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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0360
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 8 3186-3191
Copyright © 2008 by The Endocrine Society

Elevated Levels of High-Molecular-Weight Adiponectin in Type 1 Diabetes

Henrik Leth, Kristian K. Andersen, Jan Frystyk, Lise Tarnow, Peter Rossing, Hans-Henrik Parving and Allan Flyvbjerg

The Medical Research Laboratories (H.L., K.K.A., J.F., A.F.), Clinical Institute, Aarhus University Hospital, DK-8000 Aarhus, Denmark; Steno Diabetes Center (L.T., P.R.), Gentofte DK-2820 Copenhagen, Denmark; and Department of Endocrinology (H.-H.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Professor Allan Flyvbjerg, M.D., D.M.Sc., The Medical Research Laboratories, Clinical Institute, Aarhus University Hospital, Nørrebrogade 44, DK-8000 Aarhus C, Denmark. E-mail: allan.flyvbjerg{at}dadlnet.dk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Several studies have shown that type 1 diabetic patients have elevated total levels of the adipocyte-derived adipocytokine adiponectin. However, adiponectin circulates in three different subforms, and the high-molecular-weight (HMW) subform is believed to be the primary biologically active form. The effects of the medium-molecular-weight (MMW) subform and the low-molecular-weight (LMW) subform are still unresolved.

Purpose: The objective of the study was to investigate the distribution of the three molecular subforms of adiponectin in well-characterized groups of type 1 diabetics with varying degrees of nephropathy as well as in healthy control subjects.

Study Population: Two hundred seven individuals were included: 58 type 1 diabetics with normoalbuminuria, 46 with microalbuminuria, 46 with macroalbuminuria, and 57 matched controls.

Methods: The HMW, MMW, and LMW subforms were measured using a validated in-house time-resolved immunoflourometric assay after separation by fast protein liquid chromatography.

Results: The absolute concentrations of total adiponectin and all subforms were higher in type 1 diabetic patients than healthy controls. However, the relative HMW fraction was up-regulated in type 1 diabetes (P < 0.001), whereas the MMW (P < 0.001) and LMW fractions (P < 0.05) were down-regulated, compared with controls. Accordingly, the increase in concentration of total adiponectin was primarily caused by a major increase of the HMW subform. Levels of total adiponectin and the HMW subform (absolute and relative) were generally unaffected by nephropathy status defined by urinary albumin excretion rate.

Conclusion: Type 1 diabetes per se is associated with higher adiponectin levels than healthy subjects. This increase is mainly explained by an elevation in the HMW subform. The elevation is unaffected by gender and diabetic kidney disease.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
The adipocyte secretes a number of peptides named adipocytokines or simply adipokines. The most abundantly secreted adipokine is adiponectin. Until now, two different cell surface receptors for globular and full-length adiponectin have been identified. Receptor stimulation leads to activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-{alpha} (1). These intracellular pathways are involved in fatty-acid oxidation and glucose uptake and suggest a role of adiponectin as an endogenous insulin sensitizer (2, 3, 4). Moreover, preclinical and clinical studies have revealed that adiponectin possesses antiinflammatory, antiatherogenic, and cardioprotective properties (1, 5, 6). Accordingly, low concentrations of adiponectin have been reported in obesity (7, 8), type 2 diabetes (7, 9), and coronary artery disease (9, 10).

Adiponectin is subjected to posttranslatory modifications, which change the three-dimensional structure of the molecule. The posttranslatory modifications are essential for the formation of different polymeric forms (11). Recent data suggest that it is changes in the ratio of the high-molecular-weight (HMW) subform to total adiponectin rather than changes in total adiponectin that contribute to the improved insulin sensitivity observed in db/db mice and type 2 diabetic patients treated with glitazones (12).

