1 deficient Cushing's patients to determine if GH/IGF-1 deficiency confers increased risk for the metabolic syndrome and visceral adiposity in cured patients;3) characterize appetite and fasting and post-meal total and active ghrelin and PYY to determine their role in the increased appetite and abnormal body composition of glucocorticoid excess;and 4) quantify body composition, particularly adipose tissue distribution, by whole-body MRI, with respect to the adipokines leptin and adiponectin. Given our unique access to a large population of patients with pituitary Cushing's Disease, we have the ability to investigate these novel chronic effects of hypercortisolemia. In doing so, we hope to yield important new information on the metabolic and body composition abnormalities resulting from excess glucocorticoid exposure, and the pathogenesis of visceral adiposity in general. The primary overall objective of this career development award application is to provide support that will enable me to gain new research skills and experience in a mentored environment, and ultimately allow me to develop into a successful independent researcher in the areas of neuroendocrinology and pituitary diseases. My current environment is ideally suited to achieve this goal. Through Dr. Post, I have access to a large cohort of Cushing's Disease patients. My two mentors, Dr. Pamela Freda and Dr. Derek LeRoith, are highly qualified and experienced researchers in the areas of pituitary disease/acromegaly and IGF-1/obesity, respectively, and are committed to providing me with the support I need to pursue my research plans and to develop into an independent investigator.

Public Health Relevance

The current widespread use of glucocorticoids results in a high prevalence of iatrogenic Cushing's Syndrome, which is associated with profound body composition changes, the metabolic syndrome, and increased cardiovascular risk. The studies outlined in this proposal aim to investigate the poorly understood mechanisms by which hypercortisolemia causes these metabolic and phenotypic changes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK082617-05
Application #
8325592
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2008-09-22
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$149,958
Indirect Cost
$11,108
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Geer, Eliza B; Islam, Julie; Buettner, Christoph (2014) Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose tissue function and lipid metabolism. Endocrinol Metab Clin North Am 43:75-102
Sundaram, Nina K; Carluccio, Alessia; Geer, Eliza B (2014) Characterization of persistent and recurrent Cushing's disease. Pituitary 17:381-91
Lambert, Jessica K; Goldberg, Levana; Fayngold, Sofia et al. (2013) Predictors of mortality and long-term outcomes in treated Cushing's disease: a study of 346 patients. J Clin Endocrinol Metab 98:1022-30
Geer, Eliza B; Shen, Wei; Strohmayer, Erika et al. (2012) Body composition and cardiovascular risk markers after remission of Cushing's disease: a prospective study using whole-body MRI. J Clin Endocrinol Metab 97:1702-11
Geer, Eliza B; Shen, Wei; Gallagher, Dympna et al. (2010) MRI assessment of lean and adipose tissue distribution in female patients with Cushing's disease. Clin Endocrinol (Oxf) 73:469-75
Geer, Eliza B; Shen, Wei (2009) Gender differences in insulin resistance, body composition, and energy balance. Gend Med 6 Suppl 1:60-75