Pathophysiology/Complications O R I G I N A L
A R T I C L E
Serum Adiponectin Is Increased in Type 1 Diabetic Patients With Nephropathy MARKKU SARAHEIMO, MD1,2 CAROL FORSBLOM, MD, DMSC1,2 JOHAN FAGERUDD, MD, DMSC12 ANNA-MAIJA TEPPO, PHD1 KIM PETTERSSON-FERNHOLM, MD, DMSC1,2
JAN FRYSTYK, MD, DMSC, PHD3 ALLAN FLYVBJERG, MD, DMSC3 PER-HENRIK GROOP, MD, DMSC1,2 ON BEHALF OF THE FINNDIANE STUDY GROUP
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found in obesity (8,9), type 2 diabetes (7,8), and in patients with coronary artery disease (7,10). Women have higher adiponectin concentrations than men (6,7), a difference that may be explained by the effect of testosterone (11). Weight reduction increases adiponectin in both diabetic and nondiabetic subjects (7). Interestingly, the thiazolidinediones (peroxisome proliferator– activated receptor ␥ agonists) have emerged as an effective treatment for insulin-resistant states (12), and one of the mechanisms may be their ability to stimulate adiponectin synthesis (13,14). The fact that adiponectin may have an anti-inflammatory effect is supported by the reciprocal association between adiponectin and C-reactive protein (CRP) in patients with coronary atherosclerosis (15). Furthermore, interleukin-6 (IL-6) downregulates adiponectin gene expression in adipocytes (16), and in obese women plasma IL-6 and CRP concentrations are inversely associated with adiponectin (17). Adiponectin concentrations have been shown to be consistently higher in patients with renal disease than in healthy control subjects (18,19), although such patients display insulin resistance and an increased risk of cardiovascular disease. The reason is still an open matter. However, in patients with advanced end-stage renal disease (ESRD), high adiponectin concentrations were associated with type 1 diabetes and lower visceral fat mass as well as with low CRP. It is noteworthy that of the 204 patients with ESRD studied, only 29 patients had type 1 diabetes, and adiponectin was determined in only 17 of them (19). Another study including 46 subjects showed elevated adiponectin in type 1 diabetic patients with short duration, normal creatinine, and stillmeasurable C-peptide (20). Although adiponectin seems to be elevated in type 1 diabetes both early after diagnosis of the disease and at a rather late stage of ESRD, it is not known whether adiponectin increases in type 1 diabetes in parallel with the severity of diabetic nephropathy and/or whether it is linked to factors interfering with the risk of cardiovascular disease, such
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OBJECTIVE — To elucidate whether serum adiponectin is associated with renal function, low-grade inflammatory markers, metabolic control, and insulin resistance in type 1 diabetic patients with and without nephropathy. RESEARCH DESIGN AND METHODS — A total of 189 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based on their urinary albumin excretion rate (AER): patients with normal AER (n ⫽ 66) had no antihypertensive medication, while patients with microalbuminuria (n ⫽ 63) or macroalbuminuria (n ⫽ 60) were all treated with an ACE inhibitor. Renal function was estimated with the Cockcroft-Gault formula. Adiponectin was measured by an in-house time-resolved immunofluorometric assay. RESULTS — Adiponectin concentrations were higher in women than in men, but since there was no significant difference in sex distribution between the groups, data were pooled. Adiponectin concentrations were higher in patients with macroalbuminuria (19.8 ⫾ 12.0 mg/l) than in patients with microalbuminuria (13.1 ⫾ 4.8 mg/l) or normoalbuminuria (11.8 ⫾ 4.2 mg/l). In a univariate analysis, adiponectin was positively