Maintenance of normal adiponectin levels, or even induction of elevated levels, is considered to be beneficial as high levels have been associated with lower risk of myocardial infarction in healthy men (13). However, adiponectin levels are increased in chronic conditions with a clearly increased cardiovascular mortality such as type 1 diabetes (with or without nephropathy) (14), chronic heart failure (15), and end-stage renal disease (16). The reason for this puzzle remains unknown, but a possible explanation could be that in these chronic conditions an elevated adiponectin level represents a beneficial counterregulatory mechanism. Of note, the molecular distribution of adiponectin remains to be evaluated in these chronic conditions. To investigate the molecular distribution of adiponectin in patients with elevated total adiponectin levels, we compared type 1 diabetic patients with varying degrees of nephropathy to healthy controls.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Research design and patients

The study population consisted of 150 type 1 diabetic patients and 57 healthy controls examined in a cross-sectional design. Type 1 diabetes was defined as age at onset of diabetes younger than 35 yr and time to definite insulin therapy less than 1 yr. Overt diabetic nephropathy (macroalbuminuria) was defined as a persistent urinary albumin excretion rate (UAER) greater than 300 mg per 24 h in two of three consecutive measurements in sterile urines and presence of retinopathy and absence of other kidney or urinary tract diseases (17). Absence of diabetic nephropathy (normoalbuminuria) was defined as a persistent UAER less than 30 mg per 24 h after at least 15 yr of type 1 diabetes in patients not treated with renin-angiotensin system inhibitors like angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Incipient nephropathy (microalbuminuria) was defined as a UAER of 30–300 mg per 24 h. All patients gave written informed consent.

Baseline clinical and laboratory investigations

Blood pressure was measured twice in the resting state. From venous samples, plasma lipid levels were determined by standard methods. Hemoglobin (Hb) A1c was determined by standard HPLC techniques with normal values in the range from 4.1 to 6.4%. In addition to the previously performed daily urinary albumin collections, urinary albumin excretion was measured in a spot urine sample by an enzyme immunoassay and expressed as urinary albumin/creatinine ratio. Serum creatinine concentration was determined by an enzymatic method. Glomerular filtration rate (GFR) was estimated by the modification of diet in renal disease equation (18). End-stage renal disease was defined as kidney transplantation or dialysis. Diabetic retinopathy was assessed by fundus photography after pupillary dilatation and graded nil, simplex, and proliferative retinopathy, respectively. Based on standardized questionnaires, current smokers of one or more cigarettes/cigars/pipes per day were classified as smokers and all others as nonsmokers. Nonfatal cardiovascular disease was considered present in patients with a history of admission for stroke or myocardial infarction.

Fractioning of adiponectin

Materials A HiLoad 16/60 Superdex 200 prep grade column (GE Healthcare, Amersham Biosciences, Buckinghamshire, UK), a Smartline 1000 pump with a 10-ml titanium pump head, an Autosampler 3800 (Knauer, Berlin, Germany), and a fraction collector CHF122SB (Advantec, Dublin, CA) were used. As running buffer, PBS [50 mM phosphate, 150 mM NaCl, 0.2% (vol/vol) Tween 20, 0.2% (wt/vol) Na-Azide, 0.2% bovine serum albumin (pH 7.2)] was used.

Fast protein liquid chromatography running conditions

Samples were fractioned using a validated in-house fast protein liquid chromatography method as previously described (19). A sample size of 500 µl, consisting of 50 µl serum and 450 µl running buffer, was eluated with a flow of 1.0 ml/min. Samples were fractioned into 12 tubes of varying volumes, which were chosen to preserve the discrimination among the three subforms. The quality of the discrimination was tested using Western blotting. After separation, the three fractions yielded different bands of 70 kDa [low molecular weight (LMW) subform], 130 kDa [medium molecular weight (MMW) subform], and greater than 250 kDa (HMW subform). The fractions did not undergo any treatment before being assayed and all assays were performed less than 30 h after fractioning.

