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Elevated Levels of Mannan-Binding Lectin in Patients with Type 1 Diabetes

Medical Department M (T.K.H., S.T.K., C.H.G., J.S.C., C.E.M., P.L.P.), Aarhus University Hospital, and Department of Medical Microbiology and Immunology (S.T.), Aarhus University, DK-8000 Aarhus, Denmark

Address all correspondence and requests for reprints to: Troels Krarup Hansen, M.D., Ph.D., Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Norrebrogade 42-44, DK-8000 Aarhus C, Denmark. E-mail: tkh{at}dadlnet.dk.

	Abstract

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The hepatic protein mannan-binding lectin (MBL) activates the complement system on binding to carbohydrate patterns and is involved in first-line defense against invading microorganisms. Emerging evidence indicates that in some situations MBL may cause inexpedient complement activation and tissue injury through binding to endothelial glycosylations. MBL levels are suppressed by insulin treatment in critically ill patients, and, hypothetically, hepatic portal hypoinsulinemia could lead to increased levels of MBL in patients with type 1 diabetes. We measured MBL and C-reactive protein (CRP) levels in 132 normoalbuminuric type 1 diabetic patients and 66 healthy age- and sex-matched controls. The median MBL concentration was higher in diabetic patients than in healthy controls [1290 µg/liter (interquartile range, IQR 354-2961 µg/liter) vs. 970 µg/liter (IQR 277-1607 µg/liter), P = 0.025], whereas CRP concentrations were similar among patients and controls [1.42 mg/liter (IQR 0.95–2.21) vs. 1.21 mg/l (IQR 0.74–2.13), NS]. In diabetic subjects, CRP levels correlated with poor glycemic control as indicated by hemoglobin A_1c and daily insulin dose, which was not the case with MBL. MBL concentrations were positively correlated with urinary albumin excretion (r = 0.22; P = 0.013) and increased with increasing urinary albumin excretion tertile (P = 0.036). In conclusion, our data demonstrate that circulating MBL concentrations are significantly elevated in patients with type 1 diabetes and suggest a possible role of MBL in the pathogenesis of renovascular complications in diabetes.

	Introduction

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THE VASCULAR COMPLICATIONS of diabetes have been associated with a generalized chronic low-grade inflammation. The progression of such complications, e.g. atherosclerosis and nephropathy, varies substantially from one patient to another. Although the major part of this variation can be explained by differences in glycemic control and blood pressure (1), genetic predispositions may exist (2). Candidate polymorphisms must present a distinct phenotype, should be found with considerable frequency, and may primarily be associated with other diseases because it is unlikely that diabetic complications have exerted significant selection pressure during human evolution.

Mannan-binding lectin (MBL, also known as mannose-binding lectin) fulfills these criteria. MBL, which belongs to the family of C-type lectins, is synthesized in the liver and binds specifically to patterns of terminal nonreducing sugars in a calcium-dependent matter. When MBL binds to such carbohydrate structures, which predominantly exist on the surface of microorganisms, the complement cascade is activated through MBL-associated serine protease-1, -2, and -3 (3, 4, 5), and MBL thus plays an important role in the primary defense against invading microorganisms (6, 7, 8, 9). The median serum concentration of MBL in healthy Caucasians is 800-1000 µg/liter (9, 10), but because of point mutations within exon 1 as well as in the promoter region of the MBL gene, basal MBL levels cover several orders of magnitude. One third of the healthy population have MBL concentrations less than 500 µg/liter, and more than 10% have concentrations less than 50 µg/liter (10). The high prevalence of gene mutations has been interpreted as evidence of some biological advantage associated with low levels of MBL (11), and as demonstrated for other parts of the immune system, it is possible that the proinflammatory properties of MBL in some situations may be detrimental. Indeed, emerging evidence indicates that MBL may cause inexpedient complement activation and tissue injury following binding to endothelial glycosylations (12, 13).

