Plasma Mannose Research Articles

High mannose correlates with surrogate indexes of insulin resistance and predicts cardiovascular events independently of glycaemic status and traditional risk factors

Abstract Background Plasma mannose, an emerging marker of insulin resistance (IR), is independently associated with coronary artery disease and cardiovascular (CV) events, not only in patients with altered glycaemic status, but also among those with normal glucose tolerance (NGT) [1, 2]. Whether mannose is a predictor of future CV events is not known. Purpose To investigate the association of mannose with surrogate indexes of IR as well as with long-term prognosis in patients with and without dysglycaemia. Methods Fasting plasma mannose was measured by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS-MS) in 696 cases with a first myocardial infarction (MI) and 707 controls matched for age, gender and living area from the PAROKRANK study [3]. Subjects free of known diabetes were further categorized as having either NGT (n=1045) or newly detected dysglycaemia (i.e., impaired glucose tolerance or type 2 diabetes; n=358) according to the results of an oral glucose tolerance test (OGTT). Surrogate indexes of IR and insulin secretion were calculated using glucose, insulin and C-peptide levels measured at 0, 30 and 120 minutes during the OGTT. The relationship between plasma mannose and different indexes was explored by fitting univariate and multivariate linear regression models. Kaplan-Meier functions were used to estimate crude survival across mannose quartiles. Unadjusted and adjusted Cox proportional hazards models were used to investigate the prognostic capacity of mannose, categorized as high (top quartile) vs low (lowest three quartiles), in relation to major adverse cardiac events (MACE) defined as CV death, MI and stroke during 10 years of follow-up. Secondary outcomes were single components of MACE and all-cause mortality. Results Mannose levels were associated with indexes of IR independently of BMI and other covariates in both the NGT and dysglycaemia subgroups. There was no difference in crude MACE-free survival between subjects with high and low mannose (log-rank p=0.10; Figure 1). However, high mannose remained as the only predictor of MACE in the overall population (Hazard ratio (HR): 1.58 (1.10-2.27); p=0.014) after multiple adjustments (Figure 2). This association was independent of the presence of dysglycaemia (interaction p between mannose category and dysglycaemia group=0.94) and IR expressed as HOMA-IR. High mannose also predicted MI, independently of the presence of a first MI (HR: 1.62 (1.00-2.62); p=0.050), while there was no significant association with the other secondary outcomes. Conclusions In a case-control setting of first MI, high mannose was the only significant predictor of future CV events, independently of traditional CV risk factors including a previous MI, glycaemic state and IR. Our findings expand the knowledge indicating that mannose might be used as a clinical tool for CV risk stratification.

Altered mannose metabolism in chronic stress and depression is rapidly reversed by vitamin B12.

GDP-Mannose Pyrophosphorylase B (GMPPB) is a key enzyme for glycosylation. Previous studies suggested a dysregulation of GMPBB and mannose in depression. Evidence, however, was sporadic and interventions to reverse these changes are unknown. Here, we show that GMPPB protein, but not RNA abundance is increased in the postmortem prefrontal cortex (PFC) of depressed patients and the chronic variable stress (CVS) mouse-model. This is accompanied by higher plasma mannose levels. Importantly, a single dose of intraperitoneally administered vitamin B12, which has previously been shown to rapidly reverse behavioral symptoms and molecular signatures of chronic stress in mice, normalized GMPPB plasma mannose levels and elevated GDP-mannose abundance. In summary, these data underline metabolic dysregulation in chronic stress and depression and provide further support for rapid effects of vitamin B12 on chronic stress.

Plasma mannose as a novel marker of myocardial infarction across different glycaemic states: a case control study

