High MBL-expressing genotypes are associated with deterioration in renal function in type 2 diabetes.

Introduction: Accumulating evidence support that mannan-binding lectin (MBL) is a promising prognostic biomarker for risk-stratification of diabetic micro- and macrovascular complications. Serum MBL levels are predominately genetically determined and depend on MBL genotype. However, Type 1 diabetes (T1D) is associated with higher MBL serum levels for a given MBL genotype, but it remains unknown if this is also the case for patients with T2D. In this study, we evaluated the impact of MBL genotypes on renal function trajectories serum MBL levels and compared MBL genotypes in newly diagnosed patients with T2D with age- and sex-matched healthy individuals. Furthermore, we evaluated differences in parameters of insulin resistance within MBL genotypes. Methods: In a cross-sectional study, we included 100 patients who were recently diagnosed with T2D and 100 age- and sex-matched individuals. We measured serum MBL levels, MBL genotype, standard biochemistry, and DEXA, in all participants. A 5-year clinical follow-up study was conducted, followed by 12-year data on follow-up biochemistry and clinical status for the progression to micro- or macroalbuminuria for the patients with T2D. Results: We found similar serum MBL levels and distribution of MBL genotypes between T2D patients and healthy individuals. The serum MBL level for a given MBL genotype did not differ between the groups neither at study entry nor at 5-year follow-up. We found that plasma creatinine increased more rapidly in patients with T2D with the high MBL expression genotype than with the medium/low MBL expression genotype over the 12-year follow-up period (p = 0.029). Serum MBL levels did not correlate with diabetes duration nor with HbA1c. Interestingly, serum MBL was inversely correlated with body fat percentage in individuals with high MBL expression genotypes both at study entry (p=0.0005) and 5-years follow-up (p=0.002). Discussion: Contrary to T1D, T2D is not per se associated with increased MBL serum level for a given MBL genotype or with diabetes duration. Serum MBL was inversely correlated with body fat percentage, and T2D patients with the high MBL expression genotype presented with deterioration of renal function.

Circulating lectin pathway proteins do not predict short-term cardiac outcomes after myocardial infarction.

Despite improvements in treatment, coronary artery disease is still responsible for one-third of all deaths globally, due predominantly to myocardial infarction (MI) and stroke. There is an important potential in developing new strategies for treatment of patients with these conditions. Inflammation, and in particular the actions of the complement system, has emerged as part of the pathogenesis in reperfusion injury in patients with MI. To further qualify this, we examined the association between the plasma levels of lectin pathway proteins and myocardial end-points, left ventricular ejection fraction (LVEF) and infarct size in a cohort of patients with ST-elevation myocardial infarction (STEMI). A blood sample was drawn the day after percutaneous coronary intervention from 73 patients with STEMI. The primary end-points, LVEF and infarct size, were measured with magnetic resonance imaging 6-9 days after the infarct. Complement pattern-recognition molecules of the lectin pathway (mannan-binding lectin, H-ficolin, L-ficolin and M-ficolin) were analysed along with soluble membrane attack complex (sMAC) and C-reactive protein (CRP) in plasma with immunofluorometric assays <50%. CRP correlated negatively with LVEF, regression coefficient = -0·17 (P = 0·01). None of the lectin pathway proteins correlated to LVEF or infarct size, nor did soluble membrane attack complex (sMAC). There were no differences in plasma levels of these complement proteins when comparing patients with ejection fraction <50% to patients with ejection fraction <50%. Pattern-recognition molecules of the lectin pathway and sMAC do not predict short-term cardiac outcomes after MI.

Early-onset type 2 diabetes: Age gradient in clinical and behavioural risk factors in 5115 persons with newly diagnosed type 2 diabetes-Results from the DD2 study.

