OBJECTIVE—The purpose of this study was to elucidate whether serum adiponectin is associated with progression of diabetic nephropathy in type 1 diabetic patients.

RESEARCH DESIGN AND METHODS—This was a prospective follow-up study as a part of the nationwide Finnish Diabetic Nephropathy Study; 1,330 type 1 diabetic patients were followed for 5.0 ± 2.2 years. Patients were divided at baseline into three groups according to their urinary albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: 818 patients with normoalbuminuria (AER <20 μg/min), 216 patients with microalbuminuria (20 μg/min ≤ AER < 200 μg/min), and 296 patients with macroalbuminuria (AER ≥200 μg/min). Progression of albuminuria was the main outcome. Adiponectin was measured by a time-resolved immunofluorometric assay, and the values were log-transformed and adjusted for age, BMI, and sex before analysis.

RESULTS—Progression either to the next albuminuria level or to end-stage renal disease (ESRD) occurred in 193 patients. No difference in adiponectin concentrations was observed between progressors and nonprogressors in patients with normoalbuminuria or microalbuminuria. In the patients with macroalbuminuria, progression to ESRD was associated with higher adiponectin in the entire group (23.4 ± 17.1 vs. 16.0 ± 8.5 mg/l, P < 0.001) and in men (P < 0.001) and women (P < 0.001) separately. Progression to ESRD was also associated with systolic blood pressure, insulin dose, A1C, serum cholesterol, serum triglycerides, AER, and estimated glomerular filtration rate (eGFR). When these covariates were inserted in a Cox regression analysis, A1C, triglycerides, eGFR, and adiponectin were significantly associated with progression from macroalbuminuria.

CONCLUSIONS—Increased serum adiponectin levels predict the progression from macroalbuminuria to ESRD in type 1 diabetic patients.

Adiponectin, a hormone that is secreted exclusively from adipocytes (1), has consistently been shown to be higher in patients with renal disease than in healthy subjects (2,3). Serum adiponectin concentrations are also increased in type 1 diabetes (4) and especially in patients who have diabetic nephropathy (5,6).

The mechanisms responsible for the increase are still unclear. However, high plasma adiponectin concentrations decrease after renal transplantation, suggesting that renal insufficiency may either have an effect on the clearance of adiponectin and/or have a stimulatory effect on adiponectin production (7). In a recent study in patients with type 2 diabetes and overt diabetic nephropathy, the increase in serum adiponectin was suggested to reflect enhanced production of adiponectin in the adipose tissue rather than a reduced clearance of adiponectin by the kidneys (8).

It could be speculated that adiponectin itself may play a compensatory role in mitigating the disease burden induced by renal disease via its antiatherogenic and anti-inflammatory properties (9). Supportive of this view, high circulating adiponectin concentrations have been associated with a better prognosis not only in patients with end-stage renal disease (ESRD) and cardiovascular disease (CVD) (10), but also in patients with mild to moderately impaired kidney function and CVD (11). Interestingly, high adiponectin concentrations were associated with the occurrence of microalbuminuria in a 6-year follow-up study in 126 patients with type 1 diabetes and normoalbuminuria at baseline (12). This observation suggests that adiponectin may in fact promote development and progression of diabetic nephropathy despite a potential protective effect regarding CVD. Therefore, this study was performed to elucidate whether adiponectin plays a role in the development and progression of diabetic nephropathy in patients with type 1 diabetes.

This study is part of the ongoing prospective Finnish Diabetic Nephropathy Study (FinnDiane), which is a nationwide, comprehensive multicenter study that started in 1998 with the aim of identifying genetic and environmental risk factors for diabetic nephropathy in patients with type 1 diabetes. At baseline, patients underwent a thorough clinical investigation that took place in conjunction with a regular visit to the attending physician. Two different approaches complementing each other were used for follow up of the patients. First, for all patients included in the present analysis, the medical files were reviewed, and any changes in renal status or the occurrence of cardiovascular events was verified. Second, all patients were reexamined at their local medical center according to the same protocol as at the baseline visit.