We recently demonstrated that circulating MBL levels are suppressed by insulin (9). The aim of the present study was to evaluate circulating MBL levels in patients with type 1 diabetes.

	Subjects and Methods

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Subjects

Fasting blood samples were collected from patients with type 1 diabetes (n = 132) and healthy controls (n = 66) at a 2:1 ratio. Patients had to be normoalbuminuric [urinary albumin excretion (UAE) < 20 µg/min in three overnight collections obtained within a week] and without other chronic diseases. None received (or had earlier received) antihypertensive or other continuous medical treatment apart from insulin. Tobacco consumption was graded as nonsmokers (without daily use of tobacco for at least the last year), moderate smokers (less than 15 cigarettes per day), and heavy smokers (more than 15 cigarettes per day). Controls and patients were age and sex matched on a group basis. The study was approved by the local ethical committee, and informed consent was obtained from each subject before entering the study.

Analyses

UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 wk. Hemoglobin (Hb)A_1c was determined by routine HPLC (nondiabetic range, 4.4–6.4%). Serum MBL concentrations were measured using an in-house time-resolved immunofluorometric assay (14). In brief, microtiter wells were coated with mannan followed by incubation with diluted samples. After washing, monoclonal anti-MBL antibody (131-1, Immunolex, Copenhagen, Denmark, labeled with europium using reagents from Wallac Oy, Turku, Finland) was added, and after incubation and washing, the amount of bound labeled antibody was assessed by time-resolved fluorometry (Delphia, Wallac). Serum concentrations of C-reactive protein (CRP) were analyzed by ultrasensitive latex-enhanced immunotechniques (Cobas Integra 700, Hoffmann-La Roche Ltd., Basel, Switzerland).

Statistical methods

Differences between diabetic patients and controls were evaluated by means of Mann-Whitney U test. For noncontinuous variables the ² test with Yates’ correction was used. Patients were grouped according to UAE tertiles, and differences between the groups were evaluated using the Kruskal-Wallis test. Spearman correlation with two-tailed probability values was used to estimate the strength of association between variables. Data are given as means ± SD or medians with interquartile ranges (IQR), except for UAE, which is presented as geometric mean x/÷ tolerance factor. Statistical significance was assumed for P < 0.05. All statistical calculations were performed with SPSS for Windows (version 11.0, SPSS, Chicago, IL).

	Results

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Subjects

Baseline characteristics of diabetic patients and controls are given in Table 1. Age and sex distributions were identical among patients and controls. When patients were divided according to UAE tertiles, there were no significant differences between tertiles regarding sex distribution and diabetes duration, but subjects in the second tertile were older, had lower HbA_1c values, and received less insulin, compared with patients in the third but not the first tertile. Sixty-nine percent of the patients were nonsmokers, 16% were light smokers, and 15% were heavy smokers.

The median serum MBL concentration among diabetic patients was 1290 µg/liter (IQR 354-2961 µg/liter), compared with 970 µg/liter (IQR 277-1607 µg/liter) in healthy controls (P = 0.025). The frequencies of MBL levels above 800 µg/liter were 57% and 55% among diabetic subjects and healthy controls, respectively (Fig. 1). In a subanalysis of subjects with MBL concentrations above 800 µg/liter, the difference between diabetic patients and healthy controls was more pronounced [2598 µg/liter (IQR 1928–4890 µg/liter), compared with 1482 µg/liter (IQR 1062–2238 µg/liter), P < 0.00001], whereas there were no differences in MBL levels in a subanalysis of subjects with MBL concentrations less than 800 µg/liter [316 µg/liter (IQR 40–494 µg/liter) and 265 µg/liter (IQR 36–404 µg/liter) in diabetic subjects and healthy controls, respectively, NS].

View larger version (28K): [in this window] [in a new window]   FIG. 1. Distribution of serum MBL concentrations in healthy controls (dark gray) and normoalbuminuric type 1 diabetes patients (light gray). Each vertical drop-line represents one subject. The hatched line at 800 µg/liter indicates the putative cut-off level of subjects homozygous for the normal MBL allele.

