| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Internal Medicine (Y.Y., H.H., I.S., K.N., T.S.) and Health Center (H.H., I.S.), Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Address all correspondence and requests for reprints to: Yukihiro Yamamoto, M.D., Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: yukihiro{at}hh.iij4u.or.jp.
| Abstract |
|---|
|
|
|---|
| Introduction |
|---|
|
|
|---|
In humans, we (8) and others (9, 10, 11) have reported that the serum adiponectin concentration was negatively correlated with insulin resistance and body weight/body mass index (BMI) in cross-sectional studies. As for lipid profile, we (8) reported that the serum adiponectin level was negatively correlated with triglycerides and low-density lipoprotein (LDL) cholesterol and was positively correlated with high-density lipoprotein (HDL) cholesterol even after adjustment for age, sex, and BMI.
However, the causal relationship of serum adiponectin concentration with insulin resistance, lipid profile, and/or body weight in humans is not clear from these cross-sectional studies. To our knowledge, there is only one longitudinal study concerning the effects of adiponectin on insulin sensitivity (positive results) (9) and body weight (no effects) (12) in adult humans. There could be, however, ethnic differences, and these two studies (9, 12) were of Pima Indians. Furthermore, there are no longitudinal studies concerning adiponectin and the lipid profile. To clarify the relationship of the baseline adiponectin level to subsequent changes in insulin resistance, body weight, and lipid profile, we performed this longitudinal study.
| Subjects and Methods |
|---|
|
|
|---|
This study included 590 male teachers and employees at Keio University, aged 3065 yr (46.4 ± 9.3 in 2000), who received annual health checkups in both 2000 and 2002. Subjects with endocrine disease, significant renal or hepatic disease, coronary artery disease, or cerebrovascular disease and those receiving medication for diabetes mellitus or hyperlipidemia were excluded from the analyses.
The present study was conducted according to the principles expressed in the Declaration of Helsinki. Informed consent was obtained from each subject after full explanation of the purpose, nature, and risk of all procedures used. The protocol was approved by the ethical review committees of the Health Center and the Department of Internal Medicine, Keio University School of Medicine (Tokyo, Japan).
Measurements
Height, weight, fasting plasma glucose, serum insulin, adiponectin, total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol levels were measured in the morning after an overnight fast. Plasma glucose and lipids were assayed by routine automated laboratory methods. The serum insulin concentration was measured by an enzyme immunoassay, using a commercially available kit (Tosoh, Tokyo, Japan) with intra- and interassay coefficients ranging from 2.94.6% and 4.57.0%, respectively. The insulin resistance index was calculated based on homeostasis model assessment (HOMA-IR) (13, 14). The serum adiponectin level was measured by ELISA without a denaturing step, with intra- and inter-assay coefficients ranging from 4.84.9% and 3.36.8%, respectively, as described previously (8, 15).
Statistical analysis
All statistical analyses were performed using the StatView program for Windows (version 5.0-J, SAS Institute, Inc., Cary, NC). Relationships between parameters in 2000 and those in 2002 were analyzed by the Wilcoxon signed-rank test. Relationships between adiponectin at baseline and changes in other parameters in 2 yr were analyzed by simple correlation and by multiple regression. Because serum insulin, triglycerides, and adiponectin levels and HOMA-IR were normally distributed after log transformation, the logarithms of these parameters were used for the analyses. All data are expressed as the mean ± SD, and P < 0.05 was considered statistically significant.
| Results |
|---|
|
|
|---|
|
|
| Discussion |
|---|
|
|
|---|
We previously reported that the serum adiponectin level was negatively correlated with HOMA-IR, triglycerides, and LDL cholesterol and was positively correlated with HDL cholesterol independently of age, sex, and BMI (8). Because the study was cross-sectional, the causal relationship has not been elucidated. Stefan et al. (9) reported that the plasma adiponectin concentration at baseline was positively correlated with insulin-stimulated glucose disposal at follow-up after adjustment for insulin-stimulated glucose disposal at baseline, sex, age at follow-up, time of follow-up, and change in percent body fat in adult Pima Indians, who have the highest prevalence of obesity and diabetes in the world. In Pima Indian children, the plasma adiponectin concentration at 5 yr of age was not predictive of the change in plasma insulin concentration (16). However, there has been no longitudinal study of the relationship between serum adiponectin level and insulin sensitivity except for these Pima Indian studies. In rhesus monkeys, the plasma adiponectin level decreased in parallel with the progression of insulin resistance (7). In the present study the serum adiponectin level at baseline was negatively correlated with subsequent change in HOMA-IR, independently of change in BMI. That is, when the adiponectin level is high, insulin sensitivity improves in the subsequent 2 yr in the Japanese population.