A total of 1,330 patients with type 1 diabetes were included in the present study. The mean ± SD follow-up time was 5.0 ± 2.2 years. Based on their urinary albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections, 818 patients had a normal AER (AER <20 μg/min or <30 mg/24 h), 216 patients had microalbuminuria (20 μg/min ≤ AER < 200 μg/min or 30 mg/24 h ≤ AER < 300 mg/24 h), and 296 patients had macroalbuminuria (AER ≥200 μg/min or AER ≥300 mg/24 h). Patients with ESRD, defined as patients undergoing dialysis or having received a kidney transplant, were not included in the analysis.

Progression of renal disease was defined as follows: all data on AER obtained between baseline and the follow-up visit were reviewed, and based on the result in two of the last three consecutive urine collections, the renal status of the patients was determined using the same cutoff values as in the baseline examination. Progression was defined as a change from one level to a higher level of AER or the development of ESRD. Patients without progression of renal disease were classified as nonprogressors. 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. The study also included healthy control subjects (n = 204) to be able to compare adiponectin concentrations between healthy subjects and patients with type 1 diabetes.

The ethics 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 the year 2000.

At the regular patient visits, data on medication and diabetic complications were registered using a standardized questionnaire, which was completed by the patient's attending physician and based on medical files and the clinical evaluation. Blood pressure was measured twice in the sitting position with a mercury sphygmomanometer after a 10-min rest and the average of these measurements were used in the analysis. Height, weight, and waist-to-hip ratio were recorded, and blood was drawn for the measurements of A1C, lipids, creatinine, and adiponectin. Estimated glucose disposal rate was calculated as described earlier and was used as a measure of insulin sensitivity (13).

A1C was determined by standardized assays at each center. Serum lipid and lipoprotein concentrations were measured at the research laboratory of the Helsinki University Central Hospital, Division of Cardiology, Helsinki, Finland, by automated enzymatic methods using the Cobas Mira analyzer (Hoffmann-La Roche, Basel, Switzerland). Serum creatinine was assessed by enzymatic methods at a central laboratory. Urinary AER was determined by radioimmunoassay (Pharmacia, Uppsala, Sweden) or immunoturbidimetry. The estimated glomerular filtration rate (eGFR) was determined with the Cockroft-Gault formula (14). Serum adiponectin was determined by a time-resolved immunofluorometric assay (15).

Statistical analysis

Data are expressed as means ± SD for normally distributed values and as median (range) for non-normally distributed values. Differences between groups for normally distributed variables were tested using ANOVA, and for nonparametric data the Kruskal-Wallis test was used. Categorical variables were analyzed with a χ2 test. Risk factors for the progression of diabetic nephropathy were assessed using Cox regression analysis. All calculations were performed with SPSS 12.01 (SPSS, Chicago, IL). P < 0.05 was considered statistically significant.

Clinical characteristics of the patients are shown in Table 1. Patients with macroalbuminuria were older and had a longer duration of diabetes than patients in the other groups. Glycemic control was worst in patients with macroalbuminuria. Serum adiponectin concentrations were similar in patients with normoalbuminuria and microalbuminuria but higher in patients with macroalbuminuria (P < 0.001). Healthy control subjects had, as expected, significantly lower adiponectin serum concentrations (9.93 ± 4.52 mg/l) than patients with type 1 diabetes and normoalbuminuria (12.1 ± 5.8 mg/l, P < 0.001) or microalbuminuria (12.3 ± 6.2 mg/l, P < 0.001).

Seventy-three of 818 patients with normoalbuminuria progressed to microalbuminuria, 37 of 216 progressed from microalbuminuria to macroalbuminuria, and 83 of 296 progressed from macroalbuminuria to ESRD. In patients with normoalbuminuria or microalbuminuria, there were no differences in the baseline adiponectin concentrations between progressors or nonprogressors (Table 2), not even when men and women were analyzed separately (data not shown). However, in the macroalbuminuria group, progressors had significantly higher serum adiponectin concentrations compared with nonprogressors (Table 2).