associated with creatinine (r ⫽ 0.41; P ⬍ 0.0001), AER (r ⫽ 0.33; P ⬍ 0.0001), interleukin-6 (r ⫽ 0.22; P ⫽ 0.002), systolic blood pressure (r ⫽ 0.22; P ⫽ 0.004), HbA1c (r ⫽ 0.17; P ⫽ 0.02), total cholesterol (r ⫽ 0.16; P ⫽ 0.03), and HDL cholesterol (r ⫽ 0.16; P ⫽ 0.03) and negatively with estimated glomerular filtration rate (GFR; r ⫽ ⫺0.52; P ⬍ 0.0001) and waist-to-hip ratio (WHR; r ⫽ ⫺0.16; P ⫽ 0.03). In a multiple linear regression analysis including the above variables, estimated GFR, AER, and WHR were independently associated with adiponectin levels (r2 ⫽ 0.32). CONCLUSIONS — Serum adiponectin concentrations are increased in type 1 diabetic patients with nephropathy, and levels are further associated with renal insufficiency. Diabetes Care 28:1410 –1414, 2005
D
iabetic nephropathy is associated with insulin resistance and low-grade inflammation in type 1 diabetes (1,2). Circulatory levels of adiponectin, a hormone that is secreted exclusively from
the adipocytes (3), correlate negatively with insulin resistance (4 – 6), serum triglycerides, fasting serum insulin, and fasting plasma glucose concentrations (5–7). Low plasma adiponectin concentrations are
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From the 1Folkha¨lsan Institute of Genetics, Folkha¨lsan Research Center, Biomedicum Helsinki, Helsinki, Finland; the 2Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; and the 3Medical Department M (Diabetes and Endocrinology) and the Medical Research Laboratories, Aarhus University Hospital, Aarhus University, Aarhus, Denmark. Address correspondence and reprint requests to Per-Henrik Groop, MD, DMSc, Folkha¨lsan Research Center, Biomedicum Helsinki (318b), Haartmaninkatu 8, P.O. Box 63, FIN-00014, University of Helsinki, Helsinki, Finland. E-mail:
[email protected]. Received for publication 11 November 2004 and accepted in revised form 14 February 2005. Abbreviations: AER, albumin excretion rate; CRP, C-reactive protein; ESRD, end-stage renal disease; GFR, glomerular filtration rate; IL-6, interleukin-6; WHR, waist-to-hip ratio. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion factors for many substances. © 2005 by the American Diabetes Association.
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Table 1—Clinical characteristics of 189 type 1 diabetic patients
n (men/women) Age (years) Age at onset (years) BMI (kg/m2) WHR Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Estimated glucose disposal rate (mg 䡠 kg⫺1 䡠 min⫺1) HbA1c (%) Total cholesterol (mmol/l) HDL cholesterol (mmol/l) Triglycerides (mmol/l) Creatinine (mol/l) GFR (Cockcroft-Gault) (ml 䡠 min⫺1 䡠 1.73 m⫺2) AER (mg/24 h)* CRP (mg/l) IL-6 (ng/l)
Normoalbuminuria
Microalbuminuria
Macroalbuminuria
P
66 (35/31) 37.2 ⫾ 8.0 15.1 ⫾ 8.1 23.9 ⫾ 3.0 0.85 ⫾ 0.08 129 ⫾ 11 78 ⫾ 9 7.6 ⫾ 2.1 8.1 ⫾ 1.2 4.95 ⫾ 0.78 1.64 ⫾ 0.41 0.9 (0.4–2.0) 82 (47–114) 101 ⫾ 20 9 (2–85) 1.7 (0.1–8.0) 1.6 (0.3–10.3)
63 (36/27) 36.3 ⫾ 7.9 13.8 ⫾ 8.0 25.3 ⫾ 2.8 0.88 ⫾ 0.08 136 ⫾ 18 83 ⫾ 11 4.6 ⫾ 1.6 8.7 ⫾ 1.5 5.07 ⫾ 1.02 1.61 ⫾ 0.48 1.0 (0.5–3.4) 89 (65–136) 98 ⫾ 23 94 (3–418) 2.5 (0.1–7.8) 2.0 (0.8–19.5)
60 (33/27) 33.1 ⫾ 7.4 11.8 ⫾ 6.3 25.4 ⫾ 3.8 0.89 ⫾ 0.08 138 ⫾ 18 85 ⫾ 8 3.8 ⫾ 1.5 9.4 ⫾ 1.9 5.67 ⫾ 1.28 1.41 ⫾ 0.45 1.5 (0.6–9.1) 111 (71–675) 72 ⫾ 33 651 (10–6069) 2.4 (0.1–18.5) 2.6 (0.6–16.4)
NS ⬍0.05 ⬍0.05 ⬍0.05 ⬍0.05 ⬍0.05 ⬍0.01 ⬍0.0001 ⬍0.0001 ⬍0.001 ⬍0.01 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.05 ⬍0.0001
Data are means ⫾ SD or median (range). Groups are named on the basis of urinary AER and matched for sex and duration of the disease. Analyses utilized Kruskall-Wallis. *These values of AER are taken from the last collection of urine, and the patients with micro- or macroalbuminuria were on ACE inhibition.
