Increased levels of mannan-binding lectin in type 1 diabetic patients with incipient and overt nephropathy

Aims/hypothesis Diabetic nephropathy is associated with insulin resistance, and low-grade inflammation and activation of the complement system may contribute to this cascade. Mannan-binding lectin (MBL) activates the complement system, and elevated MBL concentrations have been observed in normoalbuminuric type 1 diabetic patients. The aim of this study was to assess whether MBL is associated with diabetic nephropathy in type 1 diabetes, and whether there is an association between MBL and low-grade inflammatory markers or insulin resistance.Methods A total of 191 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based upon their AER. Patients with normal AER (n=67) did not take antihypertensive medication, while patients with microalbuminuria (n=62) or macroalbuminuria (n=62) were all treated with an ACE inhibitor. As a measure of insulin sensitivity we used estimated glucose disposal rate. MBL was measured by an immunofluorometric assay, C-reactive protein by a radioimmunoassay and IL-6 by high-sensitivity enzyme immunoassay.Results Patients with normal AER (median [interquartile range]: 1,154 g/l [180–2,202 g/l]) had lower levels of MBL than patients with microalbuminuria (1,713 g/l [724–2,760 g/l]; p=0.029) or macroalbuminuria (1,648 g/l [568–3,394 g/l]; p=0.019). There was a significant correlation between MBL and estimated glucose disposal rate, but not between MBL and C-reactive protein or IL-6 levels in univariate analysis. However, in a multiple regression analysis, HbA1c was the single variable independently associated with MBL (±SEM: 0.26±0.08; p=0.003).Conclusions/interpretation MBL concentrations are increased in type 1 diabetic patients with diabetic nephropathy. MBL was not associated with low-grade inflammatory markers.     

Elevated levels of paf-acether in blood of patients with type 1 diabetes mellitus.

Infusion of paf-acether (paf, first described as platelet-activating factor) into animals stimulates glycogenolysis and lipolysis and decreases insulin levels. This study reports a 50-fold increase in blood levels of paf in patients with Type 1 insulin-dependent diabetes mellitus without micro or macrovascular complications (1.07 +/- 0.42 ng/ml, n = 10) as compared with healthy volunteers (0.04 +/- 0.02 ng/ml, n = 9). By contrast, paf is not statistically elevated (p greater than 0.05) in patients with Type 2 non-insulin-dependent, diabetes mellitus with lipid abnormalities and micro or macrovascular complications (0.32 +/- 0.18 ng/ml, n = 9). In the three groups same levels of paf precursors and acetylhydrolase activity (the enzyme which inactivates paf) were noted suggesting an increase in paf biosynthesis by Type 1 diabetic patients. Elevated paf levels could perpetuate hyperglycaemia and tend to promote or accentuate micro or macrovascular complications. This study adds another biological difference between Type 1 and Type 2 diabetes.     

Thyroid hormone increases mannan-binding lectin levels

BACKGROUND: Recent studies have indicated the existence of causal links between the endocrine and immune systems and cardiovascular disease. Mannan-binding lectin (MBL), a protein of the innate immune system, may constitute a connection between these fields. METHODS: To test whether thyroid hormone regulates MBL levels, we studied eight patients with Graves' hyperthyroidism before and after methimazole therapy, eight healthy subjects before and after short-term experimental hyperthyroidism, and eight hypothyroid patients with chronic auto-immune thyroiditis before and after L-thyroxine substitution. RESULTS: In all hyperthyroid patients, MBL levels were increased--median (range), 1886 ng/ml (1478-7344) --before treatment and decreased to 954 ng/ml (312-3222) after treatment (P = 0.01, paired comparison: Wilcoxon's signed ranks test). The healthy subjects had MBL levels of 1081 ng/ml (312-1578). Administration of thyroid hormones to these persons induced mild hyperthyroidism and increased MBL levels significantly to 1714 ng/ml (356-2488) (P = 0.01). Two of the eight hypothyroid patients had undetectably low levels of MBL both before and after L-thyroxine substitution. The other six hypothyroid patients had decreased levels of MBL of 145 ng/ml (20-457) compared with 979 ng/ml (214-1533) after L-thyroxine substitution (P = 0.03, paired comparison: Wilcoxon's signed ranks test). CONCLUSION: Our data show that thyroid hormone increases levels of MBL. MBL is part of the inflammatory complement system, and this modulation of complement activation may play a role in the pathogenesis of a number of key components of thyroid diseases.     

