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OBSERVATIONS Serum Visceral Adipose Tissue–Derived Serine Protease Inhibitor Concentrations in Human Obesity and Polycystic Ovary Syndrome
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dipokines, such as the insulinsensitizing adipokine visceral adipose tissue– derived serine protease inhibitor (vaspin), play an important role in the interaction among androgen excess, abdominal adiposity, and insulin resistance in polycystic ovary syndrome (PCOS) (1). A recently published small case-control study suggests that PCOS patients have increased vaspin mRNA and protein in omental adipose tissue and increased circulating vaspin concentrations that decrease after treatment with the insulin-sensitizer drug metformin (2). We measured vaspin levels in serum samples from 42 PCOS patients and 42 nonhyperandrogenic women matched for age, BMI, and frequency of obesity (48%, as defined by a BMI ⱖ30 kg/m2) in samples from 26 severely obese premenopausal women (15 had PCOS) obtained before and after bariatric surgery and in samples from 34 different PCOS patients submitted to treatment with either metformin (n ⫽ 19) or an antiandrogenic oral contraceptive pill (n ⫽ 15) (3). Serum vaspin concentrations were measured in duplicate within a single ELISA assay (AdipoGen Inc., Seoul, Korea) modified as to cover a 0.16 –20 ng/ml range. Data were submitted to multivariate or repeated-measures general linear models to evaluate the impact of PCOS, obesity, and the interventions on serum vaspin levels. Neither PCOS nor obesity had any statistically significant effect on serum vaspin concentrations (PCOS mean ⫾ SD
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0.8 ⫾ 0.7 ng/ml vs. control 0.9 ⫾ 0.7 ng/ml, F ⫽ 0.357, P ⫽ 0.552; obese 0.8 ⫾ 0.7 ng/ml vs. nonobese 0.9 ⫾ 0.8 ng/ml, F ⫽ 0.458, P ⫽ 0.500; and F ⫽ 1.545, P ⫽ 0.218 for the interaction between PCOS and obesity). Circulating vaspin was similar in women presenting with normal or abnormal glucose tolerance (normal 0.9 ⫾ 0.7 ng/ml vs. abnormal 0.7 ⫾ 0.7 ng/ml, F ⫽ 0.891, P ⫽ 0.348) irrespective of PCOS or obesity (F ⫽ 0.228, P ⫽ 0.635 for the interaction between glucose tolerance and PCOS; F ⫽ 0.658, P ⫽ 0.420 for the interaction between glucose tolerance, PCOS, and obesity). After bariatric surgery (women lost 39 ⫾ 13 kg and 22 ⫾ 12 cm of waist circumference), serum vaspin levels decreased (baseline 1.4 ⫾ 0.9 ng/ml vs. postsurgery 1.0 ⫾ 0.9 ng/ml, F ⫽ 5.709, P ⫽ 0.025) irrespective of the presence or absence of PCOS (F ⫽ 0.864, P ⫽ 0.362 for the interaction). Finally, serum vaspin levels decreased slightly during treatment with metformin (baseline 2.0 ⫾ 4.4 ng/ml, 12 weeks 0.8 ⫾ 1.0 ng/ml, and 24 weeks 0.7 ⫾ 0.4 ng/ml) and increased dramatically in the women treated with oral contraceptives (baseline 3.6 ⫾ 6.7 ng/ml, 12 weeks 9.7 ⫾ 6.9 ng/ml, and 24 weeks 11.8 ⫾ 7.6 ng/ml) (F ⫽ 11.225, P ⬍ 0.001 for patients completing the study; F ⫽ 17.773, P ⬍ 0.001 by intention-to-treat analysis). In summary, our present results indicate that serum vaspin concentrations in premenopausal women are not affected by PCOS, obesity, or glucose tolerance disorders. On the contrary, interventions ameliorating insulin resistance and glucose intolerance (weight loss and metformin) result in a decrease in serum vaspin levels, whereas interventions that might worsen insulin resistance and glucose tolerance (oral contraceptives) increase these levels. Overall, the changes in serum vaspin levels observed in our study may represent a compensatory mechanism (4) aiming to maintain normal insulin sensitivity and glucose tolerance. HE´CTOR F. ESCOBAR-MORREALE, MD, PHD1,2 MANUEL LUQUE-RAMÍREZ, MD, PHD1,2 JOSE´ L. SAN-MILLA´N, PHD2,3
From the 1Department of Endocrinology, Hospital Universitario Ramo´n y Cajal, Universidad de Alcala´, Madrid, Spain; the 2Centro de Investigacio´n Biome´dica en Red Diabetes y Enfermedades Metabo´licas Asociadas (CIBERDEM), Barcelona, Spain; and the 3Department of Molecular Genetics, Hospital Universitario Ramo´n y Cajal, Universidad de Alcala´, Madrid, Spain. Corresponding author: He´ctor F. Escobar-Morreale,
[email protected]. DOI: 10.2337/dc08-1690. Clinical trial reg. no. NCT00428311, clinicaltrials.gov. © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http:// creativecommons.org/licenses/by-nc-nd/3.0/ for details.
Acknowledgments — This study was supported by grant PI050341 from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation. Centro de Investigacio´n Biome´dica en Red Diabetes y Enfermedades Metabo´licas Asociadas (CIBERDEM) is an initiative of the Instituto de Salud Carlos III. No potential conflicts of interest relevant to this article were reported.
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References 1. Escobar-Morreale HF, San Milla´n JL: Abdominal adiposity and the polycystic ovary syndrome. Trends Endocrinol Metab 18:266 –272, 2007 2. Tan BK, Heutling D, Chen J, Farhatullah S, Adya R, Keay SD, Kennedy CR, Lehnert H, Randeva HS: Metformin decreases the adipokine vaspin in overweight women with polycystic ovary syndrome concomitant with improvement in insulin sensitivity and a decrease in insulin resistance. Diabetes 57:1501–1507, 2008 3. Luque-Ramirez M, Alvarez-Blasco F, Botella-Carretero JI, Martinez-Bermejo E, Lasuncion MA, Escobar-Morreale HF: Comparison of ethinyl-estradiol plus cyproterone acetate versus metformin effects on classic metabolic cardiovascular risk factors in women with the polycystic ovary syndrome. J Clin Endocrinol Metab 92:2453–2461, 2007 4. Youn BS, Klo¨ting N, Kratzsch J, Lee N, Park JW, Song ES, Ruschke K, Oberbach A, Fasshauer M, Stumvoll M, Blu¨her M: Serum vaspin concentrations in human obesity and type 2 diabetes. Diabetes 57: 372–377, 2008
DIABETES CARE, VOLUME 32, NUMBER 1, JANUARY 2009