There were no sex differences in MBL levels, whereas CRP concentrations were significantly higher in females than in males among diabetic patients [1.68 mg/liter (IQR 1.16–2.68) vs. 1.16 mg/liter (IQR 0.84–1.68), P < 0.001] but not among healthy subjects [1.21 mg/liter (IQR 0.74–2.00) vs. 1.21 mg/liter (IQR 0.76–2.13), NS]. MBL correlated negatively with age in the entire study population (r = -0.18, P = 0.012) but only tended to do so when diabetic patients and controls were considered separately (r = -0.17, P = 0.052; and r = -0.22, P = 0.074, respectively). MBL levels did not correlate with glycemic control as indicated by HbA_1c (r = 0.07, NS) or daily insulin dosage (r = -0.01, NS), and there were no differences in MBL levels among patients with different smoking habits. CRP levels did not correlate with age but increased with increasing HbA_1c (r = 0.26, P = 0.003) and increasing daily insulin dose (r = 0.22, P = 0.014). Among diabetic subjects CRP tended to increase with increasing tobacco consumption (P = 0.057). When male and female patients were considered separately, this relation was significant among males [1.05 mg/liter (IQR 0.74–1.47), 1.52 mg/liter (IQR 1.18–1.68), and 1.47 mg/liter (IQR 1.26–2.52) for nonsmokers, moderate smokers, and heavy smokers, respectively, P = 0.011] but not among females (NS).

There was a significant positive correlation between MBL and UAE in patients with diabetes (r = 0.22 P = 0.013) but not between UAE and CRP (r = 0.13, NS). The median MBL concentration increased with increasing UAE tertile (Fig. 2A), which was not the case with CRP (Fig. 2B). UAE was not different between male and female patients, and there was no correlations between UAE and age (r = -0.15, NS).

View larger version (13K): [in this window] [in a new window]   FIG. 2. Serum levels of MBL (A) and CRP (B) in healthy controls and normoalbuminuric type 1 diabetes patients divided according to UAE tertiles. Bars represent medians, and boxes indicate IQRs. P values refer to Kruskal-Wallis test for differences between groups.

	Discussion

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Interindividual differences in MBL levels are predominantly genetically determined by point mutations that occur with high incidence in the promoter region and within exon 1 of the MBL2 gene on chromosome 10. The median MBL concentration among healthy Caucasians is approximately 800-1000 µg/liter (sometimes reported as mean values 1000–1500 µg/liter) (9, 10, 15), but as a consequence of the genetic polymorphisms, approximately one third of the population have MBL concentrations less than 500 µg/liter, and more than 10% have concentrations less than 50 µg/liter (10). Serum levels may increase 2- to 3-fold during acute phase responses (9, 16) and following GH administration (15), but generally the within-subject variations of MBL concentrations are very small, compared with the genetically determined between-subject differences (15, 17). We have recently demonstrated a significant suppressive effect of intensive insulin treatment on circulating MBL levels in critically ill patients (9), an effect that was more than merely a consequence of the antiinflammatory effects of insulin because it was also present among patients without signs of infection. MBL is synthesized in the liver, and it seems conceivable that hepatic MBL expression is down-regulated by insulin. In type 1 diabetic patients, treatment with injectable preparations of insulin is associated with systemic hyperinsulinemia and hepatic portal hypoinsulinemia, which could offer an explanation to the marked differences in MBL concentrations between controls and diabetic patients observed in the present study.

Because MBL is a weak acute phase protein, another possible mechanism could be reactive up-regulation because of the existence of chronic low-grade inflammation, which has been documented in both type 1 and type 2 diabetic subjects (18, 19). However, we observed no significant differences in serum concentrations of the much more sensitive acute phase reactant CRP, and there was no correlation between MBL and CRP levels. In diabetic subjects, CRP correlated with markers of glycemic control, i.e. HbA_1c and daily insulin dose, which was not the case with MBL. Although the synthesis of MBL and CRP may be regulated by different stimuli, the lack of association between MBL and CRP levels speaks against a decisive role of chronic inflammation in the observed increased MBL levels, at least in our group of normoalbuminuric patients with relatively uncomplicated diabetes.