丙型肝炎病毒感染者的血清甘露聚糖结合凝集素分析

目的分析丙型肝炎病毒（HCV）感染者的血清甘露聚糖结合凝集素（MBL）,探讨血清MBL水平与HCV感染及其致病程度的关系。方法收集HCV感染者128例,分成HCV携带者、轻度慢性丙型肝炎患者和中度慢性丙型肝炎患者三组。通过酶联免疫吸附法测定血清MBL的水平。结果HCV感染者血清MBL浓度均值为（1．729±0．529）μg／ml,高于正常对照组均值（0．974±0．305）μg／ml（P〈0．01）,且血清MBL水平随患者肝功能损害程度加重而增加。结论作为急性时相反应蛋白,血清MBL可反应HCV感染导致的慢性病理状态,它可能也参与肝脏纤维化的过程。     

Elevated plasma endothelin-1 levels in diabetes mellitus

BACKGROUND: This study compares plasma endothelin-1 (ET-1) levels in patients with diabetes mellitus or hypertension with healthy controls, and investigates whether ET-1 levels are correlated with glycemic control, metabolic parameters, and vascular complications. METHODS: The study population consisted of 103 patients with type 1 diabetes, 124 patients with type 2 diabetes, 35 hypertensive patients without diabetes mellitus, and 99 controls. RESULTS: Plasma ET-1 concentrations were significantly higher in patients with type 1 diabetes (0.28 +/- 0.34 fmol/mL, P =.001), type 2 diabetes (0.31 +/- 0.32 fmol/mL, P <.0001), and hypertension (0.35 +/- 0.26 fmol/mL, P <.0001) compared to controls (0.08 +/- 0.13 fmol/mL). Diabetic patients taking angiotensin converting enzyme (ACE) inhibitors had significantly lower plasma ET-1 levels than patients without (0.22 +/- 0.20 fmol/mL v 0.38 +/- 0.39 fmol/mL, P =.029). There were significant associations between ET-1 levels and age (r = 0.38, P <.05) and systolic blood pressure (BP) (r = 0.27, P <.05) in healthy controls. In diabetes we found only nonsignificant associations between ET-1 levels and age or vascular complications and a weak association between plasma ET-1 levels and glycemic control. CONCLUSIONS: Patients with diabetes or hypertension have elevated ET-1 levels, but do not exhibit positive correlations between ET-1 levels and BP, which was observed in healthy controls. Increased ET-1 levels do not induce hypertension in diabetes, but were lower in diabetic patients taking ACE inhibitors compared to those without ACE inhibitors. There is no significant association between ET-1 levels and vascular complications. These findings suggest that the plasma ET-1 level is not a marker of endothelial dysfunction but changes in plasma ET-1 levels may precede vascular complications associated with hypertension and diabetes.     

Chemotherapy-related infections in patients with multiple myeloma: associations with mannan-binding lectin genotypes

