| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Unit of Diabetes, Endocrinology and Nutrition, Department of Internal Medicine, University Hospital of Girona "Dr. Josep Trueta," 17007 Girona, Spain
Address all correspondence and requests for reprints to: J. M. Fernández-Real, M.D., Ph.D., Unit of Diabetes, Endocrinology and Nutrition, Hospital de Girona "Dr. Josep Trueta," Ctra. França s/n, 17007 Girona, Spain. E-mail: uden.jmfernandezreal{at}htrueta.scs.es.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Insulin sensitivity (minimal model analysis) and plasma soluble fractions of TNF-
receptor 1 (sTNFR1) and 2 (sTNFR2), adrenal and thyroid function, and adiponectin were evaluated in 68 apparently healthy subjects. An additional group of type 2 diabetic patients (n = 19) similarly studied, except for insulin sensitivity, were also included in the analysis.
As reported by others, serum adiponectin concentrations were higher in women than in men (13.55 ± 9.79 vs. 8.64 ± 7.83 mg/liter; P = 0.018). They were also higher in healthy subjects compared with diabetic patients (10.35 ± 8.48 vs. 7.41 ± 8.31 mg/liter; P = 0.021). As expected also, circulating adiponectin was significantly associated with waist to hip ratio (r = -0.28; P = 0.013), diastolic blood pressure (r = -0.25; P = 0.027), fasting plasma high-density lipoprotein cholesterol (r = 0.35; P = 0.001), triglycerides (r = -0.37; P = 0.001), and insulin sensitivity (r = 0.30; P = 0.011). Additionally, subjects in the higher quartile of circulating adiponectin had lower sTNFR2 concentrations (3.05 vs. 4.37 µg/liter; P = 0.012), a trend to lower sTNFR1 concentrations (1.76 vs. 2.20 µg/liter; P = 0.055), higher concentration of serum morning cortisol (16.86 vs. 13.52 µg/dl; P = 0.027), and higher serum free T4 levels (1.31 vs. 1.20 ng/dl; P = 0.038). Multiple regression analysis models were constructed to predict adiponectin concentrations. Predictive variables in these models included insulin sensitivity, waist to hip ratio and free T4, contributing to 17%, 10%, and 8% of adiponectin variance, respectively, These findings suggest that circulating adiponectin differentially modulates insulin action and that thyroid-axis, inflammatory cytokines, and the adrenal cortex might intervene in this modulation.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
(3, 4, 5, 6, 7, 8). It is noteworthy that these abnormalities appear to be independent of the development of obesity, because adiponectin null mice show diet-induced insulin resistance despite similar increases in body weight as control mice (8, 9). In humans, adiponectin has been demonstrated to circulate in inverse proportion to the degree of insulin resistance (10, 11, 12). The mechanisms underlying the observed close association between plasma adiponectin concentration and insulin resistance are being elucidated (13, 14). Although insulin up-regulates the expression of the adiponectin gene, known as ApM1, in rodents (2, 15), a direct effect of insulin on ApM1 expression in humans is unlikely, because plasma adiponectin does not change postprandially (16). However, a 21% reduction in mean body mass index (BMI) was accompanied by a 46% increase in circulating adiponectin in a recent study, suggesting a long-term regulation of adiponectin levels by changes in insulin sensitivity (16).
One potential mechanism could be the modulation of the inflammatory cascade. Adiponectin has been postulated to have antiinflammatory effects, especially in endothelial cells and in macrophages (7, 17). Adiponectin reduced TNF- induced monocyte attachment to cultured human aortic endothelial cells (6). The cross-talk between adiponectin and TNF- is also demonstrated by the suppressive effect of TNF- on adiponectin gene expression in vitro (18) and by the suppressive effect of adiponectin on phagocytic activity and lipopolysaccharide-induced TNF- production in cultured macrophages (17). Adiponectin has also shown to inhibit TNF- induction of nuclear factor 
B through activation of the cAMP-protein kinase A pathway (7). Most recent observations appear to corroborate these findings, because the adiponectin knockout mouse exhibits increased levels of TNF- in adipose tissue and plasma (8). However, no human studies have related adiponectin concentrations to either TNF- levels or action.
On the other hand, adiponectin has been shown to modulate a wide array of biological functions. The promoter region of Apm1 contains consensus sequences for glucocorticosteroid receptor binding and therefore could be subject to environmental modifications in relation to stress (19). The carboxy terminal globular structure of adiponectin also suggests use of gC1q receptor, a molecule with broad tissue distribution that includes liver, smooth muscle, endothelium, immune cells, thyroid, and adrenals, organs and tissues likely to be involved in the biology of complex disorders such as insulin resistance (20). It has long been recognized that mutual influences exist between the hypothalamo-pituitary-adrenal axis and insulin resistance (21). Regarding the thyroid, evidence exists to support also an interaction between circulating thyroid hormones and insulin resistance (22).
