Association between mannose-binding lectin and vascular complications in type 1 diabetes

Complement activation and inflammation have been suggested in the pathogenesis of diabetic vascular lesions. We investigated serum mannose-binding lectin (MBL) levels and polymorphisms in the MBL gene in type 1 diabetic patients with and without diabetic nephropathy and associated macrovascular complications. Polymorphisms in the MBL gene and serum MBL levels were determined in 199 type 1 diabetic patients with overt nephropathy and 192 type 1 diabetic patients with persistent normoalbuminuria matched for age, sex, and duration of diabetes, as well as in 100 healthy control subjects. The frequencies of high- and low-expression MBL genotypes were similar in patients with type 1 diabetic and healthy control subjects. High MBL genotypes were significantly more frequent in diabetic patients with nephropathy than in the normoalbuminuric group, and the risk of having nephropathy given a high MBL genotype assessed by odds ratio (OR) was 1.52 (1.02-2.27, P = 0.04). Median serum MBL concentrations were significantly higher in patients with nephropathy than in patients with normoalbuminuria: 2,306 microg/l (interquartile range [IQR] 753-4,867 microg/l) vs. 1,491 microg/l (577-2,944 microg/l), P = 0.0003. In addition, even when comparing patients with identical genotypes, serum MBL levels were higher in the nephropathy group than in the normoalbuminuric group. Patients with a history of cardiovascular disease had significantly elevated MBL levels independent of nephropathy status (3,178 microg/l [IQR 636-5,231 microg/l] vs. 1,741 microg/l [656-3,149 microg/l], P = 0.02). The differences in MBL levels between patients with and without vascular complications were driven primarily by pronounced differences among carriers of high MBL genotypes (P < 0.0001). Our findings suggest that MBL may be involved in the pathogenesis of micro- and macrovascular complications in type 1 diabetes, and that determination of MBL status might be used to identify patients at increased risk of developing these complications.     

Serum Uric Acid as a Predictor for Development of Diabetic Nephropathy in Type 1 Diabetes: An Inception Cohort Study

OBJECTIVE

Experimental and clinical studies have suggested that uric acid may contribute to the development of hypertension and kidney disease. Whether uric acid has a causal role in the development of diabetic nephropathy is not known. The objective of the present study is to evaluate uric acid as a predictor of persistent micro- and macroalbuminuria.

RESEARCH DESIGN AND METHODS

This prospective observational follow-up study consisted of an inception cohort of 277 patients followed from onset of type 1 diabetes. Of these, 270 patients had blood samples taken at baseline. In seven cases, uric acid could not be determined; therefore, 263 patients (156 men) were available for analysis. Uric acid was measured 3 years after onset of diabetes and before any patient developed microalbuminuria.

RESULTS

During a median follow-up of 18.1 years (range 1.0–21.8), 23 of 263 patients developed persistent macroalbuminuria (urinary albumin excretion rate >300 mg/24 h in at least two of three consecutive samples). In patients with uric acid levels in the highest quartile (>249 μmol/l), the cumulative incidence of persistent macroalbumnuria was 22.3% (95% CI 10.3–34.3) compared with 9.5% (3.8–15.2) in patients with uric acid in the three lower quartiles (log-rank test, P = 0.006). In a Cox proportional hazards model with sex and age as fixed covariates, uric acid was associated with subsequent development of persistent macroalbuminuria (hazard ratio 2.37 [95% CI 1.04–5.37] per 100 μmol/l increase in uric acid level; P = 0.04). Adjustment for confounders did not change the estimate significantly.

CONCLUSIONS

Uric acid level soon after onset of type 1 diabetes is independently associated with risk for later development of diabetic nephropathy.Diabetes is the leading cause of end-stage renal disease (ESRD) in the Western world, and the number of patients diagnosed each year with ESRD due to diabetes is rising (1). The complex pathogenesis for the development of diabetic nephropathy is not fully understood (2). One factor that has been associated with cardiovascular and renal disease is serum uric acid. Recently, experimental and clinical studies have suggested that uric acid may contribute to the development of hypertension, the metabolic syndrome, and kidney disease (3). The role of uric acid in the development of diabetic nephropathy is not understood. The objective of the present study is therefore to evaluate uric acid as a predictor of persistent micro- and macroalbuminuria in an inception cohort of type 1 diabetic patients followed from onset of diabetes.     

Increased levels of alpha-defensin (-1, -2 and -3) in type 1 diabetic patients with nephropathy.