In patients with macroalbuminuria, systolic blood pressure, insulin dose, A1C, cholesterol, triglycerides, creatinine, AER, and eGFR were all associated with progression from macroalbuminuria to ESRD in univariate analyses (Table 3). When systolic blood pressure, insulin dose, A1C, cholesterol, triglycerides, eGFR, and adiponectin were inserted in a Cox regression analysis, A1C, triglycerides, eGFR, and adiponectin were significantly associated with progression from macroalbuminuria to ESRD (Table 4).

The major new finding of the present study is the demonstration that an increased serum concentration of adiponectin at baseline is prognostic for the progression from overt diabetic nephropathy to ESRD in patients with type 1 diabetes. However, we could not observe any differences in the serum adiponectin concentrations in patients with normoalbuminuria or microalbuminuria irrespective of whether or not they were progressors.

These data are in contrast to results from a previously published study; however, that study included only 126 patients with type 1 diabetes (12). It is notable that we studied a substantially larger patient population, which may explain the observed difference. Furthermore, our patients with normoalbuminuria were younger and had better glycemic control and higher BMI.

Notably, our observation is also in contrast to the observation made in the Modification of Diet in Renal Disease (MDRD) study, in which the investigators could not find an association between adiponectin and the progression of kidney disease, even if they included patients with moderate to advanced kidney disease (16). A plausible explanation for this discrepancy might be our larger patient population and the fact that the MDRD study included only 42 patients with diabetes, and none of them had type 1 diabetes.

As expected, most of our patients with type 1 diabetes and diabetic nephropathy were treated with an ACE inhibitor or an ARB, agents that have been shown to increase serum adiponectin in nondiabetic patients with hypertension (17). However, we could not observe any differences in adiponectin concentrations whether or not the patients were taking ACE inhibitors, an observation that is in line what has been shown recently in a study of patients with type 2 diabetes and hypertension (18). In patients with type 1 diabetes, treatment with an ARB was shown to increase the adiponectin concentration in a small-scale study (19), but in two other later studies, there was no effect of an ACE inhibitor or an ARB (15,20). The great majority of the patients in the macroalbuminuric group in our study were receiving ACE inhibitor treatment and only 25 patients were receiving ARB treatment.

The reason that adiponectin may be prognostic for the progression from macroalbuminuria to ESRD in patients with type 1 diabetes is not yet known. However, it may be a mechanism by which the body compensates for the demands created by the diabetic milieu. Importantly, glycosylation represents one of the major post-translational modifications of adiponectin, which, together with hydroxylation, is supposed to be critical for the three-dimensional structure of the biologically active adiponectin molecule (21–23). Notably, even a relatively short period of high plasma glucose has been reported to lead to an increase in the production of the biologically highly active high–molecular weight adiponectin (23). Whether this mechanism is still present in chronic hyperglycemia in type 1 diabetic patients with macroalbuminuria is unknown; however, in support of this hypothesis, the present patients with type 1 diabetes and macroalbuminuria had worse glycemic control than patients with normo- or microalbuminuria. Further, A1C and adiponectin were both associated with the progression of diabetic nephropathy. In addition, renal insufficiency per se has been suggested to trigger an increase in adiponectin concentrations. According to a study in patients with type 2 diabetes and overt diabetic nephropathy, enhanced production of adiponectin has been suggested to be a stronger determinant of serum adiponectin concentrations than a reduction in the clearance of adiponectin by the kidneys (8). It is of note that in our study adiponectin was an independent predictor of progression from macroalbuminuria to ESRD irrespective of patients’ eGFRs.

In summary, increased adiponectin concentration is prognostic for the progression from overt diabetic nephropathy to ESRD in patients with type 1 diabetes.