OBJECTIVES: To study a possible association between mannan-binding lectin genotypes and severe infections in patients with multiple myeloma receiving moderate strength induction chemotherapy. METHODS: Chemotherapy-related infections were identified retrospectively using clinical records and database files. Mannan-binding lectin genotypes were identified with polymerase chain reaction on stored samples of stem cells or formalin-fixed paraffin-embedded bone marrow biopsies. RESULTS: We included 138 myeloma patients. In five patients, data were incomplete, and 133 patients were analysed. Eighty-eight patients were homozygous for wild-type MBL2 (AA) and forty-five patients were heterozygous or homozygous for variant genotypes (AO/OO). A total of 390 chemotherapy cycles were reviewed. Common Toxicity Criteria grades 3 and 4 infections in general were seen in relation to 104 cycles and were not more common in patient with variant MBL2 (P = 0.90). Septicaemia was seen after 10% of chemotherapy cycles in AA patients vs. 15% in AO/OO patients (P = 0.15). In multi-variate analyses, we found indication of a reduced risk of septicaemia in AA patients [OR 0.27 (0.08-0.90), P = 0.03], after first chemotherapy cycle, but reduction of the risk including all cycles was not significant. A similar trend was seen for grades 3 and 4 infections in general. CONCLUSIONS: During induction chemotherapy in patients with multiple myeloma, a general protective effect of wild-type MBL2 against chemotherapy-related infections was not apparent in this study. However, we found indications of a reduced occurrence of septicaemia in patients with wild-type compared with variant MBL2. Further studies in larger cohorts of patients are relevant.     

Elevated levels of VE-cadherin-positive endothelial microparticles in patients with type 2 diabetes mellitus and coronary artery disease

OBJECTIVES: The purpose of this study was to examine whether CD144-EMP (endothelium-derived microparticles) is useful as a specific marker of endothelial cell (EC) dysfunction and to determine whether plasma levels of circulating CD144-EMP predicted coronary artery disease (CAD) in patients with type 2 diabetes mellitus (DM). BACKGROUND: Endothelial cell dysfunction is involved in atherogenesis; however, the quantitative assessment of EC dysfunction has yet to be established clinically. Endothelium-derived microparticles are small, membrane-shed vesicles that are generated from the EC surface in response to cellular dysfunction and/or injury. Diabetes mellitus is known to be associated with EC dysfunction and accelerated atherosclerosis. METHODS: We characterized EMP using anti-CD144 (VE-Cadherin) antibody in various atherosclerosis-related cells and investigated the association between the levels of CD144-positive microparticles and hydrogen-peroxide-induced EC injury and acetylcholine-induced coronary vasomotion. Furthermore, we evaluated plasma CD144-EMP levels in patients with and without DM. RESULTS: We demonstrated that CD144-positive microparticles were derived selectively from human EC. The levels of CD144-EMP reflected the degree of in vitro hydrogen-peroxide-induced EC injury and impairment of in vivo endothelium-dependent coronary vasodilation (p < 0.01). Plasma CD144-EMP levels were increased significantly in DM patients compared with patients without DM (p < 0.001). In DM patients, the elevated levels of CD144-EMP were the most significant risk factor for CAD relative to all other traditional risk factors (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.8 to 6.9, p < 0.001). Notably, plasma CD144-EMP identified a subpopulation of established CAD patients in DM subjects without typical anginal symptoms (OR 10.6, 95% CI 3.9 to 29.5, p < 0.001). CONCLUSIONS: The CD144-positive EMP exist in human plasma, and plasma CD144-EMP levels can be a clinically specific and quantitative marker of EC dysfunction and/or injury. Measurement of CD144-EMP, by providing a quantitative assessment of EC dysfunction, may be useful for identifying DM patients with increased risk of CAD.     

Raised C-reactive protein levels in patients with recent onset type 1 diabetes

BACKGROUND: To investigate serum concentrations of high-sensitive C-reactive protein (CRP) and alpha(1)-acid glycoprotein (AGP) in patients with T1DM, at diagnosis and after 12 months of intensive insulin therapy (T12). METHODS: CRP and AGP were measured in 44 recent onset T1DM patients (26M/18F, mean age 14.9 +/- 9.1 years), and 44 age- and sex-matched controls, using a highly sensitive immunonephelometric assay. RESULTS: There were no significant differences in the concentrations of high-sensitive C-reactive protein (hs-CRP) and AGP between patients and controls. hs-CRP levels significantly increased in patients at T12 compared to the levels at diagnosis [0.69 (0.14-15.5) versus 0.43 (0.14-7.47) mg/L, p < 0.05; for males: 0.77 (0.14-15.5) versus 0.35 (0.14-7.47) mg/L, p < 0.05; for females the increase was not significant]. AGP levels were not different at T12 compared to diagnosis. No significant correlations were found between hs-CRP and body mass index (BMI), C-peptide, glycosylated haemoglobin, or insulin dose. A strong correlation was found between hs-CRP values at diagnosis and those at T12 (rho = 0.73, p < 0.001); indeed, patients with hs-CRP levels above the 50th percentile at diagnosis showed significantly increased hs-CRP values at T12 compared to patients with baseline hs-CRP levels under the 50th percentile [1.61 (0.18-15.5) versus 0.16 (0.14-1.92) mg/L, p < 0.0001)], and to controls [0.55 (0.14-6.50), p = 0.001]. CONCLUSIONS: This is the first report showing that, despite good metabolic control, 1 year of overt T1DM is sufficient to increase hs-CRP levels, especially in males. hs-CRP levels at diagnosis is a predictor for the values observed at 12 months, suggesting the possibility to select a subgroup of patients requiring strict follow-up for cardiovascular complications.     