BackgroundPlasma mannose, an emerging novel biomarker of insulin resistance, is associated with both diabetes mellitus and coronary atherosclerosis, but the relationship between mannose concentrations and myocardial infarction (MI) across different glycaemic states remains to be elucidated. The aim of this study was to investigate the independent association between mannose and a first MI in a group of subjects characterized according to their glycaemic state.MethodsFasting plasma mannose concentrations were analysed in 777 patients 6–10 weeks after a first myocardial infarction and in 770 matched controls by means of high-performance liquid chromatography coupled to tandem mass spectrometry. Participants without known diabetes mellitus were categorized by an oral glucose tolerance test (OGTT) as having normal glucose tolerance (NGT, n = 1045), impaired glucose tolerance (IGT, n = 246) or newly detected type 2 diabetes (T2DM, n = 112). The association between mannose and MI was investigated across these glycaemic states by logistic regression.ResultsMannose levels increased across the glycaemic states (p < 0.0001) and were significantly associated with a first MI in the whole study population (odds ratio, OR: 2.2; 95% CI 1.4 to − 3.5). Considering the different subgroups separately, the association persisted only in subjects with NGT (adjusted OR: 2.0; 95% CI 1.2–3.6), but not in subgroups with glucose perturbations (adjusted OR: 1.8, 95% CI 0.8–3.7).ConclusionsMannose concentrations increased across worsening levels of glucose perturbations but were independently associated with a first MI only in NGT individuals. Thus, mannose might be a novel, independent risk marker for MI, possibly targeted for the early management of previously unidentified patients at high cardiovascular risk.

Associations between serum lipids and mannose levels in coronary artery disease among nondiabetic patients.

Aim: Nondiabetic patients have been studied to determine whether modest elevations in plasma mannose levels may be associated with a greater incidence of coronary artery disease (CAD). Materials & methods: The plasma mannose, lipids (triglyceride, low-density lipoprotein, high-density lipoprotein, verylow-density lipoprotein) and lactate dehydrogenase levels were successfully evaluated with respect to subsequent CADusing records of120 nondiabetic patients and 120 healthy volunteers. CAD was identified from myocardial infarction and new diagnoses of angina. Results: Of 120 patients studied, the plasma mannose, triglyceride, lactate dehydrogenase and very low-density lipoprotein levels of patients were significantly higher than control groups. Conclusion: Our findings showed that elevated baseline mannose in plasma was associated with a progressive risk of CAD with time.

Systems Biology: A Multi-Omics Integration Approach to Metabolism and the Microbiome

The complex and dynamic nature of human physiology, as exemplified by metabolism, has often been overlooked due to the lack of quantitative and systems approaches. Recently, systems biology approaches have pushed the boundaries of our current understanding of complex biochemical, physiological, and environmental interactions, enabling proactive medicine in the near future. From this perspective, we review how state-of-the-art computational modelling of human metabolism, i.e., genome-scale metabolic modelling, could be used to identify the metabolic footprints of diseases, to guide the design of personalized treatments, and to estimate the microbiome contributions to host metabolism. These state-of-the-art models can serve as a scaffold for integrating multi-omics data, thereby enabling the identification of signatures of dysregulated metabolism by systems approaches. For example, increased plasma mannose levels due to decreased uptake in the liver have been identified as a potential biomarker of early insulin resistance by multi-omics approaches. In addition, we also review the emerging axis of human physiology and the human microbiome, discussing its contribution to host metabolism and quantitative approaches to study its variations in individuals.

Molecular and Biochemical Parameters Related to Plasma Mannose Levels in Coronary Artery Disease Among Nondiabetic Patients

Aims: Nondiabetic patients were studied to determine whether modest elevations in plasma mannose may be associated with a greater incidence of coronary artery disease (CAD). Materials and Methods: Plasma insulin, mannose, glucose, hexokinase 1-2, GLUT1-GLUT4 levels, and serum mannose phosphate isomerase enzyme levels were evaluated with respect to subsequent CAD using records from 120 nondiabetic CAD patients and 120 healthy volunteers. CAD was identified from myocardial infarction and new diagnoses of angina. Results: Of 120 nondiabetic CAD patients studied, their plasma GLUT4 and HK1 levels were significantly lower than those of the control group. In addition, a significant increase in plasma mannose levels was found in the patient group compared to the control group. Conclusion: Our findings showed that elevated baseline mannose levels in plasma are associated with an increased risk of CAD over time.

