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Departments of Clinical Chemistry (C.G.S.) and Internal Medicine VU University Medical Center (M.T.S., C.D.A.S.) and Institute for Cardiovascular Research (C.G.S., M.T.S., C.D.A.S.), Vrije Universiteit, 1007 MB Amsterdam, The Netherlands; International Centre for Circulatory Health and National Heart and Lung Institute (N.C.), Imperial College London, London W2 IPG, United Kingdom; and Department of Epidemiology and Public-Health (J.H.F.), Royal Free and University College London Medical School, London WC1E 6BT, United Kingdom
Address all correspondence and requests for reprints to: Casper G. Schalkwijk, Department of Internal Medicine, University Hospital Maastricht, P Debyelaan 25, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail: C.Schalkwijk{at}intmed.unimaas.nl.
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Abstract |
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Design: Cross-sectional data on 543 type 1 diabetic patients from the EURODIAB Prospective Complications Study were analyzed. We determined adiponectin, TNF-
, IL-6, C-reactive protein, soluble vascular cell adhesion molecule (sVCAM-1), and sE-selectin by ELISA.
Results: We found that adiponectin was negatively correlated with body mass index, waist to hip ratio, insulin, and fasting triglyceride, and positively with high-density lipoprotein, low-density lipoprotein, and total cholesterol, TNF-, and sVCAM-1, but was not related to C-reactive protein, IL-6, and sE-selectin. Surprisingly, significantly raised concentrations of adiponectin were found with albuminuria, retinopathy, and cardiovascular diseases (for all, P < 0.0001). Adiponectin levels were inversely associated with glomerular filtration rate (GFR) (P < 0.0001). Multivariate regression models showed that the associations of adiponectin with albuminuria and GFR were independent of established risk factors. The association between adiponectin and albuminuria was attenuated by GFR, whereas the association of adiponectin with retinopathy and cardiovascular disease disappeared after adjustments for established risk factors. The association of adiponectin with sVCAM-1 was independent of established risk factors.
Conclusion: We conclude that in type 1 diabetic patients, adiponectin is associated with impaired renal function. Adiponectin may be enhanced in type 1 diabetic patients as a physiological counterregulatory response to mitigate endothelial damage and vascular damage.
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Introduction |
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In addition to important roles in the regulation of energy homeostasis and insulin sensitivity, adiponectin has recently been shown to modulate a wide array of biological functions in vitro with antiatherogenic and antiinflammatory properties (10). In humans, hypoadiponectinemia is associated with impaired vasoreactivity (11, 12, 13). The inverse relation of adiponectin with markers of inflammation (14, 15) also suggests that decreased production of adiponectin contributes to vascular complications. Moreover, hypoadiponectinemia has been shown to be a novel cardiovascular risk factor in patients with the metabolic syndrome and in patients with early stages of chronic kidney disease (10, 13, 16).
The pathogenesis of vascular complications in type 1 diabetes is poorly understood but may involve chronic, low-grade inflammation (17, 18, 19, 20, 21). Because of the antiinflammatory and vasculoprotective properties of adiponectin (18), we examined, in type 1 diabetic patients, the association of adiponectin with several cardiovascular risk factors and the relationship between plasma adiponectin levels with micro and macrovascular complications.