OBJECTIVE: Diabetic nephropathy is associated with low-grade inflammation and activation of the complement system. Defensins, as part of the innate immune system, may play a regulatory role in the complement cascade and may also augment the production of proinflammatory cytokines. The aim of this study was therefore to elucidate whether alpha-defensin is associated with diabetic nephropathy, low-grade inflammation and lipid profiles. RESEARCH DESIGN AND METHODS: Data were obtained from 189 patients with type 1 diabetes selected from the FinnDiane Study. Patients were divided into three groups according to their albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: normoalbuminuria (AER <20 microg/min or <30 mg/24 h), microalbuminuria (20 200 microg/min or >300 mg/24 h). Alpha-defensin was determined by a novel, solid-phase radioimmunoassay (RIA) based on a monoclonal antibody, which recognizes alpha-defensin isoforms 1-3. RESULTS: Total serum alpha-defensin (-1, -2 and -3) concentrations were higher (P < 0.001) in patients with macroalbuminuria compared to micro- and normoalbuminuria, but no difference was observed between normoalbuminuria and microalbuminuria. In multiple linear regression analysis alpha-defensin was associated with systolic blood pressure (P = 0.032), HDL-cholesterol (P = 0.013), total cholesterol (P = 0.008), age (P = 0.001) and estimated glomerular filtration rate (P = 0.001), but not with low-grade inflammatory markers. CONCLUSIONS; Serum alpha-defensin (-1, -2 and -3) concentrations are increased in type 1 diabetic patients with diabetic nephropathy.     

Familial clustering of diabetic nephropathy in Brazilian type 2 diabetic patients

There is evidence for genetic predisposition to diabetic nephropathy in type 1 diabetic patients. However, there are few studies on type 2 diabetic patients, and most of those have been conducted on ethnic minorities or Caucasian individuals. The aim of this study was to ascertain the presence of an inherited predisposition to diabetic nephropathy in a sample of Brazilian type 2 diabetic patients. Families with two or more type 2 diabetic siblings were identified. Subjects with the longest duration of known diabetes were considered probands. Some 90 probands and their 107 diabetic siblings were studied. Urinary albumin excretion rate was measured in a sterile 24-h urine sample on at least three different occasions. Probands and siblings were classified according to urinary albumin excretion rate as normo- (<20 microg/min), micro- (20-200 microg/min), or macroalbuminuric (>200 microg/min). Patients with end-stage renal disease were included in the macroalbuminuric group. Macroalbuminuria was identified in 5.2% of the siblings of normoalbuminuric probands and in 24.1% of the siblings of macroalbuminuric probands (P = 0.024). In multiple logistic regression, the presence of diabetic nephropathy in probands (micro- or macroalbuminuria and end-stage renal disease) was significantly associated with the presence of sibling diabetic nephropathy (odds ratio = 3.75, 95% CI = 1.36-10.40, P = 0.011) adjusted for proband fasting plasma glucose and diabetes duration. Interpretation of these results should take into account the possibility that the families including siblings with diabetic nephropathy may have been overcounted and, on the other hand, that the siblings without diabetic nephropathy may have been undercounted. In conclusion, there is a familial aggregation of diabetic nephropathy in this sample of type 2 diabetic patients.     

How to predict nephropathy in type 1 diabetic patients

OBJECTIVE: Do exaggerated increases in blood pressure and albuminuria during exercise occur earlier than microalbuminuria and which type of test is most predictive of diabetic nephropathy? MATERIAL AND METHODS: A total of 33 insulin-dependent normoalbuminuric men (mean duration of diabetes 14 years; mean age 28 years) and 34 age-matched apparently healthy control subjects were studied. Urinary albumin excretion, heart rate and blood pressure were measured during fixed workload (150 W) and fixed heart rate (155 beats/min) tests. Mean follow-up time was 13.1 +/- 3.2 years. A urinary albumin level in early-morning urine persistently >30 mg/l was considered a sign of diabetic nephropathy. RESULTS: Sixteen patients reached the endpoints of the study. Eleven had developed microalbuminuria and five macroalbuminuria (persistent levels of urinary albumin >300 mg/l). Of the latter patients, two needed dialysis. Systolic blood pressure and albumin excretion during the fixed heart rate test were higher in diabetic patients who developed signs of nephropathy than in control subjects and diabetic subjects with persistent healthy kidneys. Such differences were not found in the fixed workload test. There were no differences in glycated haemoglobin, blood pressure levels or albumin excretion at baseline between the two diabetic groups. CONCLUSIONS: To predict the development of diabetic nephropathy it seems important to choose a fixed heart rate test. High levels of systolic blood pressure in such a test were associated with the development of micro- and macroalbuminuria.     