Adiponectin immunoassay

Serum concentrations of adiponectin subforms as well as total adiponectin were determined by a validated in-house time-resolved immunofluorometric assay as previously described (14). In brief, 96-well Delfia microtiter plates (PerkinElmer Life Sciences, Turku, Finland) were coated with a monoclonal antibody MAB 10651 (R&D Systems, Abingdon, UK) diluted in a phosphate buffer. After blocking, wells were washed once. Assay standards were made from recombinant human adiponectin. By dilution in assay buffer, a series of concentrations ranging from 2 to 1000 µg/liter were made. One hundred microliters of assay buffer containing second antibody (BAM 1065) and Streptavidin-europium in concentrations of 1:250 and 1:500 were added and the plates incubated for 3 h at room temperature. Afterward plates were washed six times before enhancement solution was added. A high, medium, and low control were included on each plate, and only assay runs with controls within given values were accepted.

Intra- and interassay variation

The intra- and interassay coefficient of variation (CV) for the adiponectin assay was less than 5% and less than 10%, respectively. Previously, the intraassay CVs corresponding to the HMW, MMW, and LMW fractions have been shown to be less than 4, 6, and 3%, respectively. The interassay CVs are less than 6, 12, and 7% for the HMW, MMW, and LMW fractions, respectively (19).

Statistical analyses

Comparison of clinical characteristics of the groups was done using ANOVA and Student’s t test as appropriate. Comparison of gender differences for adiponectin fractions was performed using Student’s t test. Nonnormally distributed variables were log transformed before analysis. Linear regression analyses were performed using Spearman’s rho multiple regression analysis was performed with total adiponectin and subforms as dependent variables and the clinical characteristics, which correlated significantly with adiponectin in univariate analyses, as independent variables. Total adiponectin and subforms were given as mean ± SEM in the figures and clinical characteristics were given as mean ± SD in the table. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Total adiponectin and subforms

The clinical characteristics of the study population are listed in Table 1Go. Of note, the four groups were similar with regard to sex and body mass index (BMI) (P = NS). Furthermore, the three diabetic groups were similar in diabetes duration (P = NS). The group with macroalbuminuria had a lower mean age (P < 0.005) and a higher percentage of smokers (P < 0.05) than the other diabetic groups. Significantly higher serum levels of total adiponectin were seen in type 1 diabetic patients when compared with healthy controls (P < 0.001) (Fig. 1Go). This difference was also seen when the participants was divided into men (P < 0.001) and women (P < 0.001) (Fig. 1Go). The elevated levels of total adiponectin were due to an increase in the concentrations of all three molecular isoforms, although the increase in HMW was the most pronounced (P < 0.001). The same pattern was seen in both men (Fig. 2AGo) and women (Figure 2BGo). The relative distribution of the three subforms was also different in type 1 diabetic patients when compared with controls because the HMW fraction was significantly up-regulated in type 1 diabetic patients (P < 0.001, data not shown). The MMW fraction was decreased in all three diabetic groups (P < 0.001), whereas the LMW fraction was decreased in normo- and microalbuminuria groups (P < 0.001). These data demonstrate that the rise in the HMW subform is the main contributor to the difference in total adiponectin between type 1 diabetic patients and healthy subjects.


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  		TABLE 1. Clinical characteristics of the study population

 

Figure 1
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  		FIG. 1. Unadjusted serum adiponectin levels in control and diabetic groups given in milligrams per liter. Black columns represent males plus females (n = 46–58 in each group), white columns males (n = 24–37 in each group), and gray columns females (n = 19–28 in each group). Data are given as mean + SEM. *, P < 0.001, compared with controls. Microalb, Microalbuminuria; Macroalb, macroalbuminuria; Normoalb, normoalbuminuria.

 

Figure 2
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  		FIG. 2. A, Unadjusted levels of molecular subforms of adiponectin in male subjects given in milligrams per liter. Black columns represent the HMW subform, white columns the MMW subform, and gray columns the LMW subform. Data are given as mean + SEM. *, P < 0.001, compared with controls. B, Unadjusted levels of molecular subforms of adiponectin in female subjects given in milligrams per liter. Black columns represent the HMW subform, white columns the MMW subform, and gray columns the LMW subform. Data are given as mean + SEM. *, P < 0.001, compared with controls. Microalb, Microalbuminuria; Macroalb, macroalbuminuria; Normoalb, normoalbuminuria.