as insulin resistance, unfavorable lipid profile, and chronic inflammation. Accordingly, the aim of the study was to measure serum adiponectin concentrations in type 1 diabetic patients with different stages of diabetic nephropathy and to elucidate whether adiponectin is associated with renal function, low-grade inflammatory markers, metabolic control, and insulin resistance. RESEARCH DESIGN AND METHODS — A total of 189 type 1 diabetic patients were selected from the ongoing, nationwide, multicenter Finnish Diabetic Nephropathy Study (FinnDiane) and divided into three groups according to their urinary albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections. Normal AER was
defined as an AER persistently ⬍20 g/ min or ⬍30 mg/24 h, microalbuminuria as an AER between 20 and 200 g/min or 30 and 300 mg/24 h, and macroalbuminuria as an AER ⬎200 g/min or ⬎300 mg/24 h in at least two out of three urine collections. Type 1 diabetes was defined as an onset of diabetes before the age of 35 years and permanent insulin treatment initiated within 1 year of diagnosis. Patients with normal AER were required to have neither antihypertensive medication nor signs of cardiovascular disease. Patients with micro- and macroalbuminuria were required to receive treatment with ACE inhibitors to be representative of type 1 diabetic patients with micro- or macroalbuminuria in Finland. Thereafter, patients were primarily matched for sex and,
Figure 1—Adiponectin concentration (mg/l) in all type 1 diabetic patients as well as men and women. Data are means ⫾ SD. Patients with normoalbuminuria (䡺), microalbuminuria (o), and macroalbuminuria (f). P values represent difference among the three groups (Kruskal-Wallis).
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secondly, for duration of diabetes. A total of 401 type 1 diabetic patients of the initial study population of 1,616 met these criteria, and from this cohort we randomly selected 189 with a duration of diabetes of at least 10 years. The ethical committees of all participating centers approved the study protocol. Written informed consent was obtained from each patient, and the study was performed in accordance with the Declaration of Helsinki as revised in 2000. Data on medication, cardiovascular status, diabetes complications, hypertension, and cardiovascular disease were obtained using a standardized questionnaire, which was completed by the patient’s attending physician based upon medical files. Blood pressure was measured twice in the sitting position with a mercury sphygmomanometer after at least a 10-min rest. Height and weight were recorded, and blood was drawn for the measurements of HbA1c, lipids, creatinine, inflammatory markers, and adiponectin. HbA1c and lipids were measured by enzymatic methods at the local hospitals. Serum creatinine was determined using a modified Jaffe´ reaction. We calculated the estimated glucose disposal rate as a surrogate measure of insulin sensitivity with an equation developed by Williams et al. (21) and modified for HbA1c. In addition to AER, we estimated glomerular filtration 1411
Adiponectin in type 1 diabetic patients
Table 2—Multiple regression analysis with adiponectin as dependent variable Variable WHR lnAER GFR (Cockroft-Gault)

SE
P
⫺1.30 0.07 ⫺0.47
0.38 0.02 0.10
⬍0.001 ⬍0.0001 ⬍0.0001
Model also included systolic blood pressure, HbA1c, lnCholesterol, estimated glucose disposal rate, and lnIL-6 (NS).
rate (GFR) by using the Cockroft-Gault formula (22). CRP was measured by radioimmunoassay and IL-6 by highsensitivity enzyme immunoassay as previously described (2). Serum adiponectin was determined by a novel in-house time-resolved immunofluorometric assay based on two monoclonal antibodies and recombinant human adiponectin (R&D Systems, Abingdon, U.K.) as recently described (23). Adiponectin has a molecular weight of ⬃30 –36 kDa depending on the degree of glycosylation, but the molecule is known to form a wide range of polymers in vivo. The predominant polymers include trimers, hexamers, and highly congregated multimers of ⬃300 kDa (24). Both of these antibodies were able to detect several adiponectin polymers in serum, including the three major molecular forms (data not shown). Within and inbetween assay coefficients of variation of standards and unknown samples averaged ⬍5 and 10%, respectively.