Quantification of d-mannose in plasma: Development and validation of a reliable and accurate HPLC-MS-MS method

The present paper describes the development and the validation process – in compliance with the EMA guidelines – of a method based on tandem mass spectrometry coupled to liquid chromatography for the accurate quantification of mannose in human plasma samples. The quick sample preparation procedure, simplified by the absence of any derivatization step, makes the assay suitable for routine use in a clinical chemistry laboratory. The method validation yielded satisfactory selectivity, with a good separation of mannose from its epimers (glucose and galactose), linearity over the whole concentration range of interest (0.31–40 μg/mL), reproducibility with RSD <10%, and accuracy in the range 96–104%. Instrumental LLOD (0.31 μg/mL) and LLOQ (1.25 μg/mL) were good enough to detect endogenous plasma mannose levels and in agreement with recent data from the literature. Sensitivity was affected by a 5-fold dilution factor, which, if necessary, can be reduced. The method robustness was proven in >600 injections, most of them being of plasma samples, used also to assess the reference ranges in healthy subjects (9.93 ± 3.37 μg/mL) and type 2 diabetic patients (23.47 ± 6.19 μg/mL).

Modulation of plasma and urine metabolome in colorectal cancer survivors consuming rice bran.

Rice bran has bioactive phytochemicals with cancer protective actions that involve metabolism by the host and the gut microbiome. Globally, colorectal cancer (CRC) is the third leading cause of cancer-related death and the increased incidence is largely attributed to poor dietary patterns, including low daily fiber intake. A dietary intervention trial was performed to investigate the impact of rice bran consumption on the plasma and urine metabolome of CRC survivors. Nineteen CRC survivors participated in a randomized-controlled trial that included consumption of heat-stabilized rice bran (30 g/day) or a control diet without rice bran for 4 weeks. A fasting plasma and first void of the morning urine sample were analyzed by non-targeted metabolomics using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). After 4 weeks of either rice bran or control diets, 12 plasma and 16 urine metabolites were significantly different between the groups (p≤0.05). Rice bran intake increased relative abundance of plasma mannose (1.373-fold) and beta-citrylglutamate (BCG) (1.593-fold), as well as increased urine N-formylphenylalanine (2.191-fold) and dehydroisoandrosterone sulfate (DHEA-S) (4.488-fold). Diet affected metabolites, such as benzoate, mannose, eicosapentaenoate (20:5n3) (EPA), and N-formylphenylalanine have been previously reported for cancer protection and were identified from the rice bran food metabolome. Nutritional metabolome changes following increased consumption of whole grains such as rice bran warrants continued investigation for colon cancer control and prevention attributes as dietary biomarkers for positive effects are needed to reduce high risk for colorectal cancer recurrence.

Fasting plasma mannose levels are associated with insulin sensitivity independent of BMI in Japanese individuals with diabetes

BackgroundRecently, an integrated network analysis has revealed dysregulation in the metabolism of mannose, a glucose epimer, in severely obese individuals without diabetes. In addition, fasting plasma mannose levels (M0) are associated with insulin resistance independent of BMI. Since the association between mannose and insulin sensitivity (IS) in those with impaired glucose tolerance remains unknown, we aimed to investigate this association in individuals without severe obesity but with varying degrees of glucose tolerance.MethodsBased on 75 g OGTT data in Japanese individuals without diabetic medication, individuals were classified as having normal glucose tolerance (NGT), impaired glucose metabolism (IGM), or diabetes (DM). In each group, 25 individuals were consecutively recruited [total 75 individuals, age: 65 ± 11 (mean ± SD); BMI: 24.9 ± 3.8 kg/m2]. QUICKI and Matsuda index (MI) were calculated as IS indices. M0 was assayed using HPLC. Normally-distributed loge-transformed (ln-) values were used for MI and leptin.ResultsIn the simple regression analysis, ln-MI was negatively correlated with BMI (NGT: r = − 0.639, IGM: r = − 0.466, DM: r = − 0.613) and ln-leptin (NGT: r = − 0.480, IGT: r = − 0.447, DM: r = − 0.593) in all 3 groups. Ln-MI was not significantly correlated with M0 in NGT (r = 0.241, P = 0.245) and IGT (r = − 0.296, P = 0.152) groups, it was moderately and negatively correlated in the DM group (r = − 0.626, P < 0.001). Similar results were obtained, when QUICKI was used instead of MI as an index of IS. In multiple regression analysis in the DM group, QUICKI (Q) and ln-MI (M) were independently predicted by BMI (Q: β = − 0.413; M: β = − 0.400) and M0 (Q: β = − 0.413, M: β = − 0.426), accounting for 51.2% (P = 0.0004) and 51.2% (P = 0.0004) of the variability, respectively, which was larger than the prediction for BMI alone (Q: 38.4%, M: 37.6%).ConclusionFasting plasma mannose was associated with IS independent of BMI in Japanese individuals with DM.

