Acromegaly is a rare disease characterized by excess GH and IGF-I and their multi-system adverse effects. Epidemiological data associate acromegaly with increased morbidity and mortality primarily from cardiovascular causes, which are often attributed to acromegaly's associated metabolic abnormalities including insulin resistance. However, these abnormalities'etiology and contribution to increased CV risk cannot necessarily be equated with those of similar metabolic syndrome components in other populations. Rather, as our novel preliminary data suggest, we hypothesize that a GH-IGF-I excess specific dysregulation of adipose tissue (AT) and lipodystrophy occur. This lipodystrophy, we propose, includes reduced central AT depots yet increased AT in muscle and contributes to insulin resistance, adipokine and appetite hormone dysregulation, endothelial cell dysfunction and ultimately increased CV risk in active acromegaly. Biochemical control of acromegaly should reverse these abnormalities. However, we have identified some patients whose remission is accompanied by significant weight gain and a rise in crp. In them, we hypothesize that as GH/IGF-I normalize, reversal of the lipodystrophy markedly increases central AT, macrophage infiltration and inflammation in AT and systemic inflammation. Whether inflammation persists and these patients'ultimate body composition as well as the role of post-therapy increases in ghrelin levels in stimulating weight gain need to be determined. We will test these hypotheses by studying patients with active acromegaly before and during therapies utilizing techniques novel to the study of acromegaly and the GH/IGF-I axis including examinations of muscle lipid by MRI and 1HMRS, hepatic lipid by 1HMRS, adipose tissue for macrophage infiltration and inflammation and function of biopsied endothelial cells. We will also relate these clinical endpoints to our modern biochemical markers of acromegaly and thereby establish clinically validated biochemical guidelines for acromegaly therapy. Understanding the consequences of this lipodystrophy and its reversal are crucial because new potent medical therapies for acromegaly now allow us to titrate therapy to particular biochemical goals and even a target for IGF-I within the spectrum of the normal range which may have long term clinical significance with regard to cardiovascular outcomes. This proposal is strengthened by its continuation of our unique, ongoing prospective acromegaly cohort study. This study, the only one on acromegaly funded by the NIH, has provided novel important data on a number of aspects of acromegaly in particular its biochemical markers. The endpoints and outcomes studied in the current application can only be achieved with long term follow up of a uniquely large, consecutive, well-characterized cohort, which we have well underway. Acromegaly provides a model through which we can improve our knowledge about the effects of GH and IGF-I excess on adipose tissue, systemic inflammation, endothelial dysfunction and CV risk which is also applicable to our understanding of the effects of GH use and over-use in other clinical settings. 1

Public Health Relevance

Acromegaly, a rare disease due to a growth hormone producing pituitary tumor, is associated with increased morbidity and mortality. In this project we will utilize modern biochemical methods, novel techniques and a uniquely large, ongoing prospective acromegaly cohort study to characterize novel features of acromegaly including an abnormal fat distribution that may contribute significantly to its increased morbidity and mortality. Our study will lead to important knowledge about the effects GH and IGF-I on body composition, adipose tissue inflammation, endothelial dysfunction and cardiovascular risk which is also applicable to our understanding of the effects of GH use and over-use in other clinical settings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064720-09
Application #
8287668
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Malozowski, Saul N
Project Start
2003-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$353,463
Indirect Cost
$133,921
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Reyes-Vidal, Carlos; Fernandez, Jean Carlos; Bruce, Jeffrey N et al. (2014) Prospective study of surgical treatment of acromegaly: effects on ghrelin, weight, adiposity, and markers of CV risk. J Clin Endocrinol Metab 99:4124-32
Reid, Tirissa J; Post, Kalmon D; Bruce, Jeffrey N et al. (2010) Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006: acromegaly remains under-recognized and under-diagnosed. Clin Endocrinol (Oxf) 72:203-8
Frystyk, Jan; Freda, Pamela; Clemmons, David R (2010) The current status of IGF-I assays--a 2009 update. Growth Horm IGF Res 20:8-18
Bidlingmaier, Martin; Freda, Pamela U (2010) Measurement of human growth hormone by immunoassays: current status, unsolved problems and clinical consequences. Growth Horm IGF Res 20:19-25
Freda, Pamela U (2009) Monitoring of acromegaly: what should be performed when GH and IGF-1 levels are discrepant? Clin Endocrinol (Oxf) 71:166-70
Freda, Pamela U; Shen, Wei; Reyes-Vidal, Carlos M et al. (2009) Skeletal muscle mass in acromegaly assessed by magnetic resonance imaging and dual-photon x-ray absorptiometry. J Clin Endocrinol Metab 94:2880-6
Freda, Pamela U; Shen, Wei; Heymsfield, Steven B et al. (2008) Lower visceral and subcutaneous but higher intermuscular adipose tissue depots in patients with growth hormone and insulin-like growth factor I excess due to acromegaly. J Clin Endocrinol Metab 93:2334-43
Ausiello, John C; Bruce, Jeffrey N; Freda, Pamela U (2008) Postoperative assessment of the patient after transsphenoidal pituitary surgery. Pituitary 11:391-401
Freda, Pamela U; Chung, Wendy K; Matsuoka, Naoki et al. (2007) Analysis of GNAS mutations in 60 growth hormone secreting pituitary tumors: correlation with clinical and pathological characteristics and surgical outcome based on highly sensitive GH and IGF-I criteria for remission. Pituitary 10:275-82
Jehle, Sigrid; Reyes, Carlos M; Sundeen, Robert E et al. (2005) Alternate-day administration of pegvisomant maintains normal serum insulin-like growth factor-I levels in patients with acromegaly. J Clin Endocrinol Metab 90:1588-93

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