Elevated circulating adiponectin in type 1 diabetes is associated with long diabetes duration

OBJECTIVE: To study circulating adiponectin concentrations in relation to diabetes duration and endogenous insulin secretion in patients with type 1 diabetes. PATIENTS: Patients with haemoglobin A1c (HbA1c) < 6% (reference range 3.6-5.4%) were selected for the study. Twenty-two men and 24 women [age 41.3 +/- 13.8 years (mean +/- SD), diabetes duration 4 months to 52 years] participated. Healthy controls (15 women and nine men, age 41.3 +/- 13.0 years) were also included. Overnight fasting serum samples were analysed for adiponectin, HbA1c, C-peptide and lipoproteins. RESULTS: Significant positive associations were found between adiponectin concentrations and diabetes duration in univariate and multiple regression analyses. Serum adiponectin averaged 9.7 +/- 5.3 [median 8.1, interquartile range (IQR) 3.6] mg/l in patients with diabetes duration less than 10 years and 17.8 +/- 10.7 (median 14.7, IQR 7.5) mg/l in patients with longer duration (P = 0.0001). Among the patients, 24 were without detectable (< 100 pmol/l) and 22 with detectable C-peptide levels (185 +/- 91 pmol/l). C-peptide levels in controls averaged 492 +/- 177 pmol/l. HbA1c was 5.7 +/- 0.6% in patients without detectable C-peptide and 5.6 +/- 0.4% in patients with detectable C-peptide (ns). Serum adiponectin was higher in patients without detectable C-peptide than in patients with detectable C-peptide [17.3 +/- 11.1 vs. 10.6 +/- 5.8 mg/l (P < 0.005)] and in the controls [10.1 +/- 2.9 mg/l (P < 0.001 vs. patients without detectable C-peptide)]. CONCLUSIONS: The increase in circulating adiponectin concentrations in patients with type 1 diabetes appears to be strongly associated with long diabetes duration, irrespective of the metabolic control. Among other factors, a putative role for residual beta-cell function in the regulation of circulating adiponectin levels can be considered but we did not find sufficient evidence for this in the present study.     

Elevated plasma levels of glucagon-like peptide-1 after oral glucose ingestion in patients with pancreatic diabetes

OBJECTIVE: The purpose of the present study was to evaluate plasma glucagon-like peptide-1 (GLP-1) responses after oral glucose ingestion in patients with chronic pancreatitis and to clarify how GLP-1 secretion relates to pancreatic diabetes. METHODS: An oral glucose tolerance test (OGTT) was performed in 17 patients with chronic pancreatitis. Plasma glucose, immunoreactive insulin (IRI), C-peptide, glucagon, and GLP-1 levels at each time point during OGTT were measured. The diagnosis of chronic pancreatitis was made by the findings of endoscopic retrograde pancreatography (ERP): evident dilation of the main pancreatic duct with or without pancreatolithiasis. RESULTS: The patients were divided into three groups according to the World Health Organization classification of diabetes based on plasma glucose levels after OGTT. The groups were: normal (three patients), impaired glucose tolerant (IGT) (six patients), and diabetic (DM) (eight patients). In the DM group, IRI and C-peptide response levels after oral glucose ingestion were significantly reduced as compared with those of the normal and IGT groups. No significant glucagon responses to oral glucose ingestion were found in the three groups. In contrast, plasma GLP-1 levels were significantly elevated after oral glucose ingestion in the DM groups as compared with normal and IGT groups. CONCLUSIONS: The present study affords evidence that plasma GLP-1 levels become elevated with development of pancreatic diabetes, although the precise mechanism of this elevation remains undetermined.     