Fasting Plasma Mannose Level Is Associated with Insulin Sensitivity Independent of BMI in Japanese Individuals with Diabetes

Recently, integrated network analysis has revealed dysregulation in the metabolism of mannose, an epimer of glucose, in individuals with severe obesity who do not have significant diabetes. It was also found that fasting plasma mannose levels (M0) are associated with insulin resistance independent of BMI. Since the association between mannose and insulin sensitivity (IS) in those with impaired glucose tolerance remains unknown, we aimed to investigate the association in individuals with varying degrees of glucose tolerance. Based on data of 75g OGTT in Japanese individuals without diabetic medication, individuals were classified as normal (NGT), impaired glucose tolerance (IGT), and diabetes (DM). In each group, 25 subjects were consecutively recruited [total 75 individuals, age: 65±11 (mean±SD); BMI: 24.9±3.8]. Matsuda index (MI) was calculated as an index of IS. M0 was assayed using HPLC. Normally-distributed loge-transformed (ln-) values were used for MI and leptin. Although fasting plasma glucose (G0), HbA1c, and ln-MI were significantly different among 3 groups, age, sex, BMI, and M0 were not different. In simple regression analysis, ln-MI was negatively correlated with BMI (NGT: r=-0.639, IGT: r=-0.466, DM: r=-0.613) and ln-leptin (NGT: r=-0.480, IGT: r=-0.447, DM: r=-0.593) in all 3 groups. Interestingly, although ln-MI was not significantly correlated with M0 in NGT (r=0.241, P=0.245) and IGT (r=-0.296, P=0.152), it was moderately and negatively correlated in DM (r=-0.626, P&amp;lt;0.001). In DM, ln-MI was slightly correlated with G0 (r=-0.484, P=0.014). In multiple regression analysis in DM, ln-MI was independently predicted by BMI (β=-0.400) and M0 (β=-0.426), accounting for 51.2% (P&amp;lt;0.001) of the variability, which was larger than that in the prediction by BMI alone (37.6%). In conclusion, in our study, fasting plasma mannose was associated with insulin sensitivity independent of BMI in Japanese individuals with diabetes. Disclosure E. Amano: None. S. Funakoshi: None. K. Yoshimura: None. S. Hirano: None. S. Ohmi: None. Y. Terada: None. S. Fujimoto: None.

Plasma mannose level, a putative indicator of glycogenolysis, and glucose tolerance in Japanese individuals.

Aims/IntroductionMannose is a monosaccharide constituent of glycoproteins and glycolipids. Experiments in rats have shown previously that the plasma mannose level decreases after glucose load, but does not decrease in diabetic rats, and that hepatic glycogenolysis is a source of this plasma mannose; however, these results are not fully elucidated in humans. Plasma mannose levels before/after glucose loading in humans with various degrees of glucose intolerance were examined to analyze their association with clinical factors.Materials and MethodsThe 75‐g oral glucose tolerance test was carried out in Japanese individuals not taking diabetes medications. Participants were classified into normal glucose tolerance, impaired glucose metabolism and diabetes mellitus groups. Insulinogenic index as an index of insulin secretion, and Matsuda Index as an index of insulin sensitivity were calculated. Mannose was assayed by the established method using high‐performance liquid chromatography after labeling.ResultsAfter glucose load, the plasma mannose level decreased gradually in the normal glucose tolerance group, but did not decrease in the diabetes mellitus group. Plasma mannose changes during 120 min from baseline (M120‐M0) were significantly different among the three groups (normal glucose tolerance: −16.7 ± 1.7; impaired glucose metabolism: −9.0 ± 1.9; diabetes mellitus: −1.4 ± 1.8 μmol/L [n = 25 in each group], P < 0.0001). Plasma glucose 120 min after glucose loading (R 2 = 0.412) or loge‐insulinogenic index, loge‐Matsuda Index and age (R 2 = 0.230) were determinants of M120‐M0 in multiple regression analyses.ConclusionsWe clarified the relationship between plasma mannose level and glucose tolerance in humans. The present results are compatible with those using rats, in which mannose derived from glycogenolysis plays an important role in the alteration of mannose levels after glucose loading.