The subjects in our study were not genotyped for MBL polymorphisms. In theory, genetically determined high concentrations of MBL could be associated with an increased risk of developing type 1 diabetes, which would appear as higher MBL levels among diabetic patients. Because of nongenetic influences, it is not possible to predict MBL genotype with certainty from circulating MBL concentrations. In practice, however, a cut-off level of 800 µg/liter will identify subjects homozygous for the normal MBL allele (A/A genotype) with a sensitivity of 91% and a specificity of 95% in healthy Caucasians (10). The frequencies of MBL levels less than 800 µg/liter were identical in healthy individuals and diabetic subjects and comparable with previously reported data (10, 20), which indirectly indicate an equal distribution of MBL polymorphisms among the two groups. The elimination half-life of injected MBL is as long as 5–7 d (21), and as a whole it seems most likely that the elevated levels of MBL in diabetic subjects are a consequence of alterations at the transcriptional level, causing increased synthesis rather than differences in genotype or degradation rate. Interestingly, subanalyses including subjects with MBL concentrations either below or above 800 µg/liter revealed that the difference between diabetic patients and healthy controls was restricted to subjects with MBL levels above 800 µg/liter (and thus presumably carriers of the A/A genotype). This could suggest that the effect of insulin may be less pronounced in carriers of the mutant alleles, but studies of the relationship between MBL genotype and circulating MBL levels in diabetic patients are needed to clarify this further.

The present study was designed primarily to evaluate possible differences in MBL levels between diabetic patients and healthy controls, rather than to study the potential consequences thereof. Nevertheless, our finding of a significant positive correlation between MBL concentrations and UAE in normoalbuminuric patients may hint a role of MBL in the development of diabetic nephropathy. Several longitudinal studies have shown that high normal UAE is predictive of progression to microalbuminuria and overt nephropathy (22, 23, 24, 25, 26). MBL-mediated complement activation has been implicated in the pathogenesis of IgA nephropathy and Henoch-Schonlein purpura nephritis (27, 28), and recently significant elevations in MBL levels were reported in patients with chronic renal failure (29). MBL is considered an important component of innate immunity, and hitherto most studies have focused on the beneficial antiinfectious characteristics of the lectin. However, from an evolutionary point of view the high prevalence of gene mutations suggests a Jekyll-and-Hyde character of MBL, and high levels of MBL may thus in some situations confer biological disadvantages (11, 30). Normally, MBL does not recognize the body’s own tissues (31), but cellular hypoxia may change cell surface glycosylation leading to increased MBL deposition and complement activation (12, 32, 33), which may again aggravate the resulting ischemic injury (13). It is well known that diabetes is associated with nonenzymatic glycosylations, not only of hemoglobin but of a broad range of endothelial structures and circulating proteins and lipids (34). Whether these changes, in turn, cause increased MBL autoreactivity remain to be elucidated, but it may be hypothesized that increased levels of MBL contribute to a state of chronic inflammation in diabetic patients through increased activation of the complement system.

In summary, circulating concentrations of MBL were significantly elevated in patients with type 1 diabetes. MBL levels were positively correlated to UAE in normoalbuminuric patients, and we hypothesize that MBL-induced activation of complement might be involved in the pathogenesis of diabetic nephropathy and other diabetic vascular complications.

	Footnotes

 
Abbreviations: CRP, C-reactive protein; Hb, hemoglobin; IQR, interquartile range; MBL, mannan-binding lectin; UAE, urinary albumin excretion.

Received April 28, 2003.

Accepted July 7, 2003.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hansen, T. K. Articles by Poulsen, P. L. Search for Related Content PubMed PubMed Citation Articles by Hansen, T. K. Articles by Poulsen, P. L.