AIM: To examine the association between early onset of type 2 diabetes mellitus (DM) and clinical and behavioural risk factors for later complications of diabetes. METHODS: We conducted a cross-sectional study of 5115 persons with incident type 2 DM enrolled during 2010-2015 in the Danish Centre for Strategic Research in Type 2 Diabetes-cohort. We compared risk factors at time of diagnosis among those diagnosed at ≤45 years (early onset) with diagnosis age 46 to 55, 56 to 65 (average onset = reference), 66 to 75, and >75 years (late onset). Prevalence ratios (PRs) were computed by using Poisson regression. RESULTS: Poor glucose control, ie, HbA1c ≥ 75 mmol/mol (≥9.0%) in the early-, average-, and late-onset groups was observed in 12%, 7%, and 1%, respectively (PR 1.70 [95% confidence intervals (CI) 1.27, 2.28] and PR 0.17 [95% CI 0.06, 0.45]). A similar age gradient was observed for severe obesity (body mass index > 40 kg/m2 : 19% vs. 8% vs. 2%; PR 2.41 [95% CI 1.83, 3.18] and 0.21 (95% CI 0.08, 0.57]), dyslipidemia (90% vs. 79% vs. 68%; PR 1.14 [95% CI 1.10, 1.19] and 0.86 [95% CI 0.79, 0.93]), and low-grade inflammation (C-reactive protein > 3.0 mg/L: 53% vs. 38% vs. 26%; PR 1.41 [95% CI 1.12, 1.78] and 0.68 [95% CI 0.42, 1.11]). Daily smoking was more frequent and meeting physical activity recommendations less likely in persons with early-onset type 2 DM. CONCLUSIONS: We found a clear age gradient, with increasing prevalence of clinical and behavioural risk factors the younger the onset age of type 2 DM. Younger persons with early-onset type 2 DM need clinical awareness and support.

Cardiac vagal tone, a non-invasive measure of parasympathetic tone, is a clinically relevant tool in Type 1 diabetes mellitus.

AIMS: To compare a novel index of parasympathetic tone, cardiac vagal tone, with established autonomic variables and to test the hypotheses that (1) cardiac vagal tone would be associated with established time and frequency domain measures of heart rate and (2) cardiac vagal tone would be lower in people with Type 1 diabetes than in a matched healthy cohort and lower still in people with established neuropathy. METHODS: Cardiac vagal tone is a validated cardiometrically derived index of parasympathetic tone. It is measured using a standard three-lead electrocardiogram which connects, via Bluetooth, to a smartphone application. A 5-min resting recording of cardiac vagal tone was undertaken and observational comparisons were made between 42 people with Type 1 diabetes and peripheral neuropathy and 23 without peripheral neuropathy and 65 healthy people. In those with neuropathy, 24-h heart rate variability values were compared with cardiac vagal tone. Correlations between cardiac vagal tone and clinical variables were also made. RESULTS: Cardiac vagal tone was lower in people with established neuropathy and Type 1 diabetes in comparison with healthy participants [median (interquartile range) linear vagal scale 3.4 (1.6-5.5 vs 7.0 (5.5-9.6); P < 0.0001]. Cardiac vagal tone was positively associated with time (r = 0.8, P < 0.0001) and frequency domain markers of heart rate variability (r = 0.75, P < 0.0001), representing established measures of parasympathetic function. Cardiac vagal tone was negatively associated with age (r=-0.32, P = 0.003), disease duration (r=-0.43, P < 0.0001) and cardiovascular risk score (r=-0.32, P = 0.006). CONCLUSIONS: Cardiac vagal tone represents a convenient, clinically relevant method of assessing parasympathetic nervous system tone, potentially facilitating the earlier identification of people with Type 1 diabetes who should undergo formal autonomic function testing.

Incident microalbuminuria and complement factor mannan-binding lectin-associated protein 19 in people with newly diagnosed type 1 diabetes.

BACKGROUND: Evidence links the lectin pathway of complement activation to diabetic kidney disease. Upon carbohydrate-recognition by pattern-recognition molecules, eg, mannan-binding lectin (MBL), the MBL-associated serine protease (MASP-2) is activated and initiates the complement cascade. The MASP2 gene encodes MASP-2 and the alternative splice product MBL-associated protein 19 (MAp19). Both MAp19 and MASP-2 circulate in complex with MBL. We tested the hypothesis that MAp19 and MASP-2 concentrations predict the risk of incident microalbuminuria. METHODS: Baseline MAp19 and MASP-2 were measured in 270 persons with newly diagnosed type 1 diabetes tracked for incidence of persistent microalbuminuria in a prospective observational 18-year-follow-up study. RESULTS: Seventy-five participants (28%) developed microalbuminuria during follow-up. MBL-associated protein 19 concentrations were higher in participants that later progressed to microalbuminuria as compared with those with persistent normoalbuminuria (268 ng/mL [95% CI, 243-293] vs 236 ng/mL [95% CI, 223-250], P = .02). Participants with MAp19 concentration within the highest quartile of the cohort had an increased risk of microalbuminuria as compared with participants with MAp19 concentration within the combined lower 3 quartiles in unadjusted Cox analysis, hazard ratio 1.86 ([95% CI, 1.17-2.96], P = .009). This remained significant in adjusted models, eg, adjusting for age, sex, HbA1c , systolic blood pressure, urinary albumin excretion, smoking, serum creatinine, and serum cholesterol. MBL-associated serine protease concentration was not associated with incidence of microalbuminuria. CONCLUSIONS: In conclusion, the results show an association between baseline MAp19 concentration and the incidence of microalbuminuria in an 18-year-follow-up study on persons with newly diagnosed type 1 diabetes.