Table 1—

Baseline clinical characteristics of the patients

NormoalbuminuriaMicroalbuminuriaMacroalbuminuriaP value overall
n (men/women) 818 (384/434) 216 (131/85)† 296 (175/121)* <0.001 
Age (years) 33.4 ± 11.0 36.4 ± 11.6* 40.2 ± 9.5*§ <0.001 
Duration of diabetes (years) 17.9 ± 10.6 24.8 ± 10.3* 29.1 ± 7.6*§ <0.001 
BMI (kg/m2) 24.7 ± 3.2 25.6 ± 3.6 26.0 ± 4.0* <0.001 
Waist-to-hip ratio     
    Men 0.892 ± 0.070 0.916 ± 0.064* 0.946 ± 0.072*§ <0.001 
    Women 0.804 ± 0.064 0.818 ± 0.066 0.835 ± 0.064* <0.001 
eGDR (mg · kg−1 · min−1) 7.5 ± 2.2 5.3 ± 2.2* 4.1 ± 1.7*§ <0.001 
Systolic blood pressure (mmHg) 128 ± 15 133 ± 16* 144 ± 19*§ <0.001 
Diastolic blood pressure (mmHg) 78 ± 9 80 ± 10† 83 ± 10*‖ <0.001 
A1C (%) 8.2 ± 1.4 8.7 ± 1.5* 8.9 ± 1.6* <0.001 
Serum cholesterol (mmol/l) 4.8 ± 0.9 5.0 ± 0.9† 5.5 ± 1.1*§ <0.001 
Serum HDL cholesterol (mmol/l) 1.3 ± 0.3 1.2 ± 0.3‡ 1.1 ± 0.4* <0.001 
Serum triglycerides (mmol/l) 0.97 (0.31–7.04) 1.16 (0.49–8.82)* 1.46 (0.54–8.38)†§ <0.001 
Serum LDL-cholesterol (mmol/l) 3.0 ± 0.8 3.1 ± 0.8‡ 3.6 ± 0.9*§ <0.001 
Serum creatinine (μmol/l) 84 (20–155) 89 (56–140)* 130 (60–848)*§ <0.001 
Serum adiponectin (mg/l) 12.1 ± 5.8 12.3 ± 6.2 18.1 ± 12.0*§ <0.001 
AER (mg/24 h)** 8 (1–190) 45 (2–342)* 503 (5–6069)*§ <0.001 
eGFR (ml/min per 1.73 m2) 96 ± 18 92 ± 19‡ 61 ± 28*§ <0.001 
NormoalbuminuriaMicroalbuminuriaMacroalbuminuriaP value overall
n (men/women) 818 (384/434) 216 (131/85)† 296 (175/121)* <0.001 
Age (years) 33.4 ± 11.0 36.4 ± 11.6* 40.2 ± 9.5*§ <0.001 
Duration of diabetes (years) 17.9 ± 10.6 24.8 ± 10.3* 29.1 ± 7.6*§ <0.001 
BMI (kg/m2) 24.7 ± 3.2 25.6 ± 3.6 26.0 ± 4.0* <0.001 
Waist-to-hip ratio     
    Men 0.892 ± 0.070 0.916 ± 0.064* 0.946 ± 0.072*§ <0.001 
    Women 0.804 ± 0.064 0.818 ± 0.066 0.835 ± 0.064* <0.001 
eGDR (mg · kg−1 · min−1) 7.5 ± 2.2 5.3 ± 2.2* 4.1 ± 1.7*§ <0.001 
Systolic blood pressure (mmHg) 128 ± 15 133 ± 16* 144 ± 19*§ <0.001 
Diastolic blood pressure (mmHg) 78 ± 9 80 ± 10† 83 ± 10*‖ <0.001 
A1C (%) 8.2 ± 1.4 8.7 ± 1.5* 8.9 ± 1.6* <0.001 
Serum cholesterol (mmol/l) 4.8 ± 0.9 5.0 ± 0.9† 5.5 ± 1.1*§ <0.001 
Serum HDL cholesterol (mmol/l) 1.3 ± 0.3 1.2 ± 0.3‡ 1.1 ± 0.4* <0.001 
Serum triglycerides (mmol/l) 0.97 (0.31–7.04) 1.16 (0.49–8.82)* 1.46 (0.54–8.38)†§ <0.001 
Serum LDL-cholesterol (mmol/l) 3.0 ± 0.8 3.1 ± 0.8‡ 3.6 ± 0.9*§ <0.001 
Serum creatinine (μmol/l) 84 (20–155) 89 (56–140)* 130 (60–848)*§ <0.001 
Serum adiponectin (mg/l) 12.1 ± 5.8 12.3 ± 6.2 18.1 ± 12.0*§ <0.001 
AER (mg/24 h)** 8 (1–190) 45 (2–342)* 503 (5–6069)*§ <0.001 
eGFR (ml/min per 1.73 m2) 96 ± 18 92 ± 19‡ 61 ± 28*§ <0.001 

Data are means ± SD or median (range).