Integrated Network Analysis Reveals an Association between Plasma Mannose Levels and Insulin Resistance

To investigate the biological processes that are altered in obese subjects, we generated cell-specific integrated networks (INs) by merging genome-scale metabolic, transcriptional regulatory and protein-protein interaction networks. We performed genome-wide transcriptomics analysis to determine the global gene expression changes in the liver and three adipose tissues from obese subjects undergoing bariatric surgery and integrated these data into the cell-specific INs. We found dysregulations in mannose metabolism in obese subjects and validated our predictions by detecting mannose levels in the plasma of the lean and obese subjects. We observed significant correlations between plasma mannose levels, BMI, and insulin resistance (IR). We also measured plasma mannose levels of the subjects in two additional different cohorts and observed that an increased plasma mannose level was associated with IR and insulin secretion. We finally identified mannose as one of the best plasma metabolites in explaining the variance in obesity-independent IR.

HIV-1 Disease Progression and Survival in an Adult Population in Zimbabwe: Is There an Effect of the Mannose Binding Lectin Deficiency?

HIV infection remains a major global health burden since its discovery in 1983. Sub-Saharan Africa is the region hardest hit by the HIV/AIDS pandemic where 63% of the 33 million infected people live. While there is marked person-to-person variability in susceptibility, progression, and survival with HIV infection, there is a paucity of predictive diagnostics associated with these clinical endpoints. In this regard, the deficiency in plasma Mannose Binding Lectin (MBL) is a common opsonic defect reported to increase susceptibility infections, including HIV. To the best of our knowledge, we report here the first study on the putative role of MBL deficiency on HIV progression and survival in an African adult population. We hypothesized that MBL deficiency has a role to play in HIV infection by increasing HIV disease progression and decreasing survival. We assessed the role of MBL deficiency on HIV disease progression and survival in a Zimbabwean adult population enrolled in the Mupfure Schistosomiasis and HIV (MUSH) cohort. We analyzed blood samples for MBL levels, MBL2 genotypes, HIV-1 status, viral load, and CD4(+) T cell counts. Participants were followed for 3 years wherein the endpoints were measured at baseline, 6 weeks, and 3, 6, 12, 24, and 36 months. Disease progression was measured as the rate of decline in CD4(+) T cell counts and the rate of increase in HIV viral load. We assessed 197 HIV positive adults where 83% (164) were women with a median age of 31 years. Prevalence of plasma MBL deficiency (less than 100 μg/L) and MBL2 deficient genetic variants (A/O and O/O genotypes) was 21% (42 out of 197) and 39% (74 out of 190), respectively. We did not observe a significant role to explain individual variation in mortality, change of CD4(+) T cell count, and viral load by MBL plasma deficiency or MBL2 genetic variants from baseline to 3 years follow up period in this adult population. We suggest the need for global OMICS research and that the present findings attest to the large between-population variability in a host of factors that can predispose individuals susceptible to HIV progression and mortality. We therefore cannot recommend at this time the use of plasma MBL levels or MBL2 genetic variants as a prognostic marker in HIV infection, disease progression, and survival in this adult population in Africa.

Mannose binding lectin genotypes are not associated with increased risk of unexplained recurrent pregnancy loss

Immune response to infections has been associated with recurrent pregnancy loss (RPL). Low plasma mannose binding lectin (MBL) levels, an innate immunity factor in infections, has been related to RPL. In this study, we tested the hypothesis that MBL genotypes that are known to cause reduced plasma MBL levels are significantly more frequent among women experiencing unexplained RPL. This study included 219 Caucasian women diagnosed with unexplained RPL and 236 control women. All participants were genotyped for two promoter (-550 C > G and -221 G > C) and three missense (R52C, G54D and G57E) mutations in exon 1. These mutations are known to be associated with variations in plasma MBL levels. Genotype frequencies were estimated by gene counting and were compared to the expectation of Hardy-Weinberg equilibrium by chi-squared (X(2)) analysis and Fisher's exact test. Allele and genotype frequencies were compared in cases and controls using X(2) contingency table analysis. There was no difference in demographics between cases and controls. The number of miscarriages in the participants with RPL ranged from 2 to 10 spontaneous abortions (SAB's) per participant. Populations genotyped were in Hardy-Weinberg equilibrium. There was no association between a history of RPL and multi-SNP genotypes at the MBL locus. In unexplained RPL, the number of SAB's and live birth rates were unaffected by MBL genotype. There was no association between MBL genotype and the risk of unexplained RPL. The occurrence of live birth was not associated with MBL genotype. Genotypes known to cause low MBL plasma levels are not associated with an increased risk of unexplained RPL.