Racial and ethnic differences in microalbuminuria prevalence in a diabetes population: the pathways study

The objective of this study was to determine whether racial or ethnic differences in prevalence of diabetic microalbuminuria were observed in a large primary care population in which comparable access to health care exists. A cross-sectional analysis of survey and automated laboratory data 2969 primary care diabetic patients of a large regional health maintenance organization was conducted. Study data were analyzed for racial/ethnic differences in microalbuminuria (30 to 300 mg albumin/g creatinine) and macroalbuminuria (>300 mg albumin/g creatinine) prevalence among diabetes registry-identified patients who completed a survey that assessed demographics, diabetes care, and depression. Computerized pharmacy, hospital, and laboratory data were linked to survey data for analysis. Racial/ethnic differences in the odds of microalbuminuria and macroalbuminuria were assessed by unconditional logistic regression, stratified by the presence of hypertension. Among those tested, the unadjusted prevalence of micro- or macroalbuminuria was 30.9%, which was similar among the various racial/ethnic groups. Among those without hypertension, microalbuminuria was twofold greater (odds ratio [OR] 2.01; 95% confidence interval [CI] 1.14 to 3.53) and macroalbuminuria was threefold greater (OR 3.17; 95% CI 1.09 to 9.26) for Asians as compared with whites. Among those with hypertension, adjusted odds of microalbuminuria were greater for Hispanics (OR 3.82; 95% CI 1.16 to 12.57) than whites, whereas adjusted odds of macroalbuminuria were threefold greater for blacks (OR 3.32; 95% CI 1.26 to 8.76) than for whites. For most racial/ethnic minorities, hypertriglyceridemia was significantly associated with greater odds of micro- and macroalbuminuria. Among a large primary care population, racial/ethnic differences exist in the adjusted prevalence of microalbuminuria and macroalbuminuria depending on hypertension status. In this setting, racial/ethnic differences in early diabetic nephropathy were observed despite comparable access to diabetes care.     

Elevated levels of plasma von Willebrand factor and the risk of macro- and microvascular disease in type 2 diabetic patients with microalbuminuria.

BACKGROUND: The purpose of this study was to examine the concept suggesting that microalbuminuria in combination with high levels of plasma von Willebrand factor is a stronger predictor for cardiovascular disease and microvascular complications than microalbuminuria alone in type 2 diabetic patients. METHODS: One hundred and sixty patients with type 2 diabetes mellitus and persistent microalbuminuria were followed for an average of 3.8 (SD 0.3) years. 70% of the patients were treated with angiotensin converting enzyme (ACE)-inhibitors. Patients in this subanalysis were divided into two groups according to baseline plasma von Willebrand factor levels below or above the median. The main outcome was cardiovascular disease (cardiovascular mortality, non-fatal stroke, non-fatal myocardial infarction, coronary artery bypass graft and revascularization or amputation of legs), progression to diabetic nephropathy or progression in diabetic retinopathy. RESULTS: At baseline the two groups were comparable for HbA(1c), fasting levels of s-total-cholesterol, s-HDL-cholesterol and s-triglycerides, systolic and diastolic blood pressure, gender, known diabetes duration, smoking habits, previous cardiovascular disease and antihypertensive therapy as well as retinopathy. Odds ratio for cardiovascular disease was 1.11 (95% CI 0.45-2.73, P=0.82) (multiple logistic regression), odds ratio for progression to nephropathy was 1.08 (0.41-2.85, P=0.87) and odds ratio for progression in retinopathy was 0.96 (0.46-2.00, P=0.92), all with plasma von Willebrand factor levels above the median. CONCLUSIONS: Our results do not support the suggestion that the combination of high plasma levels of von Willebrand factor and microalbuminuria is a stronger predictor for cardiovascular disease, progression to diabetic nephropathy or progression in diabetic retinopathy than microalbuminuria alone in patients with type 2 diabetes and persistent microalbuminuria.     

