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-1beta, and IL-1 receptor antagonist (IL-1Ra)], and glucose metabolism (homeostasis model assessment). In vitro effects of GH/IGF-I on IL-1beta/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-1beta and IL-1beta 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-1beta, 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.


CONCLUSIONS
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.
Ueland
Thor
T
Section of Endocrinology, Research Institute for Internal Medicine, University of Oslo, N-0027 Oslo, Norway. thor.ueland@medisin.uio.no
Fougner
Stine L
SL
Godang
Kristin
K
Lekva
Tove
T
Schurgers
Leon J
LJ
Scholz
Hanne
H
Halvorsen
Bente
B
Schreiner
Thomas
T
Aukrust
Pål
P
Bollerslev
Jens
J
D000172:Acromegaly / Q000097:blood* / Q000378:metabolism* / Q000503:physiopathology; D054392:Adipokines / Q000097:blood; D000328:Adult; D000368:Aged; D001823:Body Composition / Q000502:physiology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D005260:Female; D019382:Human Growth Hormone / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000502:physiology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood*; D008297:Male; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood* / Q000494:pharmacology
D054392:Adipokines; D016207:Cytokines; C507763:IL1RN protein, human; D007328:Insulin; D053590:Interleukin 1 Receptor Antagonist Protein; D015675:Osteocalcin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I