We aimed to explore the interaction between circulating proinflammatory parameters and the thyroid and adrenal cortex axis on the adiponectin/insulin sensitivity relationship.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
All subjects were of Caucasian origin and reported that their body weight had been stable for at least 3 months before the study. None of the healthy subjects (n = 68) was taking any medication or had any evidence of metabolic disease other than obesity. Inclusion criteria for this group were: 1) BMI (weight in kilograms divided by the square of height in meters) below 40 kg/m2; 2) absence of any systemic disease; 3) absence of any infections in the previous month. A group of type 2 diabetic patients (n = 19), diagnosed according to the American Diabetes Association criteria, were also recruited for the study and were pooled with the group of healthy subjects for the analysis (unless otherwise specified, the data presented in this manuscript refers to the whole group of subjects). Diabetic patients were included if their metabolic control had been stable in the preceding 6 months, as defined by stable hemoglobin A1c values, and if they also complied with the above-mentioned inclusion criteria for healthy subjects.
Informed written consent was obtained after the purpose, nature, and potential risks of the study were explained to the subjects. The experimental protocol was approved by the Ethics Committee of the Hospital of Girona (Girona, Spain). Alcohol, caffeine, and all medications, including sulfonylurea, metformin, and insulin, were withheld within 12 h of performing the various tests.
Measurements
Each subject was studied in the examination room in the postabsorptive state. BMI was calculated as weight (in kilograms) divided by height (in meters) squared. Each subject’s waist was measured with a soft tape midway between the lowest rib and the iliac crest. The hip circumference was measured at the widest part of the gluteal region. The waist to hip ratio (WHR) was then calculated. Blood pressure was measured in the supine position on the right arm after a 10-min rest; a standard sphygmomanometer of appropriate cuff size was used, and the first and fifth phases were recorded. Values used in the analysis are the average of three readings taken at 5-min intervals.
Insulin sensitivity was measured in healthy subjects using the frequently sampled iv glucose tolerance test on a different day. In brief, the experimental protocol started between 0800 and 0830 h after an overnight fast. A butterfly needle was inserted into an antecubital vein, and patency was maintained with a slow saline drip. Basal blood samples were drawn at -20, -10, and -5 min, after which glucose (300 mg/kg body weight) was injected over 1 min, starting at time 0, and insulin (Actrapid, Novo Nordisk A/S, Bagsvaerd, Denmark; 0.03 U/kg) was administered at time 20 min. Additional samples were obtained from a contralateral antecubital vein up to 180 min, as previously described (23).
Analytical methods
Serum glucose concentrations were measured in duplicate by the glucose oxidase method using a Beckman Glucose Analyzer II (Beckman Instruments, Brea, CA). The coefficient of variation was 1.9%. Total serum cholesterol was measured through the reaction of cholesterol esterase/cholesterol oxidase/peroxidase. High-density lipoprotein (HDL)-cholesterol was quantified after precipitation with polyethylene glycol at room temperature. Total serum triglycerides were measured through the reaction of glycerol-phosphate-oxidase and peroxidase. Serum cortisol was determined by microparticle enzyme immunoassay (IMX System, Abbott Laboratories, North Chicago, IL) with intra- and interassay coefficients of variation less than 8%. Free T4 was measured by electrochemiluminescence (ECLIA; Roche Diagnostics, Basel, Switzerland) with intra- and interassay coefficients of variation less than 7%.
Serum insulin levels during the frequently sampled iv glucose tolerance test were measured in duplicate by monoclonal immunoradiometric assay (IRMA; Medgenix Diagnostics, Fleunes, Belgium). Intra- and interassay coefficients of variation were similar to those previously reported.
Serum soluble TNF receptor 1 (sTNFR1) and receptor 2 (sTNFR2) levels were analyzed as surrogate markers of TNF- actions using a commercially available solid-phase Enzyme Amplified Sensitivity Immunoassay (EASIA) sTNFR1 (Medgenix) and sTNF-R2 EASIAM (Biosource Technologies, Inc. Europe S.A., Fleunes, Belgium). The intra- and interassay coefficients of variation were less than 7% and less than 9%. sTNFR1 EASIA does not cross-react with sTNFR2. TNF- does not interfere with the assay.
Plasma adiponectin concentrations were measured by RIA (Linco Research, Inc., St. Charles, MO). Samples were diluted 500 times before the assay. Sensitivity of the method is 2 mg/liter. The intra- and interassay coefficients of variation were less than 5%.