mated GFR as the dependent variable were used to assess independent relationships. The distribution of triglycerides, creatinine, AER, CRP, IL-6, and adiponectin were all skewed and therefore logarithmically transformed before analyses. All calculations were performed with a BMDP statistical package (Biomedical Data Processing Statistical Software, Los Angeles, CA). P values ⬍0.05 were considered statistically significant.
multiple linear regression analysis, including all variables that were associated with adiponectin in the univariate analysis, estimated GFR, AER, and WHR were independently associated with adiponectin concentrations (r 2 ⫽ 0.32) (Table 2). On the other hand, in a similar analysis when AER was used as dependent variable, adiponectin, WHR, estimated GFR, and estimated glucose disposal rate were independently associated with AER (r 2 ⫽ 0.46) (Table 3). With estimated GFR as dependent variable, adiponectin, AER, and HbA1c were independently associated with GFR (r 2 ⫽ 0.26) (Table 4).
Model also included lnCholesterol, lnIL-6, systolic blood pressure, and HbA1c (NS).
CONCLUSIONS — The major new finding in this study is the demonstration of markedly increased serum concentrations of adiponectin in type 1 diabetic patients with overt nephropathy and further that adiponectin is associated with renal insufficiency. On the contrary, there was no independent association between adiponectin and inflammatory markers in this patient population, which is in contrast to the findings in predialytic patients with ESRD (19) but in line with the findings in ESRD patients on dialysis (25). This may be due to the fact that patients with ESRD presumably have more confounding factors, like polypharmacy and uremic toxins, that can have a more profound impact on adiponectin and inflammatory markers than a patient population with mildly impaired kidney function. Notably, a recent study (26) in patients with early stages of chronic nondiabetic kidney disease did not observe any relationship between adiponectin and CRP. Interestingly, we also found an association between adiponectin and WHR, a strong feature of insulin resistance, but not between adiponectin and more direct indices of insulin resistance. Antihypertensive medication itself has been suggested to have an effect on adiponectin (27). In a small group of patients (n ⫽ 16) with essential hypertension, treatment with an ACE inhibitor or an angiotensin II receptor blocker was associated with an increase in adiponectin. In our study, all micro- and macroalbuminuric patients were on an ACE inhibitor, whereas normoalbuminuric patients did not have any antihypertensive medication at all. If the increase in adiponectin would have been solely due to the ACE inhibition, a significant increase in adiponectin concentrations could have been
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Statistical analysis Data are expressed as means ⫾ SD for normally distributed values and median (range) for nonnormally distributed values. Frequencies are given as percentages. Differences among groups for normally distributed variables were tested using ANOVA, and nonparametric data were analyzed using the Kruskal-Wallis and Mann-Whitney U test. Correlations were calculated using the Pearson correlation coefficient. Multiple linear regression analyses with adiponectin, AER, and esti-
RESULTS — The clinical characteristics of the patient population are shown in Table 1. The adiponectin concentrations were higher in women than in men. However, since there was no difference in sex distribution among the groups, data were pooled. Adiponectin concentrations were higher in patients with macroalbuminuria than in patients with microalbuminuria (P ⬍ 0.001) or normoalbuminuria (P ⬍ 0.0001) (Fig. 1). No difference was observed between patients with normoalbuminuria or microalbuminuria (P ⫽ 0.2). Adiponectin was positively associated with creatinine (r ⫽ 0.41; P ⬍ 0.0001), AER (r ⫽ 0.33; P ⬍ 0.0001), IL-6 (r ⫽ 0.22; P ⫽ 0.002), systolic blood pressure (r ⫽ 0.21; P ⫽ 0.004), HbA1c (r ⫽ 0.17; P ⫽ 0.02), total cholesterol (r ⫽ 0.16; P ⫽ 0.03), and HDL cholesterol (r ⫽ 0.16; P ⫽ 0.03) and negatively with estimated GFR (r ⫽ ⫺0.52; P ⬍ 0.0001) and waist-to-hip ratio (WHR, r ⫽ ⫺0.16; P ⫽ 0.03) in a univariate analysis. No association was observed with age, duration of diabetes, BMI, diastolic blood pressure, estimated glucose disposal rate, triglyceride, or CRP (data not shown). In a
Table 3—Multiple regression analysis with AER as dependent variable Variable WHR lnAdiponectin GFR (Cockroft-Gault) Estimated glucose disposal rate

SE
P
⫺4.83 0.85 ⫺1.22 ⫺0.55
2.12 0.33 0.44 0.07
⬍0.05 ⬍0.05 ⬍0.01 ⬍0.0001
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Table 4—Multiple regression analysis with GFR (Cockroft-Gault) as dependent variable Variable lnAER HbA1c lnAdiponectin

SE
P
⫺0.03 0.04 ⫺0.29
0.01 0.01 0.05
⬍0.01 ⬍0.01 ⬍0.0001
Model also included lnIL-6, systolic blood pressure, WHR, estimated glucose disposal rate, and lnCholesterol (NS).