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Subjects and Methods |
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The EURODIAB Prospective Complications Study (PCS) (1997–1999) is a follow-up of the EURODIAB Type 1 Diabetes Complications Study (1989–1991). The study was set up to explore risk factors for diabetic complications in 3250 people with type 1 diabetes, selected by stratified (age, sex, and diabetes duration) random sampling, aged 15–60 yr, and attending 31 diabetes centers in 16 European countries. Type 1 diabetes was clinically defined as a diagnosis made before the age of 36 yr, with a continuous need for insulin therapy within 1 yr of diagnosis. Ethics committee approval was obtained at each center, and all subjects provided written informed consent. Seven years after baseline examinations, study participants were invited for reexamination. Of the 3250 patients, 1880 (57.8%) returned for examination. To examine adiponectin in relation to micro- and macrovascular complications, an unmatched nested case-control study was designed including 533 subjects with available serum aliquots at the follow-up examination. Cases were selected as those with at least one complication from retinopathy, nephropathy, and cardiovascular disease (CVD). There were 359 cases, of which 303 had any retinopathy (147 nonproliferative and 156 proliferative), 210 had albuminuria (82 microalbuminuria and 128 macroalbuminuria), and 132 had CVD. Control subjects (n = 174) included all of those who had no complications at the follow-up examination. No matching on any variables was performed because we wished to examine the impact of key risk factors, such as age and duration, on the relationship between adiponectin and complications; matching would preclude such analyses. Data on these 533 subjects, recruited from 24 centers in 13 European countries, were analyzed cross-sectionally.
Risk factors
Blood pressure (BP) was measured by a random zero sphygmomanometer (Hawskley, Lancing, UK) as the mean of two measurements. Hypertension was defined as a systolic BP equal to or more than 140 mm Hg or diastolic BP equal to or more than 90 mm Hg and/or the current use of BP-lowering drugs. Body mass index (BMI) (kilograms per meter squared) and waist to hip ratio (WHR) were determined.
Blood samples were taken, fasting if possible, for measurement of lipids and glycemic control. At a central laboratory, cholesterol and triglyceride (TG) levels were measured by enzymatic colorimetric tests, and high-density lipoprotein (HDL) cholesterol was measured directly. Non-HDL cholesterol was calculated as HDL cholesterol subtracted from total cholesterol. Low-density lipoprotein (LDL) cholesterol was calculated from Friedewald’s formula.
Glycated hemoglobin (HbA1c) was measured by a latex-enhanced turbidimetric immunoassay (Roche Products Ltd., Welwyn Garden City, UK). The reference range for this assay was 4.2–6.2%.
The concentration of adiponectin was measured in serum in duplicate by ELISA (B-Bridge, San Jose, CA). In this study, the intra- and interassay coefficients of variation for adiponectin were 2.7 and 7.2%, respectively. Based on published data from four studies using the same ELISA (4, 22, 23, 24), we calculated a reference range in healthy controls of 3.9–10.2 µg/ml. For comparability with other studies, we also measured adiponectin in a subset of 40 serum samples with a RIA (Linco Research, Inc., St. Charles, MO). Data obtained with these assays were highly correlated (regression coefficient = 0.96), although we found slightly higher levels of adiponectin with the ELISA as compared with the RIA (B-Bridge = 1.24 x Linco + 0.75).
Soluble vascular cell adhesion molecule (sVCAM-1) and sE-selectin were measured by ELISA (R&D Systems, Oxon, UK). The intra- and interassay coefficients of variation for sVCAM-1 were 4.0 and 9.1%, respectively, and for sE-selectin, 2.1 and 3.1%, respectively. Plasma levels of C-reactive protein (CRP) were measured with a highly sensitive in-house ELISA with intra- and interassay coefficients of variation of 3.9 and 8.7%. Plasma levels of IL-6 and TNF- were measured by use of commercially available ELISA kits (R&D Systems), with intra- and interassay coefficients of variation of 4.5 and 9.0% and 7.3 and 8.5%, respectively, as determined in our laboratory.
Complications
All complications were measured to a standardized protocol. Retinopathy was assessed from retinal photographs (two fields per eye) according to the EURODIAB protocol. Grading was performed by the retinopathy grading center at the Hammersmith Hospital of Imperial College London (UK). Retinopathy was classified as no (level 0), nonproliferative (level 1–3), and proliferative (levels 4 and 5) retinopathy. Two 24-h urine collections were performed to measure albumin excretion rate (AER). Aliquots were frozen and sent to London for analysis of urinary albumin, using an immunoturbidimetric method using goat antihuman albumin antisera (SANOFI Research Center, Montpellier, France) and human serum albumin standards (ORHA 20/21 grade human serum albumin; Behring Diagnostics, Somerville, NJ). AER was categorized as normoalbuminuria (<20 µg/min), microalbuminuria (between 20 and 200 µg/min), and macroalbuminuria (
200 µg/min). We estimated glomerular filtration rate (GFR) by the Cockcroft-Gault formula. Plasma creatinine was assayed by the Jaffé reaction (Roche Diagnostics, Indianapolis, IN).