Our findings coincide with animal studies demonstrating that replenishment of adiponectin increases insulin sensitivity in both lipoatrophic diabetic mice and murine models of obesity and type 2 diabetes (3) and with studies demonstrating reduced insulin sensitivity in adiponectin-knockout mice (5, 6). As for the mechanism, adiponectin activates 5'-AMP-activated protein kinase (AMPK), which then mediates phosphorylation of acetyl-coenzyme A carboxylase and fatty acid oxidation in myocytes and hepatocytes, and thereby directly regulates glucose metabolism and insulin sensitivity (17). Further studies are needed to clarify whether the same mechanism applies to improving insulin sensitivity in humans.
As for the lipid profile, it was reported that the serum adiponectin level was negatively correlated with triglycerides and was positively correlated with HDL cholesterol in Japanese (8, 18, 19) and Caucasians (11) in cross-sectional studies. The causal relationship has not been elucidated, because no animal study or longitudinal human study focusing on the relationship between adiponectin and the lipid profile has been reported. In the present longitudinal study the serum adiponectin level at baseline was not correlated with subsequent change in lipid profile. Taking this result into consideration, adiponectin may not directly affect lipid metabolism. However, because in cross-sectional studies the serum adiponectin level was positively correlated with HDL cholesterol, even after adjustment for insulin sensitivity (8, 11), a direct effect of adiponectin on lipid metabolism cannot be ruled out.
As mentioned above, adiponectin activates AMPK (17). 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) is often used in experiments as an AMPK activator (20). Infusion of AICAR in an animal model of diabetes activates AMPK and then improves glucose tolerance (21, 22). The effect of AICAR on lipid metabolism is controversial. One study reported that treatment with AICAR in diabetic animals decreased plasma triglycerides (21), but others reported that the treatment increased plasma triglycerides (22). The effect of adiponectin on lipid metabolism through activation of AMPK and/or another as yet unknown mechanism needs to be validated.
The serum adiponectin level was negatively correlated with body weight and BMI in cross-sectional human studies (8, 9, 10, 11, 12, 18, 23, 24). Weight reduction significantly elevated the serum adiponectin level after 2 months of a calorie-restricted diet (18) and in obese patients who received gastric partition surgery (25). In the present study the baseline adiponectin level did not affect subsequent change in body weight or BMI. This result is consistent with that reported by Vozarova et al. in Pima Indians (12). In humans no other studies have been reported. In mice the administration of adiponectin caused weight reduction without affecting food intake, through its ability to stimulate lipid oxidation (26). In humans, however, the serum adiponectin level was not associated with fat oxidation (27). This discrepancy may be due to differences in adiponectin concentration (pharmacological or physiological), diet (high fat/high sucrose diet or not), and/or adiposity. At least in humans, weight reduction affects the serum adiponectin level, but the serum adiponectin level does not seem to affect weight reduction.
To summarize, the findings of this study suggest that the serum adiponectin concentration predicts the subsequent change in insulin resistance, but not changes in lipid profile or body weight. With a longer study period, it is possible that these factors might also be affected. In conclusion, it is suggested that in humans adiponectin plays an important role in insulin sensitivity. However, further studies are needed to clarify the effects of adiponectin on lipid metabolism and body weight in humans.
| Acknowledgments |
|---|
| Footnotes |
|---|
Abbreviations: AICAR, 5-Aminoimidazole-4-carboxamide ribonucleoside; AMPK, 5'-AMP-activated protein kinase; BMI, body mass index; HDL, high-density lipoprotein; HOMA-IR, insulin resistance index based on homeostasis model assessment; LDL, low-density lipoprotein.
Received July 8, 2003.
Accepted September 15, 2003.