Evaluation of serum IgA levels in Iranian patients with type 1 diabetes mellitus

An increased prevalence of immunoglobulin (Ig) A deficiency has been documented in a number of autoimmune diseases; however, its association with type 1 diabetes mellitus (DM1) is a subject of debate. This study was performed to evaluate serum IgA levels in a group of pediatric patients with DM1. Three hundred patients with mean age of 12.6 ± 6.7 years were enrolled in this study. Serum IgA and other immunoglobulins levels were measured using enzyme-linked immunosorbant assay. Mean serum IgA level of patients was 271.0 ± 141.4 mg/dl. Only two patients had IgA deficiency (IgA < 10 mg/dl), who were two boys with ages of 9 and 10 years. Although associated autoimmune disorders were found in a number of patients with DM1, no other autoimmune disorder was detected in these two patients with IgA deficiency. Serum levels of all other immunoglobulins were normal. Serum IgA levels did not significantly differ by grouping the patients according to age variation, sex distribution, disease duration, and associated disorders. There was no significant correlation between IgA levels and hemoglobin A1c. This study showed the prevalence of IgA deficiency in Iranian patients with DM1 as 0.7% (1:150), which is much higher than reported prevalences in general populations. Further studies are needed for better understanding the possible etiologies of increased IgA deficiency in DM1 and its effects on diabetes control.     

Increased activity of the mannan-binding lectin complement activation pathway in patients with colorectal cancer

BACKGROUND: Postoperative bacterial infectious complications are frequent in patients with colorectal cancer (CRC), with subsequent increased recurrence rates and poor prognosis. Deficiency of the mannan-binding lectin (MBL) complement activation pathway may cause increased risk of infection in certain patient groups. It is hypothesized that a deficient MBL pathway might be more frequent among patients with CRC than in healthy individuals. The MBL pathway was therefore evaluated in serum obtained preoperatively from 193 patients with primary CRC and in serum from 150 healthy volunteers. METHODS: Serum MBL concentrations and MBL/MASP activity were determined using immunofluorometric assays. The levels are presented as the median, inter-quartile range and range. RESULTS: Serum MBL levels were significantly (P < 0.0002) increased in patients with colorectal cancer (1384 (400-2188) ng/mL) (median, inter-quartile range) compared with levels in healthy blood donors (924 (230-1476) ng/mL). Similarly, the MBL/MASP activity was significantly (P < 0.0002) increased in patients (584 (202-914) mU/mL) compared with in blood donors (319 (0-684) mU/mL). This was independent of age, gender, tumour location in the colon or rectum, and disease stages according to Dukes' classification. No statistical difference (P=0.20) in frequency of MBL deficiency was found between the patients (20%) and the donors (27%). CONCLUSIONS: Overall, the MBL complement activation pathway is significantly increased in patients with colorectal cancer compared with healthy persons. However, similar frequencies of MBL pathway deficiency are observed in patients and healthy persons.     

Anemia in patients with type 1 diabetes

Anemia is a common finding in diabetes, although most patients in these studies have type 2 disease. This study examines the prevalence and predictors of anemia in outpatients with type 1 diabetes. A full blood count was obtained in addition to routine testing in patients with type 1 diabetes at the Austin Medical Centre (n = 135), Melbourne, the Royal Prince Alfred Hospital (n = 42), and the Royal North Shore Hospital (n = 135), both in Sydney, Australia.One in seven patients had anemia (14%). Patients at greatest risk could be identified by the presence of diabetic kidney disease. More than half (52%) of patients with macroalbuminuria had anemia, compared with 24% of patients with microalbuminuria and less than 8% of normoalbuminuric patients. Patients with diabetes and renal impairment were more than six times more likely to have anemia than those with normal renal function. Patients with anemia were more likely to have retinopathy and macrovascular complications than were patients with a normal hemoglobin level, independent of comorbid renal disease.Anemia is a prevalent finding in patients with type 1 diabetes and represents a significant unrecognized burden. Patients at greatest risk can be identified by the presence of renal disease, in the form of albuminuria and/or renal impairment.     