expected in the patients with microalbuminuria as well. The collagenous domain of the adiponectin molecule has four conserved lysines that can be hydroxylated and glycosylated. Both hydroxylation and glycosylation are suggested to be critical for the three-dimensional structure of the biologically active adiponectin molecule (28). It is likely that glycosylation is one of the major posttranslational modifications of adiponectin (28). In diabetic patients with constant hyperglycemia, the glycosylation process is probably altered, and this could lead to an altered adiponectin function. Consequently, a modified adiponectin molecule could lead to a diminished negative feedback, a mechanism that is an essential part of hormonal systems, and thus to increased adiponectin concentrations in diabetes. An essential question to be answered is why advanced diabetic nephropathy is associated with increased concentrations of adiponectin. The opposite would be expected, since a typical feature of nephropathy is insulin resistance, which in type 2 diabetic patients has been associated with suppressed/low serum adiponectin concentrations (8). One possibility could be that the renal insufficiency per se further stimulates adiponectin production or alternatively leads to a defect in the clearance of adiponectin. The latter suggestion is supported by the finding that succesful kidney transplantation is followed by decreased plasma adiponectin concentrations (29). Although the true mechanisms responsible for the increase in circulating adiponectin in diabetic nephropathy are still unclear, one can speculate that adiponectin itself may have a role in mitigating the micro- and macrovascular burden in diabetic nephropathy, like it has been suggested to do in ESRD (25). Interestingly, adiponectin has been shown to be associated with endothelium-dependent vasodilatation (30) and, further, to modulate endothelial DIABETES CARE, VOLUME 28, NUMBER 6, JUNE 2005
function by inhibiting the deleterious effects of tumor necrosis factor-␣ (10). Proteinuria has been shown to be positively associated with adiponectin in patients with the nephrotic syndrome, although that study could not detect any association between GFR and adiponectin (18). In another study (19) including both type 1 and type 2 diabetic patients with ESRD, there was neither any association between AER and adiponectin nor between GFR and adiponectin. Our results show that not only AER but also estimated GFR is independently associated with increased adiponectin concentrations in type 1 diabetic patients with nephropathy. The question arises as to why our results differ from previous studies. The most plausible explanation is the inclusion of different patient populations as well as the number of type 1 diabetic patients, which was significantly higher in our study than in the previous studies. Notably, in a recent study in type 2 diabetic Pima Indians, adiponectin was associated with elevated serum creatinine and macroalbuminuria (31). In conclusion, serum adiponectin concentrations are increased in type 1 diabetic patients with nephropathy, and levels are further associated with renal insufficiency. The reason why insulinresistant conditions like proteinuria and advanced nephropathy are associated with high circulating adiponectin levels is still unclear. Acknowledgments — The study was supported by grants from the Folkha¨lsan Research Foundation, Samfundet Folkha¨lsan, the Wilhelm and Else Stockmann Foundation, the Liv och Ha¨lsa Foundation, the Finnish Medical Society (Finska La¨karesa¨llskapet), European Commission (Euragedic), the National Danish Research Council, and the Danish Diabetes Association awards. Part of this study was published in abstract form at the American Society of Nephrology meeting 2004. The skillful assistance of the
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