Urinary sulphated glycosaminoglycans and Tamm-Horsfall protein in type 1 diabetic patients

OBJECTIVE: In diabetic nephropathy there is a decrease in glycosaminoglycans (GAG) in basement membranes and in Tamm-Horsfall protein (THP) in the distal tubules of the kidneys. Since GAG is present in both glomerular and tubular basement membranes, and the synthesis of both GAG and THP involves glycosylation, this study was carried out in order to investigate whether urinary excretion of these substances is interrelated. MATERIAL AND METHODS: 24-h urinary collections were analysed. A total of 94 diabetic patients were grouped in accordance with the urinary albumin excretion rate as normo- (<20 microg/min) (n = 35), micro- (20-200 microg/min) (n = 30) and macroalbuminuria (>200 microg/min) (n = 29). RESULTS: In comparison with 26 control subjects, the excretion rate of GAG was decreased in patients with micro- and macroalbuminuria and excretion of Tamm-Horsfall protein in patients with macroalbuminuria. The excretion rates of GAG and THP were associated (r = 0.64, p < 0.001) and correlated with creatinine clearance (r= 0.46 and r= 0.53, p < 0.001; respectively) but not with levels of HbA1c. CONCLUSIONS: In conclusion, albuminuria was associated with decreased urinary excretion of sulphated GAGs, which was associated with the excretion rate of Tamm-Horsfall protein, indicating that excretion of GAG was associated with distal tubular dysfunction in diabetic patients.     

Insulin resistance and microalbuminuria: a cross-sectional, case-control study of 158 patients with type 2 diabetes and different degrees of urinary albumin excretion

Microalbuminuria is a risk factor for renal and cardiovascular disease. A role for insulin resistance in the pathogenesis of microalbuminuria has been suggested but is still unproven. In this case-control, cross-sectional study, we compared glucose disposal rate (GDR), measured by hyperinsulinemic-euglycemic clamp, in 50 pairs of matched type 2 diabetic patients with micro- or normoalbuminuria (main study) and in 29 matched pairs of diabetic patients with macro- or microalbuminuria (substudy). In the main study, GDR was approximately 25% lower in micro- than in normoalbuminuric patients (5.20 +/- 1.91 vs. 6.86 +/- 2.88 mg . kg(-1) . min(-1), P < 0.05) and was independently associated with microalbuminuria (P = 0.002), with each 1 mg . kg(-1) . min(-1) decrease predicting approximately 40% increased prevalence (odds ratio 1.37 [95% CI 1.14-1.70]). Microalbuminuria was threefold more frequent in patients with GDR < or =7.50 +/- 2.56 mg . kg(-1) . min(-1) than in those with higher GDR (60% vs. 20%, P < 0.005). In the substudy, GDR in macro- and microalbuminuric patients was comparable (5.52 +/- 2.56 vs. 5.16 +/- 1.61 mg . kg(-1) . min(-1)) and independent of macroalbuminuria. GDR was significantly correlated with urinary albumin excretion rate in the main study (P = 0.004) but not in the substudy (P = 0.60). In type 2 diabetes, more severe insulin resistance is independently associated with microalbuminuria. Longitudinal studies are needed to clarify the role of insulin resistance in the pathogenesis of microalbuminuria and related complications.     

Low pretransplantation mannose-binding lectin levels predict superior patient and graft survival after simultaneous pancreas-kidney transplantation

Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice for patients with type 1 diabetes and renal failure. However, this procedure is characterized by a high rate of postoperative infections, acute rejection episodes, and cardiovascular mortality. The lectin pathway of complement activation contributes to cardiovascular disease in diabetes and may play an important role in inflammatory damage after organ transplantation. This study therefore sought to determine how mannose-binding lectin (MBL), a major recognition molecule of the lectin pathway of complement activation, influences outcome after SPKT. MBL serum levels were determined in 99 and MBL genotypes in 97 consecutive patients who received an SPKT from 1990 through 2000 and related to patient and graft survival. At 12 yr, cumulative death-censored kidney graft survival was 87.5% in patients with an MBL level <400 ng/ml and 74.8% in the group with MBL levels >400 ng/ml (P = 0.021). Pancreas graft survival was significantly better in patients with low MBL levels (P = 0.016). MBL levels >400 ng/ml were associated with a hazard ratio of 6.28 for patient death (95% confidence interval 1.8 to 20.3; P = 0.003). Accordingly, survival was significantly better in recipients with MBL gene polymorphisms associated with low MBL levels. These findings identify MBL as a potential risk factor for graft and patient survival in SPKT. It is hypothesized that MBL contributes to the pathogenesis of inflammation-induced vascular damage both in the transplanted organs and in the recipient's native blood vessels.     