Increased circulating plasma mannose binding lectin associated serine protease (MASP) as a result of enu-induced mutation in MASP-1

<h3>Aim</h3> The study of immune responses in animal models has been paramount in guiding current understanding of human immune function. N-ethyl-N-nitrosourea (ENU) is a chemical mutagen that introduces a high rate of random point mutations into the mouse germline. ENU directed mutagenesis resulted in a C-T base change, (amino acid 550, E→K) in exon 13 of mannose-binding lectin associated serine protease (MASP) 1. MASP-1^ENU mice were studied to assess changes in free MASP and other blood parameters. <h3>Methods</h3> MASP-1 level was determined by ELISA (USCN Life Science) and blood physiology compared between affected and unaffected mice (unpaired T test, 95%CI). Differential blood count (RBC, platelet, neutrophil lymphocyte, monocyte, eosinophil, ba-sophil, reticulocytes) and haematological parameters (haemoglobin, haematocrit, mean cell volume) were assessed (ADVIA). <h3>Results</h3> The MASP-1^ENU pedigree was viable. Both heterozygous and homozygous MASP-1^ENU mice demonstrated significantly elevated levels of free MASP-1 in circulation (<i>p</i> < 0.05 for both heterozygotes and homozygotes compared to unaffected). Mutation in MASP-1 did not result in changes in any of the other blood parameters studied. <h3>Conclusions</h3> The novel ENU-induced MASP-1 mutation resulted in increased circulating plasma MASP suggesting mutation in the peptidase-S1A region of MASP-1 may impact on binding of MASP to MBL. Dissociation of MASP/MBL may result in alterations in important MASP dependant pathways including complement and coagulation.

Sustained high plasma mannose less sensitive to fluctuating blood glucose in glycogen storage disease type Ia children

Plasma mannose is suggested to be largely generated from liver glycogen-oriented glucose-6-phosphate. This study examined plasma mannose in glycogen storage disease type Ia (GSD Ia) lacking conversion of glucose-6-phosphate to glucose in the liver. We initially examined fasting--and postprandial 2 h--plasma mannose and other blood carbohydrates and lipids for seven GSD Ia children receiving dietary interventions using cornstarch and six healthy age-matched children. Next, one-day successive intra-individual parameter changes were examined for six affected and two control children. Although there were no significant differences in fasting--and postprandial 2 h--glucose and insulin levels, the mannose level of the affected group was invariably much higher than that of the control group (p < 0.001): the fasting level of the affected group was about two-fold that of the control group; the postprandial-2 h level remained almost unchanged in the affected group, although it was one-half of the fasting level in the control group. Inter-individual analyses revealed that the GSD Ia group mannose level was significantly and positively correlated with lactate and triglycerides levels at both time points (p < 0.01). In each control, mannose levels fluctuated greatly, maintaining strong and significant negative correlations with glucose and insulin levels (p < 0.001). Correlations were lower or nonexistent in GSD Ia children. In individuals with high lactate and triglycerides levels, strikingly high mannose levels never changed against glucose and insulin fluctuations. Plasma mannose is less sensitive to blood glucose and insulin in GSD Ia children. Its basal level and the fluctuation pattern differ by their metabolic activity.

Increased plasma mannose binding lectin levels are associated with bronchiolitis obliterans after lung transplantation

Increased plasma mannose binding lectin levels are associated with bronchiolitis obliterans after lung transplantation

Increased plasma mannose binding lectin levels are associated with bronchiolitis obliterans after lung transplantation

BackgroundLong-term lung allograft survival is limited by bronchiolitis obliterans syndrome (BOS). Mannose binding lectin (MBL) belongs to the innate immune system, participates in complement activation, and may predispose to graft rejection. We investigated mannose binding (MBL) during cold ischemia and in tissue samples from explanted lungs with BOS, and assessed MBL and complement proteins in plasma post-lung transplantation relative to BOS staging.MethodsMBL was detected by immunohistochemistry lung tissue at the time of cold ischemia and in samples with BOS. MBL was assayed in the peripheral blood of 66 lung transplant patients transplanted between 1990–2007.ResultsMBL localized to vasculature and basement membrane during cold ischemia and BOS. Patients further out post-lung transplant > 5 years (n = 33), had significantly lower levels of MBL in the blood compared to lung transplant patients < 5 years with BOS Op-3 (n = 17), 1738 ± 250 ng/ml vs 3198 ± 370 ng/ml, p = 0.027, and similar levels to lung transplant patients < 5 years with BOS 0 (n = 16), 1738 ± 250 ng/ml vs 1808 ± 345 ng/ml. MBL levels in all BOS 0 (n = 30) vs. all BOS Op-3 (n = 36) were 1378 ± 275 ng/ml vs. 2578 ± 390 ng/ml, p = 0.001, respectively. C3 plasma levels in BOS 0 (n = 30) vs. BOS Op-3 (n = 36) were 101 ± 19.8 mg/ml vs. 114 ± 25.2 mg/ml, p = 0.024, respectively.ConclusionsMBL localizes within the lung during graft ischemia and BOS, higher levels of plasma MBL are associated with BOS Op-3 and < 5 years post-transplant, and higher level of plasma complement protein C3 was associated with BOS Op-3 clinical status. MBL may serve as a biomarker for poorer outcome post-lung transplantation.

Effects of metformin on plasma concentrations of glucose and mannose, G6Pase and PEPCK activity, and mRNA expression in the liver and kidney of chickens

1. The objective of this study was to determine the effects of the gluconeogenesis inhibitor metformin on 21-d old chickens. The following parameters were measured in the liver and kidney: plasma glucose, plasma mannose, enzyme activities and mRNA expression levels of glucose-6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK). 2. Chickens were divided into two groups, and received either metformin (300 mg/kg body weight) or water. Plasma glucose and mannose concentrations were analysed by high performance liquid chromatography (HPLC). G6Pase and PEPCK activities were determined by glucose 6-phosphate and malic acid substrate methods, respectively. The expression levels of mRNA were determined by real-time PCR. 3. Plasma glucose and mannose reached their lowest concentrations 1 h after metformin administration. At 0·5 h–1 h after metformin administration, the enzyme activities and mRNA expression levels of G6Pase and PEPCK reached their lowest point in the kidney and their highest point in the liver. The decrease observed in the kidney may have been associated with reductions in both plasma glucose and mannose concentrations. 4. In conclusion, the effect of metformin on the kidney of chickens is similar to its effect in mammals. In contrast, no suppression of enzyme activity or mRNA expression was observed in chicken liver. Therefore, the mode of action of metformin, via AMPK activation, may be different in the chicken liver.

Inositol and Mannose Utilization Rates in Term and Late-Preterm Infants Exceed Nutritional Intakes

Nonglucose carbohydrates such as mannose and inositol are important in early growth and development, although little is known about their metabolism. Our aim in this study was to determine the plasma appearance rates (Ra) for mannose and inositol in newborns as an index of utilization and as an improved guide to supplementation practices. We studied late-preterm (n = 9) and term (n = 5) infants (median 34 wk gestation, range 33–41 wk) using a multiple isotope infusion start time protocol to determine Ra for each carbohydrate. The plasma mannose concentration [median (range)] was 69.83 (48.60–111.75) μmol/L and the Ra was 0.59 (0.42–0.98) μmol·kg−1·min−1 (854 μmol·kg−1·d−1). The plasma inositol concentration was 175.74 (59.71–300.60) μmol/L and Ra was 1.06 (0.33–1.75) μmol·kg−1·min−1 (1521 μmol·kg−1·d−1). The Ra for mannose and inositol are >10-fold higher than the amounts a breast-fed infant typically ingests, which are ∼6 μmol·kg−1·d−1 mannose and 150 μmol·kg−1·d−1 inositol. Thus, for both mannose and inositol, the newborn infant must produce these compounds from glucose at rates sufficient to meet nutritional requirements.