Plasma levels of MASP-1, MASP-3 and MAp44 in patients with type 2 diabetes: influence of glycaemic control, body composition and polymorphisms in the MASP1 gene.

Mounting evidence indicates that adverse activation of the complement system plays a role in the development of diabetic vascular complications. Plasma levels of the complement proteins mannan-binding lectin (MBL) and its associated serine proteases (MASP-1 and MASP-2) are elevated in diabetes. We hypothesized that single nucleotide polymorphisms (SNPs) in the MASP1 gene may contribute to altered plasma levels of the belonging gene products; MASP-1, MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44) in patients with type 2 diabetes. To investigate this, we compared plasma levels of MASP-1, MASP-3 and MAp44 in 100 patients with type 2 diabetes and 100 sex- and age-matched controls. Ten carefully selected SNPs were analysed using TaqMan® genotyping assay. Additionally, we included a streptozotocin-induced diabetes mouse model to directly examine the effect of inducing diabetes on MASP-1 levels. MASP-1 levels were significantly higher among patients with type 2 diabetes compared with healthy controls (P = 0·017). Five SNPs (rs874603, rs72549254, rs3774275, rs67143992, rs850312) in the MASP1 gene were associated with plasma levels of MASP-1, MASP-3 and MAp44. In the diabetes mouse model, diabetic mice had significantly higher MASP-1 levels than control mice (P = 0·003). In conclusion, MASP-1 levels were higher among patients with type 2 diabetes and diabetic mice. The mechanism behind this increase remains elusive.

Heart rate time series characteristics for early detection of infections in critically ill patients.

It is difficult to make a distinction between inflammation and infection. Therefore, new strategies are required to allow accurate detection of infection. Here, we hypothesize that we can distinguish infected from non-infected ICU patients based on dynamic features of serum cytokine concentrations and heart rate time series. Serum cytokine profiles and heart rate time series of 39 patients were available for this study. The serum concentration of ten cytokines were measured using blood sampled every 10 min between 2100 and 0600 hours. Heart rate was recorded every minute. Ten metrics were used to extract features from these time series to obtain an accurate classification of infected patients. The predictive power of the metrics derived from the heart rate time series was investigated using decision tree analysis. Finally, logistic regression methods were used to examine whether classification performance improved with inclusion of features derived from the cytokine time series. The AUC of a decision tree based on two heart rate features was 0.88. The model had good calibration with 0.09 Hosmer-Lemeshow p value. There was no significant additional value of adding static cytokine levels or cytokine time series information to the generated decision tree model. The results suggest that heart rate is a better marker for infection than information captured by cytokine time series when the exact stage of infection is not known. The predictive value of (expensive) biomarkers should always be weighed against the routinely monitored data, and such biomarkers have to demonstrate added value.

Objective measurements of activity patterns in people with newly diagnosed Type 2 diabetes demonstrate a sedentary lifestyle.

AIMS: To evaluate physical activity in people with newly diagnosed Type 2 diabetes using objective measures. METHODS: We analysed data from a study aimed at assessing carotid femoral pulse wave velocity in which a piezoelectric accelerometer was worn by 100 people with newly diagnosed Type 2 diabetes and by 100 age- and sex-matched control subjects. Differences in physical activity patterns were investigated. RESULTS: Compared with the control group, the people with Type 2 diabetes spent significantly more time engaged in sedentary or lower level activities during the day, with a mean (sd) time of 926 (44) vs 898 (70) min, P < 0.001). This difference remained significant after correction for differences in BMI between the two groups. CONCLUSIONS: Using objective measurements, our findings demonstrate that people with newly diagnosed Type 2 diabetes have a more sedentary lifestyle compared with well-matched controls.