Prevalence and risk factors for micro- and macroalbuminuria in diabetic subjects and entire population of Nauru

Rates of elevated urinary albumin concentration, defined as microalbuminuria (30-299 micrograms/ml) and macroalbuminuria (greater than or equal to 300 micrograms/ml), were determined on random morning urine specimens in the population of Nauru, which has a high prevalence of non-insulin-dependent diabetes mellitus. The prevalence of elevated urinary albumin levels in the total Nauruan population was very high: 26 and 30% of men and women, respectively, had microalbuminuria, whereas 13% of both sexes had macroalbuminuria. Of the subjects with macroalbuminuria, 66% had diabetes. The prevalence increased with worsening glucose tolerance; 26% of subjects with normal glucose tolerance had either micro- or macroalbuminuria, increasing to 43% of subjects with impaired glucose tolerance, 63% of newly diagnosed diabetic subjects, and 75% of previously diagnosed diabetic subjects. Associations between elevated urinary albumin concentration and putative risk factors were assessed for both the total population (n = 1184) and the diabetic subgroup alone (n = 318). Fasting plasma glucose and hypertension were the most important independent correlates for the whole population, whereas plasma creatinine was also important in diabetic subjects. Age at onset and duration of diabetes were not found to be significantly associated with elevated albumin concentration. In subjects with normal glucose tolerance, hypertension and hyperuricemia were the most important associated factors. These results suggest that blood glucose, blood pressure, and possibly obesity and plasma uric acid are important modifiable risk factors for both micro- and macroalbuminuria in this population.     

Significant elevations in serum mannose-binding lectin levels in patients with chronic renal failure

BACKGROUND/AIMS: Mannose-binding lectin (MBL), a liver-derived C-type serum lectin, activates the complement cascade through the lectin pathway. Since the complement system contributes to the host defense against infections and mediates inflammatory processes including atherosclerosis, and since chronic renal failure (CRF) patients are prone to the development of infectious complications and cardiovascular disease, we focused on serum MBL levels in CRF patients who were either uremic, or who were receiving hemodialysis treatment. METHODS: MBL levels were measured in the sera of subjects with CRF before they began dialysis treatment (pre-HD patients; n = 23) and in the sera of subjects who were receiving maintenance hemodialysis (HD patients; n = 178), by ELISA using polyclonal anti-rabbit IgG and a monoclonal antibody directed against MBL (3E7). METHODS: Mean levels (+/- SD) of serum MBL were significantly higher in pre-HD subjects (4.343 +/- 2.533 microg/ml, p < 0.05) and in HD subjects (8.897 +/- 4.920 microg/ml, p < 0.05), than in healthy controls (1.452 +/- 0.692 microg/ml). Levels were also significantly higher in HD subjects than in pre-HD subjects (p < 0.05). CONCLUSIONS: Elevated serum MBL levels in patients with CRF might have significantly influence pathologic conditions such as alterations of the immune system and acceleration of atherogenesis.     

Prevalence of raised sodium-lithium countertransport activity in type 1 diabetic patients.

The prevalence of raised Na+/Li+ countertransport (CT) activity (greater than 0.41 mmol/liter RBC/hr) was assessed in 185 consecutive insulin-dependent diabetic patients attending an outpatient diabetic clinic. Normoalbuminuria was defined as an overnight albumin excretion rate (AER) of less than 20 micrograms/min (N = 121), microalbuminuria as AER between 20 and 150 micrograms/min (N = 35) and macroalbuminuria as AER greater than or equal to 150 micrograms/min (N = 29). The prevalence of elevated Na+/Li+CT (greater than 0.41 mmol/liter RBC/hr) was 21.5, 42.8 and 51.7% (P = 0.0005), in patients with normo-, micro- and macroalbuminuria, respectively. In the whole group, Na+/Li+CT was significantly related to mean blood pressure (MBP; rs = 0.37, P less than 0.001) and AER (rs = 0.38, P less than 0.001). In a multiple regression analysis the significant correlates of AER, as a continuous variable, or of proteinuria (micro + macroalbuminuria), as a categorical variable, were Na+/Li+CT, MBP, duration of diabetes and glycosylated hemoglobin (HbA1). The frequency of normoalbuminuric patients with high Na+/Li+CT activity fell with duration of diabetes. The risk of proteinuria was significantly greater in patients with raised Na+/Li+CT compared to those with Na+/Li+CT within the normal range (odds ratio 3.8, 95% CI, 1.9 and 7.8). A relative excess of patients with proteinuria (micro + macroalbuminuria) was found in the group with elevated Na+/Li+CT and HbA1 above the median value (8.05%) of the whole population (chi 2 = 9.7, P less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)     