*

P < 0.001 versus normoalbuminuria;

†

P < 0.01 versus normoalbuminuria;

‡

P < 0.05 versus normoalbuminuria;

§

P < 0.001 versus microalbuminuria;

‖

P < 0.01 versus microalbuminuria;

P < 0.05 versus microalbuminuria.

**

The AER presented is the last measurement of each patient. Because the classification was based on two of three consecutive samples, a single value may be higher. A low value may be due to the effect of treatment. eGDR, estimated glucose disposal rate.

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Table 2—

Baseline serum adiponectin concentrations (mg/l) and progression from one stage to the next in diabetic nephropathy

Serum adiponectin (mg/l)
P value
ProgressorNonprogressor
Normoalbuminuria 12.0 ± 6.1 (73) 12.1 ± 5.8 (745) NS 
Microalbuminuria 12.5 ± 6.0 (37) 12.2 ± 6.3 (179) NS 
Macroalbuminuria (all) 23.4 ± 17.1 (83) 16.0 ± 8.5 (213) <0.001 
Macroalbuminuria (men) 19.1 ± 9.9 (56) 13.5 ± 7.0 (119) <0.001 
Macroalbuminuria (women) 32.2 ± 24.5 (27) 19.1 ± 9.3 (94) <0.001 
Serum adiponectin (mg/l)
P value
ProgressorNonprogressor
Normoalbuminuria 12.0 ± 6.1 (73) 12.1 ± 5.8 (745) NS 
Microalbuminuria 12.5 ± 6.0 (37) 12.2 ± 6.3 (179) NS 
Macroalbuminuria (all) 23.4 ± 17.1 (83) 16.0 ± 8.5 (213) <0.001 
Macroalbuminuria (men) 19.1 ± 9.9 (56) 13.5 ± 7.0 (119) <0.001 
Macroalbuminuria (women) 32.2 ± 24.5 (27) 19.1 ± 9.3 (94) <0.001 

Data are means ± SD (n).

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Table 3—

Clinical parameters between progressors and nonprogressors of patients with macroalbuminuria