CVD was defined as physician-diagnosed myocardial infarction, angina, coronary artery bypass graft, or stroke and/or ischemic changes on centrally Minnesota-coded electrocardiograms.
Statistical analysis
All analyses were performed with SPSS 9.0 for Windows 95 (SPSS, Inc., Chicago, IL). Variables with a skewed distribution were ln-transformed in all analyses. We used linear regression analyses to investigate the association of adiponectin with vascular risk factors.
The patient population was divided into groups with normo-, micro-, and macroalbuminuria; no, nonproliferative, and proliferative retinopathy; and with vs. without CVD (in the latter group, we excluded those in whom CVD was absent but micro- or macroalbuminuria or retinopathy was present (227 of 348). We used ANOVA to estimate mean values of adiponectin according to the presence or absence and severity of vascular complications. We then adjusted these analyses for age, sex, HbA1c, duration of diabetes, and systolic BP (model 1). We used linear regression analyses to investigate the association of adiponectin with GFR.
P < 0.05 was considered statistically significant.
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Results |
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shows the baseline characteristics of the study population. The plasma adiponectin levels were higher in women than in men (21.0 ± 9.7 and 16.8 ± 9.6 µg/ml, respectively, P < 0.0001). In women, the use of oral contraceptives was not associated with plasma adiponectin levels [users (n = 152), 21.7 ± 10.5 µg/ml and nonusers (n = 110), 19.9 ± 8.6 µg/ml; P = 0.11].
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gives the correlations between adiponectin and vascular risk factors. There were inverse correlations between adiponectin and BMI, insulin, WHR, fasting TG and GFR, and positive correlations between adiponectin and HDL, LDL, and total cholesterol. Plasma adiponectin was positively related to TNF- and sVCAM-1 but was not related to CRP, IL-6, and sE-selectin.
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shows the univariate and multivariate relationships between adiponectin and albuminuria, retinopathy, CVD, and GFR. Raised concentrations of adiponectin were found with increasing albuminuria, retinopathy, and CVD in crude models (Fig. 1). Analyses in men and women separately showed similar relationships. After adjustment for age, sex, duration of diabetes, systolic BP, and HbA1c (model 1), adiponectin remained significantly associated with albuminuria and GFR, whereas the association of adiponectin with retinopathy and CVD disappeared, mainly affected by adjustment for duration of diabetes. The association between adiponectin and albuminuria was not markedly changed by further adjustment for BMI, insulin, TNF-, sVCAM-1, TGs, HDL and LDL cholesterol, and total cholesterol (data not shown) but was attenuated by GFR (P = 0.20).
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shows that adiponectin was associated with GFR in crude analyses and after adjustment (model 1, Fig. 2). Additional adjustment for BMI, AER, or insulin did not materially change these results.
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were significantly associated with adiponectin in crude [standardized ß (stß), 0.344, P < 0.0001; and stß, 0.199, P < 0.0001] and adjusted (model 1, stß, 0.217, P < 0.0001; and stß, 0.149, P = 0.001) analyses. Additional adjustment for GFR did not change the association between sVCAM-1 and adiponectin (stß, 0.217; P < 0.0001), whereas the association between adiponectin and TNF- disappeared after adjustment for GFR (stß, –0.01; P = 0.813). Additional adjustment for the use of ACE-inhibitors did not materially change the results, although ACE inhibitor use (n = 137) was associated with higher adiponectin levels (21.9 vs. 17.8 µg/ml, P < 0.001).