Diabetes-induced changes in mannan-binding lectin levels and complement activation in a mouse model of type 1 diabetes.

Circulating mannan-binding lectin (MBL) levels are elevated in type 1 diabetes. Further, high MBL levels are associated with the development of diabetic nephropathy. In animals, a direct effect of MBL on diabetic kidney changes is observed. We hypothesized that MBL levels and detrimental complement activation increase as a consequence of diabetes. We measured plasma MBL before and 7 weeks after inducing diabetes by streptozotocin. Mice have two MBLs, MBL-A and MBL-C. Diabetes induction led to an increase in MBL-C concentration, whereas no change during the study was found in the control group. The increase in MBL-C was associated with the increasing plasma glucose levels. In accordance with the observed changes in circulating MBL levels, liver expression of Mbl2mRNA (encoding MBL-C) was increased in diabetes. Mbl1expression (encoding MBL-A) did not differ between diabetic and control animals. The estimated half-life of recombinant human MBL was significantly prolonged in mice with diabetes compared with control mice. Complement activation in plasma and glomeruli did not differ between groups. We demonstrate for the first time that MBL levels increase after induction of diabetes and in parallel with increasing plasma glucose. Our findings support the previous clinical observations of increased MBL in type 1 diabetes. This change may be explained by alternations in both MBL production and turnover.

The effect of weight loss on serum mannose-binding lectin levels.

BACKGROUND: Serum levels of the mannose-binding lectin (MBL), which is an activator of the complement system, have been considered as a pathogenic factor in a broad range of diseases, and means of modulating MBL are therefore being evaluated. In this study we examine the effects of weight loss on MBL levels, and in continuation of this if MBL is synthesized in human adipose tissue. METHODS: 36 nondiabetic obese subjects received a very low-calorie diet (VLCD) of 800 kcal/day for 8 weeks. Blood samples were collected at baseline and after VLCD. Furthermore, we measured MBL mRNA levels by the real-time RT-PCR on human adipose tissue compared to liver tissue. RESULTS: The mean body weight was reduced from 106.3 ± 2.6 kg to 92.8 ± 2.4 kg, P < 0.0001. Median MBL at baseline was 746 µg/L (IQR 316-1190) versus 892 µg/L (IQR 336-1511) after 8 weeks, P = 0.23. No correlations were found between weight loss and changes in MBL (r = -0.098, P = 0.57). MBL real-time RT-PCR showed no expression of mRNA in adipose tissue, but as expected a good expression in liver tissue was seen. CONCLUSIONS: MBL levels are not affected by weight loss and MBL is not synthesized in human adipose tissue.

Mannose-binding lectin genotype and phenotype in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial.

OBJECTIVE: The present study characterizes mannose-binding lectin (MBL), an activator of the complement system and thereby important for inflammatory activation, in patients with diabetes and myocardial infarction. RESEARCH DESIGN AND METHODS: Serum (S)-MBL was determined at hospital admission in 387 patients with type 2 diabetes (median age 70 years; 68% male) with myocardial infarction, and genotyping was performed in 287 patients. Cardiovascular events (cardiovascular mortality and nonfatal myocardial infarction or stroke) were recorded during 2.5 years. RESULTS: Median S-MBL was 1,212 µg/l (interquartile range [IQR] 346-2,681 µg/l). Of the subjects, 54% in the geno- and phenotype subgroup had a high-coding MBL genotype (median S-MBL=2,658 µg/l [IQR 1,715-3,829]) and 46% a low-coding MBL genotype (373 µg/l [100-765]). S-MBL did not correlate with age, BMI, creatinine clearance, glucose, or A1C. Cardiovascular events occurred in 136 (35%) patients. S-MBL did not predict events in univariable analyses (hazard ratio 0.93 [95% CI 0.85-1.01]; P=0.09). In unadjusted analyses, the risk of events was lower in patients with a high genotype and S-MBL above the median for their genotype (0.49 [0.26-0.92]; P=0.026) than for patients with a low genotype and S-MBL below the median for their genotype. The prediction capacity of the geno- and phenotype model was of borderline significance in adjusted Cox regression. CONCLUSIONS: Patients with type 2 diabetes and myocardial infarction have MBL genotypes that are similar to those known in the general population. The combination of a low-coding MBL genotype with a low S-MBL appears to be prognostically unfavorable, but the association is blunted by traditional risk markers.