ProgressorsNonprogressorsP value
n (men/women) 83 (56/27) 213 (119/94) 0.068 
Age (years) 40 ± 10 40 ± 10 NS 
Duration of diabetes (years) 28 ± 8 29 ± 7 NS 
BMI (kg/m2) 25.5 ± 4.6 26.2 ± 3.8 NS 
Waist-to-hip ratio    
    Men 0.95 ± 0.07 0.95 ± 0.07 NS 
    Women 0.83 ± 0.05 0.84 ± 0.07 NS 
eGDR (mg · kg−1 · min−1) 3.8 ± 1.6 4.2 ± 1.7 0.062 
ACE inhibitor/ARB treatment (%) 75 84 0.093 
Systolic blood pressure (mmHg) 148 ± 20 141 ± 19 0.022 
Diastolic blood pressure (mmHg) 84 ± 10 82 ± 10 0.073 
Insulin dose (IU/kg) 0.63 ± 0.19 0.73 ± 0.24 0.001 
A1C (%) 9.2 ± 1.8 8.8 ± 1.4 0.040 
Serum cholesterol (mmol/l) 5.8 ± 1.3 5.4 ± 0.9 0.007 
Serum HDL cholesterol(mmol/l) 1.10 ± 0.43 1.15 ± 0.33 NS 
Serum Triglycerides (mmol/l) 1.66 (0.6–8.4) 1.39 (0.5–7.4) <0.001 
Serum LDL cholesterol (mmol/l) 3.66 ± 1.06 3.53 ± 0.85 NS 
Serum creatinine (μmol/l) 272 (70–708) 116 (56–848) <0.001 
AER (mg/24 h)* 1,593 (12–6,069) 368 (5–4,636) <0.001 
eGFR (ml/min per 1.73 m2) 38 ± 24 69 ± 24 <0.001 
ProgressorsNonprogressorsP value
n (men/women) 83 (56/27) 213 (119/94) 0.068 
Age (years) 40 ± 10 40 ± 10 NS 
Duration of diabetes (years) 28 ± 8 29 ± 7 NS 
BMI (kg/m2) 25.5 ± 4.6 26.2 ± 3.8 NS 
Waist-to-hip ratio    
    Men 0.95 ± 0.07 0.95 ± 0.07 NS 
    Women 0.83 ± 0.05 0.84 ± 0.07 NS 
eGDR (mg · kg−1 · min−1) 3.8 ± 1.6 4.2 ± 1.7 0.062 
ACE inhibitor/ARB treatment (%) 75 84 0.093 
Systolic blood pressure (mmHg) 148 ± 20 141 ± 19 0.022 
Diastolic blood pressure (mmHg) 84 ± 10 82 ± 10 0.073 
Insulin dose (IU/kg) 0.63 ± 0.19 0.73 ± 0.24 0.001 
A1C (%) 9.2 ± 1.8 8.8 ± 1.4 0.040 
Serum cholesterol (mmol/l) 5.8 ± 1.3 5.4 ± 0.9 0.007 
Serum HDL cholesterol(mmol/l) 1.10 ± 0.43 1.15 ± 0.33 NS 
Serum Triglycerides (mmol/l) 1.66 (0.6–8.4) 1.39 (0.5–7.4) <0.001 
Serum LDL cholesterol (mmol/l) 3.66 ± 1.06 3.53 ± 0.85 NS 
Serum creatinine (μmol/l) 272 (70–708) 116 (56–848) <0.001 
AER (mg/24 h)* 1,593 (12–6,069) 368 (5–4,636) <0.001 
eGFR (ml/min per 1.73 m2) 38 ± 24 69 ± 24 <0.001 

Data are means ± SD or median (range).

*

The AER presented is the last measurement of each patient. Because the classification was based on two of three consecutive samples, a single value may be higher. A low value may be due to the effect of treatment. eGDR, estimated glucose disposal rate.

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Table 4—

Cox regression analysis of risk factors for progression from macroalbuminuria to ESRD

BSEHazard ratio (95% CI)P value
eGFR (ml/min per 1.73 m2)* −0.065 0.008 0.937 (0.923–0.952) 0.000 
Systolic blood pressure (mmHg) 0.009 0.006 1.009 (0.997–1.021) 0.158 
A1C (%) 0.203 0.076 1.225 (1.055–1.422) 0.008 
Triglycerides (mmol/l) 0.355 0.098 1.426 (1.176–1.728) 0.000 
Adiponectin (mg/l) 0.021 0.008 1.022 (1.005–1.039) 0.011 
Insulin (IU/kg) −0.473 0.681 0.623 (0.164–2.366) 0.487 
Total cholesterol −0.110 0.128 0.896 (0.697–1.152) 0.391 
BSEHazard ratio (95% CI)P value
eGFR (ml/min per 1.73 m2)* −0.065 0.008 0.937 (0.923–0.952) 0.000 
Systolic blood pressure (mmHg) 0.009 0.006 1.009 (0.997–1.021) 0.158 
A1C (%) 0.203 0.076 1.225 (1.055–1.422) 0.008 
Triglycerides (mmol/l) 0.355 0.098 1.426 (1.176–1.728) 0.000 
Adiponectin (mg/l) 0.021 0.008 1.022 (1.005–1.039) 0.011 
Insulin (IU/kg) −0.473 0.681 0.623 (0.164–2.366) 0.487 
Total cholesterol −0.110 0.128 0.896 (0.697–1.152) 0.391 
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This study was supported by the Danish Medical Research Council, the Danish Diabetes Association, the Novo Nordisk Foundation, and the Clinical Institute, Aarhus University, Aarhus, Denmark. The FinnDiane Study was supported by grants from the Folkhälsan Research Foundation, Samfundet Folkhälsan, Wilhelm and Else Stockmann Foundation, Liv och Hälsa Foundation, and the Finnish Medical Society (Finska Läkaresällskapet).