Platelet glycoprotein IIIa PlA1/A2 polymorphism and its relationship with diabetic nephropathy in type 2 diabetic patients

OBJECTIVE: The increased prevalence of cardiovascular events in type 2-diabetic patients with micro- or macroalbuminuria is not completely explained by an excess of conventional risk factors for atherosclerosis. Genetic polymorphism within the platelet glycoprotein IIIa has been implicated in the etiology of acute coronary syndromes. We tested the hypothesis that the PI(A1/A2) polymorphism could in part account for the increased cardiovascular risk of type 2-diabetic patients with micro- or macroalbuminuria compared to normoalbuminuric diabetic patients. RESEARCH DESIGN AND METHODS: We have examined the PI(A1/A2) polymorphism of the platelet glycoprotein IIIa in type 2-diabetic patients: 94 with micro-, macroalbuminuria, and 94 with normoalbuminuria, matched for age, sex and body mass index. PI(A) genotypes were performed by polymerase chain reaction and restriction enzyme digestion. RESULTS: There was no significant difference in the prevalence of PI(A2)-positive genotypes (either PI(A1/A2) or PI(A2/A2)) in the two groups of patients (chi2 = 0.19, df = 1 , p = 0.66). CONCLUSIONS: These results suggest that carriage of the platelet glycoprotein IIIa PI(A2) allele does not contribute to explain the increased cardiovascular risk associated with micro- or macroalbuminuria in type 2 diabetes.     

Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type-1 diabetic patients.

BACKGROUND: Predictors of diabetic nephropathy are only partly known. The role of glomerular hyperfiltration is much discussed. We have studied the cumulative incidence of micro and macroalbuminuria and the predictive value of glomerular filtration rate (GFR) and screening value of albumin excretion rate (AER) in type-1 diabetes. METHODS: A cohort of diabetic children was followed up at a mean duration of 29+/-3 years. All 75 children treated in one hospital with diabetes duration > or =8 years were prospectively followed for 8 years examining GFR, AER, blood pressure and HbA1c. After another 8-10 years, 60 of them were traced for endpoint follow-up. RESULTS: Seven patients (12%) developed macroalbuminuria, i.e. persistent overnight AER>200 mg/min, 12 (20%) developed persistent microalbuminuria (AER 15-200 mg/min) and 17 (28%) transient microalbuminuria (>15 mg/min on two consecutive occasions, normalized at endpoint). One baseline screening value of 24-h AER>15 mg/min predicted 93% of patients with persistent micro or macroalbuminuria. The negative predictive value was 78%. Six of seven macroalbuminuric and 10 of 12 microalbuminuric patients had a baseline GFR above the normal limit of the method (> or =125 ml/min/1.73 m(2)). When adjusted for diabetes duration, increased GFR predicted macro or microalbuminuria (odds ratios=5.44, P=0.04). The positive predictive value for having an increased baseline GFR was 53%.The negative predictive value was 77%. Stratification for HbA1c did not change the effect of an increased GFR. CONCLUSIONS: At a mean diabetes duration of 29 years the cumulative incidence of macroalbuminuria was 12%; however, another 20% had persistent microalbuminuria. A screening value of 24-h AER >15 mg/min was a strong predictor, whereas increased GFR was a weaker but significant predictor for micro and macroalbuminuria.     

Elevated MBL Concentrations Are Not an Indication of Association Between the MBL2 Gene and Type 1 Diabetes or Diabetic Nephropathy

OBJECTIVE

Mannose-binding lectin (MBL) is an essential component of the acute-phase immune response and may thus play a role in the pathogenesis of type 1 diabetes and diabetic nephropathy. The serum concentration of MBL is mainly genetically determined, and elevated concentrations have been associated with both type 1 diabetes and diabetic nephropathy. Previous genetic studies have not been conclusive due to the small number of patients and polymorphisms studied. We investigated whether MBL2 polymorphisms are associated with type 1 diabetes or diabetic nephropathy and whether patients with nephropathy have elevated MBL concentrations as indicated previously. Furthermore, we studied the association between MBL2 polymorphisms and MBL concentration.

RESEARCH DESIGN AND METHODS

We genotyped 20 MBL2 single nucleotide polymorphisms (SNPs) in a large, well-characterized Finnish case-control sample consisting of 1,297 patients with type 1 diabetes with or without nephropathy and 701 nondiabetic individuals. The serum concentration of MBL was available for 1,064 patients.