Statistical methods
Descriptive results of continuous variables are expressed as mean ± SD. Before statistical analysis, normal distribution and homogeneity of the variances were tested. Parameters that did not fulfil these tests (insulin sensitivity, serum triglycerides, sTNFR1, sTNFR2) were log-transformed. The relations between variables were analyzed by unpaired t test, simple correlation (Pearson’s and Spearman’s tests), and multiple regression in a stepwise manner. Levels of statistical significance were set at P value less than 0.05.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
and 2, respectively.
|
|
: Ref. 11). Serum concentrations of this adipokine, however, did not change with increasing age (whole group, r = -0.11; P = 0.31). In healthy subjects, adiponectin was also found to be significantly associated with insulin sensitivity, as determined by minimal model analysis (r = 0.30; P = 0.011). Additionally, adiponectin correlated with known components of the insulin resistance syndrome, namely WHR (r = -0.28; P = 0.013), diastolic blood pressure (r = -0.25; P = 0.027), HDL cholesterol (r = 0.35; P = 0.001), and fasting plasma triglycerides (r = -0.37; P = 0.001).
Because adiponectin has shown to exhibit antiinflammatory properties and because we and others have shown that insulin resistance is a low-grade chronic inflammatory condition (25), we wished to investigate the relationship between plasma adiponectin and proinflammatory parameters, such as circulating sTNFR1 and sTNFR2 [in humans, sTNFR1 and sTNFR2 are surrogates of previous TNF- action and have been shown to be stable and reproducible in the same individual (Ref. 26)]. Although adiponectin did not correlate with either sTNFR1 or sTNFR2 (P = 0.51 and P = 0.93, respectively), subjects in the highest quartile of circulating adiponectin had lower sTNFR2 concentrations (3.05 vs. 4.37 µg/liter; P = 0.012) and a trend to lower sTNFR1 concentrations (1.76 vs. 2.20 µg/liter; P = 0.055; Table 3 and Fig. 1). These results were reproducible when the analysis was restricted to the group of healthy subjects.
|
|
and Figs. 2 and 3]. Similar results were observed when the analysis was restricted to the group of healthy subjects.
|
|
). In the first model, insulin sensitivity and free T4 explained 17% and 8% of adiponectin variance, respectively. Nonpredictive variables in this model included sex, diastolic blood pressure, sTNFR2, and cortisol. Additional models studied the independent effect of either BMI or WHR on adiponectin levels. In these models, free T4 and WHR were significant predictors of adiponectin concentrations (6% and 10%, respectively). Excluded variables were sex, diastolic blood pressure, sTNFR2, and cortisol, in addition to BMI. The results were reproducible when the analysis was restricted to the group of healthy subjects.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
We further found lower concentrations of sTNFR2 in the highest quartile of circulating adiponectin. To our knowledge, this is the first description of an association between adiponectin and sTNFR2 levels in humans. Importantly, the recently described adiponectin null mice have been shown to have increased levels of TNF- in adipose tissue and plasma, pointing at an important interaction of adiponectin with the TNF- axis (8).
The findings above lend further support to the antiinflammatory actions of adiponectin. This hypothesis is sustained by the direct association between fasting cortisol and adiponectin, indicative of a possible feedback with the main antiinflammatory hormone. Serum cortisol has been postulated to contribute to the development of insulin resistance (28), because it increases with the severity of obesity (29). However, inverse associations between total cortisol and both BMI and insulin levels have been reported (23, 30), which fits well with cortisol as an antiinflammatory molecule. In fact, the promoter region of Apm1 contains consensus sequences for glucocorticosteroid receptor binding and thus could be subject to environmental modification in relation to stress (19). Either lower fasting cortisol or loss of rhythmicity in cortisol production, as observed in complicated obesity (23), is speculated to lead to decreased adiponectin secretion and insulin resistance.
We also observed an association between circulating adiponectin concentration and free T4, which persisted after adjustment for additional covariates. This association could be indirect through the modulation of insulin sensitivity. Indeed, increased insulin secretion is expected with increasing insulin resistance, and thyroid hormones are known to increase the expression of a number of genes involved in insulin production (31, 32). Conversely, the carboxy terminal globular structure of adiponectin, through its use of gC1q receptor found in the mitochondria of the thyroid, could be a regulator of thyroid hormone production (2, 20). Additional evidence for a role of thyroid hormones in the regulation of adiponectin expression comes from a recent study showing increased adiponectin levels in mice exposed to cold (33). In this study, it was postulated that adiponectin could regulate body temperature and basal metabolic rate in response to changing environmental conditions. In fact, adiponectin is known to have structural similarities with hibernation-associated plasma proteins HP-27, HP-25, and HP-20 in chipmunks (34). It was then concluded that adiponectin might have a role in adaptive thermogenesis. The implied relationship between thyroid hormones and adiponectin may be either direct, through the stimulation of the synthesis of either hormone, or indirect, through the improvement in insulin sensitivity during cold exposure (35).