Association between mannose-binding lectin, high-sensitivity C-reactive protein and the progression of diabetic nephropathy in type 1 diabetes.

AIMS/HYPOTHESIS: Diabetic nephropathy has been associated with low-grade inflammation and activation of the complement system in cross-sectional studies. Data from prospective studies are sparse. We investigated the associations of the complement activator mannose-binding lectin (MBL) and the inflammatory marker high-sensitivity C-reactive protein (hsCRP) with the development of nephropathy in a large prospective study of patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study. METHODS: Baseline MBL and hsCRP were measured in 1,564 type 1 diabetes patients from the FinnDiane study, of whom 1,010 had a normal albumin excretion rate, 236 had microalbuminuria and 318 had macroalbuminuria. The main outcome was progression in renal disease during follow-up. RESULTS: Both baseline MBL (p = 0.038) and hsCRP (p < 0.001) increased with increasing level of albuminuria. During 5.8 +/- 2.2 years of follow-up, progression to a higher albuminuria level or end-stage renal disease (ESRD) occurred in 201 patients. MBL levels were higher in progressors compared with non-progressors at all steps of progression, and in a covariate adjusted multivariate Cox-regression analysis MBL levels above the median were significantly associated with progression from macroalbuminuria to ESRD (hazard ratio 1.88, 95% CI 1.06-3.32, p = 0.030). In a univariate analysis, hsCRP levels above the median were significantly associated with progression from normal albumin excretion rate to microalbuminuria, but the association was only borderline significant after adjustment for covariates (hazard ratio 1.56, 95% CI 0.97-2.51, p = 0.068). CONCLUSIONS/INTERPRETATION: This study demonstrates that concentrations of both MBL and hsCRP are associated with the progression of renal disease in type 1 diabetes.

The prevalence of food hypersensitivity in young adults.

rising prevalence of food hypersensitivity (FHS) and severe allergic reactions to foods have been reported in the last decade. However, little is known on the prevalence in young adults. This study estimated the prevalence of FHS to the most common allergenic foods in an unselected population of young adults. We investigated a cohort of 1272 young adults 22 years of age by questionnaire, skin prick test (SPT) and histamin release (HR) followed by oral challenge to the most common allergenic foods. FHS was divided into primary and secondary FHS. Primary FHS was defined as being independent of pollen sensitization, whereas secondary FHS was defined as reactions to pollen related fruits and vegetables in pollen allergic patients. The questionnaire was returned by 77.1%. Primary FHS was reported by 19.6% and secondary FHS by 16.7% of the participants. Confirmed primary FHS by oral challenge was 1.7% [1.1% - 2.95%]. In primary FHS, the most common allergenic food was peanut (0.6%) followed by additives (0.5%), shrimp (0.2%), codfish (0.1%), cow's milk (0.1%), octopus (0.1%) and soy (0.1%). In secondary FHS, kiwi allergy was reported by 7.8% of the participants followed by hazelnut (6.6%), pineapple (4.4%), apple (4.3%), orange (4.2%), tomato (3.8%), peach (3.0%) and brazil nut (2.7%). This study found a 1.7% [1.1% - 2.95%] prevalence of primary FHS confirmed by oral challenge to the most common allergenic foods in an unselected population of young adults.

Complement activation and cardiovascular disease.

The mechanisms by which tissue injury after acute myocardial infarction occurs have not been fully elucidated, but considerable evidence suggests that activation of complement plays an important role in the pathophysiology. Reperfusion of the ischemic myocardium is strictly necessary to rescue the exposed tissue from eventual death. However, reversion of the blood supply is also associated with reperfusion injury contributing to tissue injury. Activation of the complement system has indisputable beneficial effects in the immune defense and in the clearance of damaged tissue and apoptotic cells, but excessive activation of the system may lead to uncontrolled tissue damage. This review focuses on the role of complement activation, with focus on the lectin pathway, endothelial dysfunction and cardiovascular diseases, including ischemic heart disease and diabetic angiopathy. Finally, potential therapeutic strategies targeting the complement system are discussed.

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice.