 
Adiponectin and clinical characteristics

There was a clear sex difference as women had elevated levels of total adiponectin and absolute HMW, compared with men (P < 0.01), in all four groups. The relative HMW fraction was elevated as well in all groups except for the macroalbuminuric patients (P < 0.05). The clinical characteristics of men and women were compared: women had significantly lower age (P < 0.05) and GFR (P < 0.05) in the microalbuminuric group, lower GFR and Hb (P < 0.001) in the normoalbuminuric group, and lower Hb (P < 0.001), systolic blood pressure (sBP) (P < 0.001), GFR (P < 0.01) and BMI (P < 0.05) in the nondiabetic group. Despite the gender difference, an increase in absolute and relative HMW was seen in both male (P < 0.001) and female (P < 0.001) type 1 diabetic patients, compared with the control group.

Total adiponectin and absolute HMW closely correlated in all diabetic groups (r = 0.99; P < 0.001) and HMW correlated positively to age (r = 0.20, P = 0.014), diabetes duration (r = 0.26, P = 0.002), urinary albumin excretion (r = 0.22, P = 0.008), and serum cholesterol (r = 0.21, P = 0.012). Furthermore, HMW was negatively correlated to GFR (r = –0.32, P < 0.001), BMI (r = –0.38, P < 0.001), daily insulin dose (r = –0.30, P < 0.001), and Hb (r = –0.36, P < 0.001) in diabetic patients. Neither total adiponectin nor its subforms were correlated to sBP, blood glucose, HbA1c, antihypertensive medications, renin-angiotensin system inhibitors, statins, aspirin, alcohol, or smoking.

Adiponectin and microvascular complications

The unadjusted levels of HMW did not differ among the three diabetic groups (P = 0.14). Furthermore, a multiple linear regression analysis in diabetic patients with difference in absolute HMW as dependent variable and nephropathy status (normo-, micro-, or macroalbuminuria), and clinical variables correlated to HMW in univariate analyses as independent variables was performed. This analysis revealed no significant differences between groups of patients with different nephropathy status (P = 0.097) after adjustment for gender, duration of diabetes, BMI, serum cholesterol, and estimated GFR. Of the 150 diabetic patients, nine patients were without retinopathy, 41 had simplex retinopathy, and 100 had proliferative retinopathy. No correlations between total adiponectin, absolute or relative HMW, and retinopathy per se or retinopathy type were seen (P = NS).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The primary objective of the present study was to compare the distribution of adiponectin subforms in type 1 diabetic patients with varying degrees of nephropathy to healthy controls. Furthermore, the study population was divided into men and women to explore whether the changes were associated with gender differences. In addition, the study was designed to examine a potential correlation between adiponectin subforms and the presence of nephropathy. The major new finding of the present study is that the previously described increase in total adiponectin in type 1 diabetes is predominantly explained by a relative and absolute increase in the HMW subform. The increase in total and HMW adiponectin was largely unassociated with gender and nephropathy status and were not correlated to the presence or type of diabetic retinopathy.

Adiponectin has received increasing attention since its discovery a decade ago. A huge number of studies have appeared on the correlation between adiponectin and diet-induced obesity, type 2 diabetes, and coronary artery disease. A down-regulation in adiponectin has been shown in all these conditions, and this phenomenon has been suggested to contribute to the pathogenesis of these diseases. Furthermore, adiponectin has been shown to have insulin-sensitizing effects through activation of AMPK in the peripheral tissues (2). These effects include stimulation of fatty acid oxidation and glucose uptake in skeletal muscle and suppression of glucose production in the liver (20). In addition to its insulin-sensitizing actions, adiponectin has central actions in the regulation of energy homeostasis. Adiponectin enhances AMPK activity in the arcuate hypothalamus via its receptor adiponectin receptor 1 and stimulates food intake and decreases energy expenditure (21). Adiponectin has been shown to have antiatherosclerotic, antiinflammatory, and cardioprotective effects (1, 5, 6). Accordingly, adiponectin suppresses the expression of adhesion molecules in vascular endothelial cells and cytokine production from macrophages, thus inhibiting the inflammatory processes that occur during the early phases of atherosclerosis (22).