Except for morning cortisol, the above-mentioned associations between inflammatory and hormonal parameters and adiponectin levels do not suggest a dose effect (Table 3; P > 0.05 for trend test for sTNFR1, sTNFR2, and free T4; P = 0.055 for trend test for cortisol). Rather, the findings above are indicative of a threshold effect.
In summary, here we describe interactions among adiponectin, the inflammatory cascade, and the thyroid and hypothalamo-pituitary adrenal axis that might prove useful in the study of adiponectin interactions with insulin action.
|
Footnotes |
|---|
Abbreviations: BMI, Body mass index; HDL, high-density lipoprotein; sTNFR, soluble TNF receptor; WHR, waist to hip ratio.
Received October 10, 2002.
Accepted March 7, 2003.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
B signaling through a cAMP-dependent pathway. Circulation 102:1296–1301
ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50:2094–2099 Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels. Diabetes 46:1468–1472[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  D. Modan-Moses, D. Stein, C. Pariente, A. Yaroslavsky, A. Ram, M. Faigin, R. Loewenthal, E. Yissachar, R. Hemi, and H. Kanety Modulation of Adiponectin and Leptin during Refeeding of Female Anorexia Nervosa Patients J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1843 - 1847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kantartzis, K. Rittig, B. Balletshofer, J. Machann, F. Schick, K. Porubska, A. Fritsche, H.-U. Haring, and N. Stefan The Relationships of Plasma Adiponectin with a Favorable Lipid Profile, Decreased Inflammation, and Less Ectopic Fat Accumulation Depend on Adiposity Clin. Chem., October 1, 2006; 52(10): 1934 - 1942. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Herder, H. Hauner, B. Haastert, K. Rohrig, W. Koenig, H. Kolb, S. Muller-Scholze, B. Thorand, R. Holle, and W. Rathmann Hypoadiponectinemia and Proinflammatory State: Two Sides of the Same Coin?: Results From the Cooperative Health Research in the Region of Augsburg Survey 4 (KORA S4) Diabetes Care, July 1, 2006; 29(7): 1626 - 1631. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Fernandez-Real, M. Straczkowski, B. Lainez, M. R Chacon, I. Kowalska, A. Lopez-Bermejo, A. Garcia-Espana, A. Nikolajuk, I. Kinalska, and W. Ricart An alternative spliced variant of circulating soluble tumor necrosis factor-{alpha} receptor-2 is paradoxically associated with insulin action. Eur. J. Endocrinol., May 1, 2006; 154(5): 723 - 730. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kowalska, M. Straczkowski, A. Nikolajuk, A. Krukowska, I. Kinalska, and M. Gorska Plasma adiponectin concentration and tumor necrosis factor-{alpha} system activity in lean non-diabetic offspring of type 2 diabetic subjects Eur. J. Endocrinol., February 1, 2006; 154(2): 319 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Malyszko, J. Malyszko, S. Wolczynski, and M. Mysliwiec Adiponectin, leptin and thyroid hormones in patients with chronic renal failure and on renal replacement therapy: are they related? Nephrol. Dial. Transplant., January 1, 2006; 21(1): 145 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Mantzoros, T. Li, J. E. Manson, J. B. Meigs, and F. B. Hu Circulating Adiponectin Levels Are Associated with Better Glycemic Control, More Favorable Lipid Profile, and Reduced Inflammation in Women with Type 2 Diabetes J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4542 - 4548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A M Diehl, Z P Li, H Z Lin, and S Q Yang Cytokines and the pathogenesis of non-alcoholic steatohepatitis Gut, February 1, 2005; 54(2): 303 - 306. [Full Text] [PDF]
|
|
|
|
|
|
A. Megia, L. Gallart, J.-M. Fernandez-Real, J. Vendrell, I. Simon, C. Gutierrez, and C. Richart Mannose-Binding Lectin Gene Polymorphisms Are Associated with Gestational Diabetes Mellitus J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5081 - 5087. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Meier and A. M. Gressner Endocrine Regulation of Energy Metabolism: Review of Pathobiochemical and Clinical Chemical Aspects of Leptin, Ghrelin, Adiponectin, and Resistin Clin. Chem., September 1, 2004; 50(9): 1511 - 1525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bottner, J. Kratzsch, G. Muller, T. M. Kapellen, S. Bluher, E. Keller, M. Bluher, and W. Kiess Gender Differences of Adiponectin Levels Develop during the Progression of Puberty and Are Related to Serum Androgen Levels J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4053 - 4061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Schulze, E. B. Rimm, I. Shai, N. Rifai, and F. B. Hu Relationship Between Adiponectin and Glycemic Control, Blood Lipids, and Inflammatory Markers in Men With Type 2 Diabetes Diabetes Care, July 1, 2004; 27(7): 1680 - 1687. [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 |