Seasonal variation of hemoglobin A1c levels in patients with type 2 diabetes

The purpose of our study was to retrospectively examine the association between hemoglobin A1c (HbA1c) with season variation in patients with type 2 diabetes from the Chinese mainland. Monthly average of HbA1c values of type 2 diabetes patients in Jinan Central Hospital between 2008 and 2011 were respectively reviewed. The effects of sex, age, and season on HbA1c levels were analyzed. Moreover, a multiple linear regression analysis was performed to discuss the correlations between HbA1c levels and sex, age, and season. The HbA1c levels were significantly higher in winter (December, January, and February) and significantly lower in summer (June, July, and August). Significant difference was found for HbA1c between men and women in the elderly group (P < 0.01). The levels of HbA1c were similar in youth and middle groups (P > 0.05), but significantly lower in the elderly group (P < 0.05). Additionally, negative correlations of HbA1c with season, age, and gender were identified (P < 0.01). Our study suggests that cold weather may elevate the levels of HbA1c in type 2 diabetic patients in mainland China. However, more detailed studies are needed to reveal the variation of HbA1c with age and gender.     

Serum levels of substance P are decreased in patients with type 1 diabetes.

Morphological and immunohistochemical studies in diabetic subjects have shown a depletion of the neuropeptide substance P (SP) in the central and peripheral nervous system. This is the first study investigating serum levels of substance P in type 1 diabetes patients (n=50) and controls (n=75) by means of an enzyme immunoassay. The serum level of SP was significantly decreased in the diabetic group compared to the control group (10.12+/-0.29 vs. 12.25+/-0.38 pg/ml; p<0.0001). In diabetic patients, there was no correlation of substance P levels with age, serum creatinine, albuminuria, total cholesterol, HDL- or LDL-cholesterol, triglycerides, HbA1c, type or duration of diabetes and gender. Furthermore, there was no difference in serum levels of SP in patients with or without retinopathy, but SP was significantly decreased in patients with neuropathy (9.59+/-0.48 vs. 10.78+/-0.83 pg/ml; p=0.04). These data show that SP is decreased in serum of type 1 diabetes patients, especially in those with diabetic neuropathy. Subsequent and already ongoing prospective studies in well validated diabetic patients with neuropathy may characterize the impact of this neurogenic marker in the course of diabetic neuropathy.     

Association of mannan-binding lectin deficiency with venous bypass graft occlusions in patients with coronary heart disease

We investigated the effect of mannan-binding lectin (MBL) deficiency on the susceptibility to bypass graft occlusion in 62 patients with coronary heart disease. MBL deficiency appeared to be associated with occlusion (p = 0.0099). A high level of anti-cardiolipin IgG as well as the number of venous bypass grafts were also involved (p = 0.0018 and p = 0.0104, respectively). Since early occlusion (<5 years after surgery) of a venous bypass graft is considered to be caused by thrombosis or fibro-intimal hyperplasia superimposed by thrombosis, our finding also implies an association of MBL deficiency with thrombotic events. It remains unclear whether the previously confirmed effect of MBL deficiency in coronary disease is mediated through this possible thrombotic mechanism, or whether plaque formation is also involved in the process. Further studies are clearly warranted.     

Elevated serum ceruloplasmin levels are associated with albuminuria in Korean men with type 2 diabetes mellitus

The aim of this study was to examine the possible association between serum ceruloplasmin, a copper carrying protein, and albuminuria in 456 males with type 2 diabetes. Multivariate regression analysis demonstrated that elevated serum ceruloplasmin was a determinant of albuminuria independently of conventional risk factors.