We thank all the patients who contributed in the study. The skillful laboratory assistance of Karen Mathiassen, Hanne Petersen, and Anette Megel at the Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark and the skilled technical assistance of Anna Sandelin and Sinikka Lindh are gratefully acknowledged. Finally, we acknowledge all the physicians and nurses at each center participating in the collection of patients: Central Finland Central Hospital: A. Halonen, A. Koistinen, P. Koskiaho, M. Laukkanen, J. Saltevo, and M. Tiihonen; Central Hospital of Kanta-Hame: P. Kinnunen, A. Orvola, T. Salonen, and A. Vähänen; Central Hospital of Kymenlaakso: R. Paldanius, M. Riihelä, and L. Ryysy; Central Hospital of Lansi-Pohja: P. Nyländen and A. Sademies; Central Ostrobothnian Hospital District: S. Anderson, B. Asplund, U. Byskata, and T. Virkkala; City of Vantaa Health Center: (Rekola) M. Eerola and E. Jatkola, (Tikkurila) R. Lönnblad, J. Mäkelä, A. Malm, and E. Rautamo; Helsinki University Central Hospital (Department of Medicine, Division of Nephrology): H. Rosvall, M. Rosengård-Bärlund; M. Rönnback, and J. Wadén; Iisalmi Hospital: E. Toivanen; Kainuu Central Hospital: S. Jokelainen, P. Kemppainen, A-M. Mankinen, and M. Sankari; Kerava Health Center: H. Stuckey and P. Suominen; Kouvola Health Center: E. Koskinen and T. Siitonen; Kuopio University Hospital: M. Laakso, L. Niskanen, I. Vauhkonen, T. Lakka, E. Voutilainen, L. Mykkänen, P. Karhapää, E. Lampainen, and E. Huttunen; Kuusamo Health Center: E. Vierimaa, E. Isopoussu, and H. Suvanto; Kuusankoski Hospital: E. Kilkki and L. Riihelä; Lapland Central Hospital: L. Hyvärinen, S. Severinkangas, and T. Tulokas; Länsi-Uusimaa Hospital, Tammisaari: J. Rinne and I.-M. Jousmaa; Mikkeli Central Hospital: A. Gynther, R. Manninen, P. Nironen, M. Salminen, and T. Vänttinen; North Karelian Hospital: U-M. Henttula, P. Kekäläinen, A. Rissanen, and M. Voutilainen; Paijat-Hame Central Hospital: H. Haapamäki, A. Helanterä, and H. Miettinen; Palokka-Vaajakoski Health Center: P. Sopanen, L. Welling, and K. Mäkinen; Pori City Hospital: K. Sävelä, P. Ahonen, and P. Merensalo; Riihimäki Hospital: L. Juurinen and E. Immonen; Salo Hospital: J. Lapinleimu, M. Virtanen, P. Rautio, and A. Alanko; Satakunta Central Hospital: M. Juhola, P. Kunelius, M-L. Lahdenmäki, P. Pääkkönen, and M. Rautavirta; Savonlinna Central Hospital: T. Pulli, P. Sallinen, H. Valtonen, and A. Vartia; Seinajoki Central Hospital: E. Korpi-Hyövälti, T. Latvala, and E. Leijala; South Karelia Hospital District: E. Hussi, T. Hotti, R. Härkönen, and U. Nyholm; Tampere University Hospital: I. Ala-Houhala, T. Kuningas, P. Lampinen, M. Määttä, H. Oksala, T. Oksanen, K. Salonen, H. Tauriainen, and S. Tulokas; Turku Health Center: I Hämäläinen, H. Virtamo, and M. Vähätalo; Turku University Central Hospital: M. Asola, K. Breitholz, R. Eskola, K. Metsärinne, U. Pietilä, P. Saarinen, R. Tuominen, and S. Áyräpää; and Vasa Central Hospital: S. Bergkulla, U. Hautamäki, V-A. Myllyniemi, and I. Rusk.

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Published ahead of print at http://care.diabetesjournals.org on 17 March 2008. DOI: 10.2337/dc07-2306.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

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2008