As mentioned above total adiponectin levels are decreased in type 2 diabetes, a finding that may be caused by a number of factors, e.g. central obesity, hyperinsulinemia, dyslipidemia, and hyperglycemia (23, 24, 25). However, several reports have shown that total adiponectin levels are increased in type 1 diabetic patients (14, 26, 27), a finding that was confirmed in the present study. Furthermore, we show for the first time that this elevation is due mainly to an increase in the HMW subform of adiponectin. It is well known that total adiponectin and relative HMW levels are higher in healthy adult females than healthy adult males. The main reason for this is probably that the levels of total adiponectin and the relative HMW fraction decrease during male puberty probably because of negative regulation by testosterone (19). The present study shows that the elevation of total adiponectin and HMW in type 1 diabetes is independent of gender, although women have higher levels than men in all groups.

The significance of the molecular distribution of adiponectin is still largely unknown. However, previously it has been shown that the HMW ratio has a stronger correlation to insulin sensitivity than total adiponectin (12), but this is not a consistent finding (28). In the present study, we found no correlation between total adiponectin or the HMW subform and metabolic control measured as HbA1c. However, it was confirmed that insulin dose and the HMW subform are negatively correlated. Moreover, our data are in agreement with the hypothesis that a change in the HMW subform is the most important contributor to the changes seen in total adiponectin.

In a previous study from our group, total adiponectin levels were higher in type 1 diabetes patients with than without microvascular complications (14). In the present study, we did not find a correlation between adiponectin and diabetic retinopathy. This may be due to the low number of patients without retinopathy. Only a weak association to nephropathy was demonstrated, indicating that adiponectin may not have a major impact on the development of diabetic nephropathy.

In conclusion, type 1 diabetic patients present with elevated total adiponectin levels, and herein we report for the first time that this elevation is due predominantly to an increase in the HMW subform. The increase in HMW was unaffected by renal status and gender, and no correlation to the presence of retinopathy was seen. Accordingly, future follow-up studies are needed to further clarify the role of adiponectin in type 1 diabetes.


   Acknowledgments
 
We thank Hanne Petersen for expert technical assistance.


   Footnotes
 
The study was supported by grants from the Danish Medical Research Council and the Danish Diabetes Association. H.L. held an Aarhus University-Novo Nordisk A/S-sponsored scholarship.

Disclosure Statement: H.L., K.K.A., and L.T. have nothing to declare. J.F. has been consultant for Hoffmann-La Roche and Pfizer Pharma, Germany. P.R. is consultant for MSD and has received lecture fees from Novartis. H.-H.P. has received consultant and lecture fees from Novartis and Sanofi-Aventis. A.F. is consultant for Hoffmann-La Roche and MSD and has received lecture fees from GlaxoSmithKline and Novo Nordisk A/S.

First Published Online May 27, 2008

Abbreviations: AMPK, AMP-activated protein kinase; BMI, body mass index; CV, coefficient of variation; GFR, glomerular filtration rate; Hb, hemoglobin; HMW, high molecular weight; LMW, low molecular weight; MMW, medium molecular weight; sBP, systolic blood pressure; UAER, urinary albumin excretion rate.

Received February 13, 2008.

Accepted May 16, 2008.


   References
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 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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L. L. Guo, Y. Pan, and H. M. Jin
Adiponectin is positively associated with insulin resistance in subjects with type 2 diabetic nephropathy and effects of angiotensin II type 1 receptor blocker losartan
Nephrol. Dial. Transplant., June 1, 2009; 24(6): 1876 - 1883.
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