RESULTS

We found that 19 SNPs were associated with the MBL concentration (P = 3 × 10⁻⁸¹–7 × 10⁻⁴). MBL concentrations were higher in patients with macroalbuminuria compared with patients without nephropathy even when the patients were stratified by the MBL2 genotypic background in accordance with previous studies. However, no evidence of association between any of the SNPs or their haplotype combinations and type 1 diabetes or diabetic nephropathy was observed.

CONCLUSIONS

Although most of the MBL2 SNPs studied were associated with the MBL concentration, no common variations (neither single SNPs nor their haplotype combinations) confer risk of type 1 diabetes or diabetic nephropathy.Diabetic nephropathy is a common and devastating long-term complication of diabetes, but its pathogenesis is poorly understood. Low-grade inflammation and complement activation may, however, play a role in the pathogenesis of both type 1 diabetes and its complications (1–3). Mannose-binding lectin (MBL) is a C-type lectin secreted by the liver as a component of the acute-phase immune response, and its binding to carbohydrate structures on microorganisms activates the MBL complement pathway (4,5).Serum concentrations of MBL are significantly elevated in patients with type 1 diabetes (1,2) and even more elevated in those patients with micro- and macrovascular complications (6,7). Moreover, high MBL concentrations early in the course of type 1 diabetes predict later development of micro- or macroalbuminuria (8), and MBL deficiency attenuates renal changes in mice with experimentally induced diabetes (9).The MBL2 gene (OMIM# +154545) on chromosome 10q21 consists of five exons, four of which are protein coding (10,11). The serum concentration of MBL is largely genetically determined (estimated heritability 0.96), and substantial interindividual variation exists (12). Three nonsynonymous variants in exon 1 named alleles B (G54D/rs1800450), C (G57E/rs1800451), and D (R52C/rs5030737) decrease MBL concentration considerably due to incorrect assembly of the mature MBL protein (13). Furthermore, several single nucleotide polymorphisms (SNPs), especially promoter variants H/L (rs11003125), P/Q (rs7095891), and X/Y (rs7096206), modify the MBL concentration (13). Based on linkage disequilibrium (LD) between these six promoter and exon 1 variants, seven common MBL2 haplotypes can be identified (13).The low-expression MBL2 variant carriers have an increased infection risk in situations of impaired immunity (14), and the role of MBL2 in various autoimmune diseases has been actively studied (15,16). Previous studies on the relationship between MBL2 and type 1 diabetes show contradictory results (1,6,17–19). This may be due to the fact that only a few polymorphisms were studied in relatively small samples, except in the Finnish study of 470 patients (17). Only the Danish study had nephropathy status available and reported association between the high-expression MBL2 genotypes and diabetic nephropathy (6). Thus, the question whether genetic variation in the MBL2 gene confers susceptibility to type 1 diabetes or diabetic nephropathy is still warranted.Here, we studied whether the MBL2 gene polymorphisms are associated with type 1 diabetes or diabetic nephropathy by genotyping a dense set of SNPs in a large well-characterized Finnish case-control sample and evaluated the association between MBL concentration and diabetic nephropathy.     

Plasminogen activator inhibitor-1 and apolipoprotein E gene polymorphisms and diabetic angiopathy.

BACKGROUND: A point mutation in the plasminogen activator inhibitor-1 (PAI-1) gene and a three-allelic variation in the apolipoprotein-E (ApoE) gene have been suggested as risk factors for the development of diabetic micro- and macrovascular complications. METHODS: We studied 198 type 1 diabetic patients with diabetic nephropathy [121 men, age (mean+/-SD) 41+/-10 years, diabetes duration 28+/-8 years] and 192 patients with persistent normoalbuminuria (118 men, age 43+/-10 years, diabetes duration 27+/-9 years). RESULTS: Male patients with nephropathy had elevated plasma PAI-1 levels [geometric mean (95% CI)], 70 (62-79) ng/ml, compared with normoalbuminuric men, 43 (38-47) ng/ml, P<0.001. Even though nephropathic patients with the 4G4G genotype tended to have higher plasma PAI-1 levels, P=0.06, no difference in allele frequency (4G/5G) was seen between patients with and without nephropathy: 0.538/0.462 vs 0.539/0.461, respectively. Nor did ApoE allele frequencies (epsilon2/epsilon3/epsilon4) differ between nephropathic and normoalbuminuric patients: 0.099/0.749/0. 152 vs 0.081/0.745/0.174, respectively. Genotype distributions were also similar, n.s. Coronary heart disease was more prevalent (36%) among nephropathic patients carrying the atherogenic epsilon4-allele compared with 12% in patients with the epsilon3,epsilon3 genotype, P<0.001. No associations between diabetic retinopathy and PAI-1 or ApoE polymorphisms were observed, n.s. CONCLUSIONS: The ApoE polymorphism may accelerate the development of coronary heart disease often seen in Caucasian patients with type 1 diabetes and diabetic nephropathy, a condition characterized by elevated plasma PAI-1 in men. Neither the PAI-1 nor the ApoE gene polymorphism contributes to the genetic susceptibility to diabetic nephropathy or retinopathy.     