| References |
|---|
|
|
|---|
This article has been cited by other articles:
![]() |
M. Broch, M. T. Auguet, R. Ramirez, M. Olona, C. Aguilar, A. Megia, M. J. Alcaide, R. Pastor, S. Martinez, E. Caubet, et al. Parallel downregulation of retinol-binding protein-4 and adiponectin expression in subcutaneous adipose tissue of non-morbidly obese subjects Eur. J. Endocrinol., July 1, 2009; 161(1): 87 - 94. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Bullon, J.M. Morillo, M.C. Ramirez-Tortosa, J.L. Quiles, H.N. Newman, and M. Battino Metabolic Syndrome and Periodontitis: Is Oxidative Stress a Common Link? Journal of Dental Research, June 1, 2009; 88(6): 503 - 518. [Abstract] [Full Text] [PDF] |
||||
![]() |
M B Snijder, A Flyvbjerg, C D A Stehouwer, J Frystyk, R M A Henry, J C Seidell, R J Heine, and J M Dekker Relationship of adiposity with arterial stiffness as mediated by adiponectin in older men and women: the Hoorn Study Eur. J. Endocrinol., March 1, 2009; 160(3): 387 - 395. [Abstract] [Full Text] [PDF] |
||||
![]() |
M.-F. Hivert, L. M. Sullivan, C. S. Fox, D. M. Nathan, R. B. D'Agostino Sr., P. W. F. Wilson, and J. B. Meigs Associations of Adiponectin, Resistin, and Tumor Necrosis Factor-{alpha} with Insulin Resistance J. Clin. Endocrinol. Metab., August 1, 2008; 93(8): 3165 - 3172. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. J. Mather, T. Funahashi, Y. Matsuzawa, S. Edelstein, G. A. Bray, S. E. Kahn, J. Crandall, S. Marcovina, B. Goldstein, R. Goldberg, et al. Adiponectin, Change in Adiponectin, and Progression to Diabetes in the Diabetes Prevention Program Diabetes, April 1, 2008; 57(4): 980 - 986. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Zhang, Y.-H. Shi, C.-F. Hao, H. F Gu, Y. Li, Y.-R. Zhao, L.-C. Wang, and Z.-J. Chen Association of +45G15G(T/G) and +276(G/T) polymorphisms in the ADIPOQ gene with polycystic ovary syndrome among Han Chinese women Eur. J. Endocrinol., February 1, 2008; 158(2): 255 - 260. [Abstract] [Full Text] [PDF] |
||||
![]() |
A Klamer, K Skogstrand, D M Hougaard, B Norgaard-Petersen, A Juul, and G Greisen Adiponectin levels measured in dried blood spot samples from neonates born small and appropriate for gestational age Eur. J. Endocrinol., August 1, 2007; 157(2): 189 - 194. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. J. G. Hanley, D. Bowden, L. E. Wagenknecht, A. Balasubramanyam, C. Langfeld, M. F. Saad, J. I. Rotter, X. Guo, Y.-D. I. Chen, M. Bryer-Ash, et al. Associations of Adiponectin with Body Fat Distribution and Insulin Sensitivity in Nondiabetic Hispanics and African-Americans J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2665 - 2671. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Siahanidou, H. Mandyla, G.-P. Papassotiriou, I. Papassotiriou, and G. Chrousos Circulating levels of adiponectin in preterm infants Arch. Dis. Child. Fetal Neonatal Ed., July 1, 2007; 92(4): F286 - F290. [Abstract] [Full Text] [PDF] |
||||
![]() |
G.D. Cooper, L.C. Pickavance, J.P.H. Wilding, J.A. HarroLd, J.C.G. HaLford, and A.J. Goudie Effects of olanzapine in male rats: enhanced adiposity in the absence of hyperphagia, weight gain or metabolic abnormalities J Psychopharmacol, June 1, 2007; 21(4): 405 - 413. [Abstract] [PDF] |
||||
![]() |
O. Y. Bang, J. L. Saver, B. Ovbiagele, Y. J. Choi, S. R. Yoon, and K. H. Lee Adiponectin levels in patients with intracranial atherosclerosis Neurology, May 29, 2007; 68(22): 1931 - 1937. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. A. Hopkins, N. Ouchi, R. Shibata, and K. Walsh Adiponectin actions in the cardiovascular system Cardiovasc Res, April 1, 2007; 74(1): 11 - 18. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. B. Snijder, R. J. Heine, J. C. Seidell, L. M. Bouter, C. D.A. Stehouwer, G. Nijpels, T. Funahashi, Y. Matsuzawa, I. Shimomura, and J. M. Dekker Associations of adiponectin levels with incident impaired glucose metabolism and type 2 diabetes in older men and women: the hoorn study. Diabetes Care, November 1, 2006; 29(11): 2498 - 2503. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. G. Woo, L. M. Dolan, R. Deka, R. D. Kaushal, Y. Shen, P. Pal, S. R. Daniels, and L. J. Martin Interactions Between Noncontiguous Haplotypes in the Adiponectin Gene ACDC Are Associated With Plasma Adiponectin Diabetes, February 1, 2006; 55(2): 523 - 529. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. C. Bush, B. E. Darnell, R. A. Oster, M. I. Goran, and B. A. Gower Adiponectin Is Lower Among African Americans and Is Independently Related to Insulin Sensitivity in Children and Adolescents Diabetes, September 1, 2005; 54(9): 2772 - 2778. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. B Ruige, D. P Ballaux, T. Funahashi, I. L Mertens, Y. Matsuzawa, and L. F Van Gaal Resting metabolic rate is an important predictor of serum adiponectin concentrations: potential implications for obesity-related disorders Am. J. Clinical Nutrition, July 1, 2005; 82(1): 21 - 25. [Abstract] [Full Text] [PDF] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |