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

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. (J Clin Endocrinol Metab 95: 361-368, 2010)