Relationship between serum Dickkopf-1 and albuminuria in patients with type 2 diabetes

BACKGROUND Diabetic kidney disease is a microvascular complication of diabetes with complex pathogenesis. Wingless signaling-mediated renal fibrosis is associated with diabetic kidney disease. Dickkopf-1, a negative regulator of Wingless, has been proven to participate in renal fibrosis, glucose metabolism, and inflammation. However, whether serum Dickkopf-1 levels are associated with diabetic kidney disease remains unclear.AIM To assess the relationship between serum Dickkopf-1 levels and albuminuria in individuals with type 2 diabetes.METHODS Seventy-three type 2 diabetes patients and 24 healthy individuals were enrolled in this case-control study. Diabetic individuals were separated into normal albuminuria, microalbuminuria, and macroalbuminuria groups based on their urinary albumin/creatinine ratios(UACRs). Clinical characteristics and metabolic indices were recorded. Serum Dickkopf-1 levels were determined by enzymelinked immunosorbent assay.RESULTS No significant difference in serum Dickkopf-1 levels was found between healthy individuals and the normal albuminuria group. However, the levels in the microalbuminuria group were significantly lower than those in the normal albuminuria group(P = 0.017), and those in the macroalbuminuria group were the lowest. Bivariate analysis revealed that serum Dickkopf-1 levels were positively correlated with hemoglobin A1 c level(r = 0.368, P 0.01) and estimated glomerular filtration rate(r = 0.339, P 0.01), but negatively correlated with diabetes duration(r =-0.231, P = 0.050), systolic blood pressure(r =-0.369, P = 0.001), serum creatinine level(r =-0.325, P 0.01), and UACR(r =-0.459, P 0.01). Multiple and logistic regression showed that serum Dickkopf-1 levels were independently associated with UACR(odds ratio = 0.627, P = 0.021).CONCLUSION Serum Dickkopf-1 levels are negatively associated with UACR. Lower serum Dickkopf-1 levels could be a critical risk factor for albuminuria in diabetes.     

Risk factors for development of diabetic nephropathy and retinopathy in Jewish IDDM patients

Risk factors associated with diabetic microvascular complications, with special reference to ethnic origin, were looked for in 231 young Jewish insulin-dependent diabetes mellitus (IDDM) patients with duration of diabetes greater than or equal to 10 yr. Median age at diagnosis of diabetes was 9.2 yr (range 0.04-26.2 yr), and median duration of the disease was 15.3 yr (range 10.0-37.2 yr). Sixty-three percent of the patients were Ashkenazi Jews, and 37% were non-Ashkenazi Jews. HbA1 was evaluated every 3 mo in the last 10 yr of follow-up, and albumin excretion rate was tested in three 24-h urine collections. Direct and indirect ophthalmoscopy was performed every year since diagnosis of diabetes, and if retinal pathology was suspected, color photographs were taken. Microalbuminuria was detected in 31% and macroalbuminuria in 7% of the patients. Nonproliferative and proliferative retinopathy was found in 44 and 12% of the patients, respectively. On logistic regression analysis, two variables were significantly and independently associated with diabetic nephropathy--non-Ashkenazi origin and mean HbA1 values over the first 5 of 10 yr of follow-up. Variables significantly and independently related to diabetic retinopathy were non-Ashkenazi origin, mean HbA1 values over the last 10 yr of follow-up, and duration of diabetes. Because non-Ashkenazi Jews in Israel are of lower socioeconomic status than Ashkenazi Jews, we stratified our patients according to their socioeconomic parameters, median HbA1 values, and duration of diabetes. Non-Ashkenazi patients were at a higher risk to develop complications in all strata.(ABSTRACT TRUNCATED AT 250 WORDS)