AIMS/HYPOTHESIS: An increasing amount of evidence indicates that mannose-binding lectin (MBL) plays a role in the development of diabetic nephropathy. The main objective of the study was to analyse whether MBL influences the effects of diabetes on the kidneys. MATERIALS AND METHODS: In one group of wild-type mice and in one group of MBL double knockout mice we induced diabetes by the use of streptozotocin as a model of type 1 diabetes. Two groups of non-diabetic mice, wild-type and MBL knockout, were also included. By two-way ANOVA we evaluated if MBL modulated the effects of diabetes by testing the interaction between diabetes and MBL. RESULTS: MBL interacted with the effects of diabetes on three outcome measures: kidney weight (p < 0.001), urinary albumin excretion (p = 0.001) and the expression of collagen IV alpha 1 (Col4a1) mRNA (p = 0.002). This means that the effects that diabetes normally has on these parameters were significantly modified by MBL. MBL showed a tendency to interact with the effects of diabetes on glomerular basement membrane thickness and total mesangial volume (p = 0.065 and p = 0.063, respectively). Glomerular volume and total mesangial volume were significantly smaller in animals lacking MBL than in wild-type animals (p = 0.006 and p = 0.047, respectively). CONCLUSIONS/INTERPRETATION: These findings, for the first time, show that the degree of kidney alteration as a consequence of diabetes is modified by MBL. These findings support a pivotal role of MBL in the development of diabetic kidney disease.

Modulation of chemokine gene expression in CD133+ cord blood-derived human mast cells by cyclosporin A and dexamethasone.

We have recently developed a protocol for generating huge numbers of mature and functional mast cells from in vitro differentiated umbilical cord blood cells. Using CD133 as a positive selection marker to isolate haematopoietic progenitors we routinely expand the number of recovered cells at least 150-fold, which vastly exceeds the yields of conventional protocols using CD34+ cells as a source of progenitors. Taking advantage of the large quantities of in vitro differentiated mast cells, here we assess at the levels of transcription and translation the kinetics of chemokine gene induction following receptor mediated mast cell activation or following pharmacological activation of specific signal transduction cascades that become activated upon classical FcepsilonRI receptor crosslinking. We demonstrate that chemokine genes encoding IL-8, MCP-1, MIP-1alpha, and MIP-1beta are induced with different kinetics and with different amplitudes in a receptor activation dependent manner, and that these events can be mimicked using pharmacological agents which activate distinct signal transduction pathways. These findings were corroborated by adding immunomodulators such as cyclosporin A and dexamethasone prior to mast cell activation. Finally, we demonstrate that the same modulators added after mast cell activation can differentially quench ongoing chemokine gene induction. Thus, considering the vast yields of mast cells, our protocol is valuable not only for studying regulation of gene expression in mast cells in general, but also as an experimental tool to develop better and more balanced treatments of mast cell related disorders.

Hormonal regulation of mannan-binding lectin synthesis in hepatocytes.

Activation of the complement system via the plasma protein mannan-binding lectin (MBL) provides a first line of defence against infections. The plasma level of MBL is, in part, determined genetically, but may also be influenced by different hormones in vivo. Here we study the hormonal regulation of MBL synthesis from the human hepatocyte cell line HuH-7. Cells were exposed to medium with growth hormone (GH), hydrocortisone, insulin-like growth factor (IGF)-1, insulin, interleukin (IL)-6 or thyroid hormones (T3 or T4). After 3 days the concentration of MBL in the culture supernatants was determined and the amount of mRNA for MBL was measured, relative to mRNA for beta2 microglobulin. GH, IL-6, T3 and T4 significantly increased MBL synthesis in a dose-dependent manner, while hydrocortisone, insulin and IGF-1 had no effect. T3 caused a fourfold increase at 1 nM of T3 (P < 0.001) and at 100 nM of T3 the production was increased more than eightfold. The effect of T4 was less potent, reaching an eightfold increase at 1 microM of T4 (P < 0.001). GH augmented the production of MBL threefold at a concentration of 100 ng/ml (P = 0.018) with no further effect up to 10 microg/ml, whereas IL-6 caused only a very weak increase in MBL production. MBL mRNA levels were stable during the first 24 h of T3 stimulation but increased significantly between 24 and 48 h. The results suggest that MBL synthesis in humans may be increased by thyroid hormone and GH, whereas it does not exhibit a classical IL-6-dependent response.