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Discussion |
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In type 1 diabetic patients with no complications, we demonstrated increased levels of adiponectin (16.7 ± 7.4 µg/ml) as compared with a calculated reference range of 3.9–10.2 µg/ml in healthy controls (4, 22, 23, 24), indicating that the high levels of adiponectin are part of the diabetes state and not simply a function of complication status. The plasma/serum levels of adiponectin in type 1 diabetic patients are in accordance with smaller cross-sectional studies (5, 6, 7, 8), whereas adiponectin levels were shown to be reduced in patients with obesity (1), as well as diseases associated with obesity (2, 3). Thus, there seems to be a clear inverse relationship between adiponectin and fat mass in humans. In accordance, adiponectin levels were also inversely correlated with BMI and WHR in type 1 diabetic patients.
The mechanism of the increase in plasma adiponectin levels in type 1 diabetic patients is not clear. Elevations in adiponectin levels could arise from alterations in synthesis, secretion, or clearance. The factors responsible for the regulation of the synthesis of adiponectin are still unclear. Although TNF- and IL-6 are strong inhibitors of adiponectin promotor activity (25, 26), we found a positive correlation between plasma levels of TNF- and adiponectin and no correlation between IL-6 and adiponectin. However, because most of the cytokines act at tissue levels at an autocrine or paracrine way, and circulating levels of cytokines may poorly reflect interstitial levels of these cytokines in the adipose tissue, we cannot exclude a role of cytokines in adiponectin production.
We show that adiponectin concentrations are higher among women than men. Such gender-dependent differences have been reported previously (1, 27, 28). The role of peripheral fat mass as a constitutive contributor to circulating adiponectin (29) may explain why women have a higher adiponectin concentration compared with men even when matched for BMI.
In a model that includes age, gender, HbA1c, duration of diabetes, systolic BP, insulin, BMI, TNF-, and sVCAM-1, adiponectin was independently associated with GFR and albuminuria. Furthermore, the relationship between plasma adiponectin and renal function was confirmed in a multiple regression analysis that showed that GFR was the only independent predictor of plasma adiponectin concentration in a group of patients with essential hypertension (30). An impaired renal function was also associated with higher serum adiponectin concentrations in type 2 diabetic patients (13, 31), in type 1 diabetic patients with or without end-stage renal disease (8, 9, 32), and in nondiabetic patients with different degrees of renal dysfunction (16, 33). It is well known that the kidneys are important organs of biodegradation of several protein hormones; therefore, it is highly probable that impaired kidney function may be responsible for adiponectin accumulation in the circulation. Alternatively, it could be that the renal insufficiency per se further stimulates adiponectin production. Indeed, a recent study revealed that successful kidney transplantation is accompanied by a significant reduction of plasma adiponectin concentration, demonstrating that adiponectin biodegradation, elimination, or increased synthesis by the failing kidney contributes to elevation of plasma concentration (34). However, no relation has been found between adiponectin and GFR after kidney transplantation; thus, it seems likely that extrarenal factors may have an important role in adiponectin synthesis or release from adipocytes as well (see above).
We confirmed that the use of ACE inhibitors increases adiponectin concentrations (35), but adjustment for the use of these inhibitors did not change the associations as found in our study.
In addition to its metabolic actions, adiponectin has been shown to modulate a wide array of biological functions including functions with antiatherogenic and antiinflammatory properties (10). For example, adiponectin treatment reduces TNF--mediated expression of the adhesion molecules VCAM-1, intercellular adhesion molecule-1, and E-selectin in endothelial cells (36), and stimulates production of nitric oxide (37, 38) and decreases TNF- production in macrophages (39). In accordance, adiponectin knockout mice have a significant increase in vascular neointimal formation (40). Thus, in vitro experiments, animal models, and studies in humans strongly indicate that hypoadiponectinemia is linked to inflammation, atherosclerosis, endothelial damage, and/or vascular diseases (4, 10, 11, 12, 23, 40, 41, 42, 43). In contrast to the antiatherogenic and antiinflammatory properties, we found, unexpectedly, that in type 1 diabetic patients, adiponectin is positively related to a marker of endothelial function, i.e. sVCAM-1.
The soluble adhesion molecule VCAM-1 is a risk indicator for generalized vascular dysfunction. Although adiponectin has recently been shown to inhibit the expression of adhesion molecules including VCAM-1 (36), we, however, found a positive relationship between adiponectin and sVCAM-1, which was independent of conventional risk factors and GFR. The positive relationship is not in agreement with the hypothesis that adiponectin may have a protective role for the cardiovascular system. It also argues against the possibility that increased levels of adiponectin may serve to mitigate endothelial damage. Although we do not have a valid explanation for the positive relationship between adiponectin and sVCAM-1, the fact that adiponectin was unrelated to CRP indicates that inflammatory processes do not play an important role in this relationship. Consistent with our result, in patients with renal failure, adiponectin was positively related to CD146, a novel marker of endothelial cell activation (44).
As with any protein, an important aspect of adiponectin is its activity. Adiponectin activity can be regulated by different processes including oligomerization (45, 46), with the high-molecular weight adiponectin complex as the most active form (47). However, the molecular events that regulate the absolute amount, the distribution of the adiponectin oligomeric complexes, and the biological activities in vivo are poorly understood (48). Therefore, not only the total amount of adiponectin but also the oligomerization state of adiponectin may be of interest to definitely draw conclusions about the physiological significance of adiponectin. One important factor involved in the interconversion of the different isoforms might be insulin (47). Because we did not find an association of insulin with outcomes (Table 1
) nor an effect of insulin on the relationship of adiponectin with outcomes (Tables 3 and 4), we do not anticipate that any effect of insulin in the conversion of different biological active isoforms of adiponectin would be important in the relationship of adiponectin with outcomes. Although speculative, this is in agreement with a recent study in vivo in the rabbit in which isoforms of adiponectin did not respond to injected insulin (49). The different isoforms were stable in vivo and did not interconvert.
A limitation of the present study is the cross-sectional character of the examination, which restricts the ability to establish whether the association of adiponectin with renal function is causal. It might be that an increased level of adiponectin is directly involved in impairment of kidney function. Follow-up data would be invaluable in testing whether our findings are due to causal relationships.
In conclusion, increased adiponectin levels were observed in type 1 diabetic patients and were positively associated with albuminuria and renal impairment. This study documented for the first time a positive association of adiponectin with a generalized marker of endothelial function, sVCAM-1. Elucidating the mechanism of the elevation of adiponectin in type 1 diabetic patients and why hyperadiponectinemia is linked to endothelial damage as measured by increased levels of sVCAM-1 in these patients are of major interest for further insight into the pathogenesis of vascular complications in type 1 diabetic patients.
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Acknowledgments |
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Members of the EURODIAB PCS Group are: B. Karamanos, A. Kofinis, and K. Petrou (Hippokration Hospital, Athens, Greece); F. Giorgino, G. Picca, A. Angarano, G. De Pergola, L. Laviola, and R. Giorgino (Internal Medicine, Endocrinology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy); C. Ionescu-Tirgoviste, A. Coszma, and C. Guja (Clinic of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania); M. Songini, A. Casu, M. Pedron, S. Pintus, and M. Fossarello (Diabetes Unit Ospedale San Michele, Cagliari, Italy); J. B. Ferriss, G. Grealy, and D. O. Keefe (Cork University Hospital, Cork, UK); M. Toeller and C. Arden (Diabetes Research Institute, Heinrich-Heine University, Dusseldorf, Germany); R. Rottiers, C. Tuyttens, and H. Priem (University Hospital of Gent, Gent, Belgium); P. Ebeling, M. Kylliäinen, and V. A. Koivisto (University Hospital of Helsinki, Helsinki, Finland); B. Idzior-Walus, J. Sieradzki, K. Cyganek, and B. Solnica (Department of Metabolic Diseases, Jagiellonian University, Krakow, Poland); H. H. P. J. Lemkes and J. C. Lemkes-Stuffken (Leiden University Medical Centre, The Netherlands); J. Nunes-Correa, M. C. Rogado, L. Gardete-Correia, M. C. Cardoso, A. Silva, J. Boavida, and M. Machado Sa Marques (Portuguese Diabetic Association, Lisbon, Portugal); G. Michel, R. Wirion, and S. Cardillo (Centre Hospitalier, Luxembourg); G. Pozza, R. Mangili, and V. Asnaghi (Ospedale San Raffaele, Milan, Italy); E. Standl, B. Schaffler, H. Brand, and A. Harms (City Hospital Schwabing, Munich, Germany); D. Ben Soussan, O. Verier-Mine, P. Fallas, and M. C. Fallas (Centre Hospitalier de Valenciennes, France); J. H. Fuller, J. Holloway, L. Asbury, and D. J. Betteridge (University College London, London, UK); G. Cathelineau, A. Bouallouche, and B. Villatte Cathelineau (Hospital Saint-Louis, Paris, France); F. Santeusanio, G. Rosi, V. D’Alessandro, C. Cagini, P. Bottini, and G. P. Reboldi (Diaprtimento di Medicina Interna, Perugia, Italy); R. Navalesi, G. Penno, S. Bandinelli, R. Miccoli, and M. Nannipieri (Dipartimento di Endocrinologia e Metabolismo, Pisa, Italy); G. Ghirlanda, C. Saponara, P. Cotroneo, A. Manto, and A. Minnella (Universita Cattolica del Sacro Cuore, Rome, Italy); J. D. Ward, S. Tesfaye, S. Eaton, and C. Mody (Royal Hallamshire Hospital, Sheffield, UK); M. Borra, P. Cavallo Perin, S. Giunti, G. Grassi, G. F. Pagano, M. Porta, R. Sivieri, F. Vitelli, and M. Veglio (Dipartimento di Medicina Interna, Università di Torino and ASO CTO/CRF/Maria Adelaide, Turin, Italy); N. Papazoglou and G. Manes (General Hospital Papageorgiou of Thessaloniki, Greece); M. Muggeo and M. Iagulli (Vittorio Cacciatori, V Cattedra di Malattie del Metabolismo, Verona, Italy); K. Irsigler and H. Abrahamian (Hospital Vienna Lainz, Austria); S. Walford, J. Sinclair, S. Hughes, V. McLelland, and J. Ward (New Cross Hospital, Wolverhampton, UK); and G. Roglic, Z. Metelko, and Z. R. Pepeonik (Vuk Vrhovac Institute for Diabetes, Zagreb, Croatia). Steering committee members were: J. H. Fuller (London, UK); B. Karamanos, Chairman (Athens, Greece); A.-K. Sjolie (Aarhus, The Netherlands); N. Chaturvedi (London, UK); M. Toeller (Dusseldorf, Germany); G. Pozza, Cochairman (Milan, Italy); B. Ferriss (Cork, UK); M. Porta (Turin, Italy); R. Rottiers (Gent, Belgium); and G. Michel (Luxembourg). Coordinating center members were: J. H. Fuller, N. Chaturvedi, J. Holloway, D. Webb, and L. Asbury (University College London, London, UK). Central laboratories members were: G.-C. Viberti, R. Swaminathan, P. Lumb, A. Collins, and S. Sankaralingham (Guy’s and St. Thomas Hospital, London, UK). Retinopathy Grading Centre members were S. Aldington, T. Mortemore, and H. Lipinski (Royal Postgraduate Medical School of Imperial College London, London, UK).
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Footnotes |
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Present address for C.G.S. and C.D.A.S.: Department of Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
First Published Online October 11, 2005
1 See Acknowledgments for names of members of the EURODIAB Prospective Complications Study Group. 
Abbreviations: AER, Albumin excretion rate; BMI, body mass index; BP, blood pressure; CRP, C-reactive protein; CVD, cardiovascular disease; GFR, glomerular filtration rate; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PCS, Prospective Complications Study; stß, standardized ß; sVCAM, soluble VCAM; TG, triglyceride; VCAM, vascular cell adhesion molecule; WHR, waist to hip ratio.
Received May 18, 2005.
Accepted October 4, 2005.
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