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This version published online on October 30, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-0422
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Submitted on February 26, 2009
Accepted on October 13, 2009

Associations between Body Composition, Circulating Interleukin-1 Receptor Antagonist, Osteocalcin, and Insulin Metabolism in Active Acromegaly

Thor Ueland*, Stine L. Fougner, Kristin Godang, Tove Lekva, Leon J. Schurgers, Hanne Scholz, Bente Halvorsen, Thomas Schreiner, Pål Aukrust, and Jens Bollerslev

Section of Endocrinology (T.U., S.L.F., K.G., T.L., T.S., J.B.), Research Institute for Internal Medicine (T.U., S.L.F., T.L., B.H., P.A.), Institute for Surgical Research and Surgical Clinic (H.S.), and the Section of Clinical Immunology and Infectious Diseases (P.A.), Rikshospitalet Medical Center, University of Oslo, N-0027 Oslo, Norway; and Department of Biochemistry and Cardiovascular Research Institute CARIM (L.J.S.), Maastricht University, NL-6200 MD Maastricht, The Netherlands

* To whom correspondence should be addressed. E-mail: thor.ueland{at}medisin.uio.no.

Objective: Patients with active acromegaly display a range of abnormalities in glucose metabolism. To elucidate interactions between bone and energy homeostasis in relation to excess GH, we sought to determine whether these patients were characterized by alterations in circulating levels of adipokines and cytokines and potential interactions with osteocalcin (OCN) and insulin resistance.

Methods: Forty-seven patients with active acromegaly: 26 women and 21 men (49 ± 11, mean ± SD) were evaluated and compared with age-, sex-, and body mass index-matched controls by x-ray absorptiometry, biochemical analysis [GH, IGF-I, OCN, leptin, adiponectin, retinol binding protein 4, IL-6, IL-1{beta}, and IL-1 receptor antagonist (IL-1Ra)], and glucose metabolism (homeostasis model assessment). In vitro effects of GH/IGF-I on IL-1{beta}/IL-1Ra in THP-1 macrophages and human white adipocytes as well as effects of GH/IGF-I in combination with carboxylated and undercarboxylated OCN on glucose-stimulated insulin release in human pancreatic islets were also investigated.

Results: Patients with acromegaly were characterized by markedly decreased serum levels of IL-1Ra and increased IL-1{beta} and IL-1{beta} to IL-1Ra ratio, suggesting enhanced IL-1 activity. The decreased IL-1Ra was strongly associated with increased OCN levels in multivariate models and was significantly correlated with decreased total body fat mass. In macrophages, IGF-I/GH significantly decreased the release of IL-1Ra and increased IL-1{beta}, suggesting that the decreased circulating IL-1Ra levels in acromegaly could reflect both direct and indirect mechanisms. Finally, circulating OCN was the main determinant of insulin resistance and {beta}-cell function in acromegaly and in vitro, a blunted insulin response was observed in the presence of OCN and GH/IGF-I.

Conclusion: These data confirm and establish novel and complex interactions between bone, energy metabolism, and adipose tissue and suggest an unfavorable effect of OCN and GH/IGF-I in combination on insulin metabolism in active acromegaly.






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