Vascular addressins in the uterus and pancreas of type 1 diabetic mice in early pregnancy.
Dong H,Burke S D,Croy B A
Distinctive patterns of vascular cell adhesion molecule expression in early mouse decidua establish niches that recruit different subtypes of immune cells. In normal gestation day (gd)8 decidua, vascular cell adhesion molecule (VCAM)-1 and mucosal addressin cell adhesion molecule (MAdCAM)-1 occur in different regions enriched by uterine Natural Killer (uNK) cells and monocytes, respectively. UNK cells prepare endometrial spiral arteries for pregnancy-induced structural modifications, a process deficient in decidua of type 1 diabetic mice and women. In non-obese diabetic (NOD) mice, onset of insulitis coincides with islet expression of VCAM-1, MAdCAM-1 and peripheral lymph node addressin (PNAd), a molecule implicated in extravasation of human uNK precursor cells. We used immunohistochemistry to address the combined effects of diabetes and pregnancy on gd6 and 8 pancreatic and decidual expression of VCAM-1, MAdCAM-1 and PNAd and assessed the effect of diabetes on early uNK cell numbers. Normoglycemic (n) and diabetic (d) NOD and C57Bl/6 (B6) mice were studied. Pregnancy increased addressin expression in the pancreata of all mice with n- and d-NOD pancreata having stronger endothelial expression of VCAM-1, MAdCAM-1 and PNAd than B6. VCAM-1 expression was localized to uterine endothelium, including that of spiral arteries and was lower in d- than in n-NOD or B6 mice. MAdCAM-1 was localized to uterine endothelium and was lower in n- and d-NOD than in B6. PNAd expression was only observed in uterine epithelium and was stronger in d- than in n-NOD or B6. In all groups, only VCAM-1 had stronger expression in decidua than in pancreas. A mild elevation in uNK cells was present in n-and d-NOD mice at gd6 but not at gd8 when a higher proliferation index was found compared with B6. Thus, in type 1 diabetic gestations in mice, signals for the recruitment of circulating cells are reduced in uterus and elevated in pancreas.
Concentration of chemokines in peripheral blood in first trimester of diabetic pregnancy.
Wender-Ozegowska E,Michalowska-Wender G,Zawiejska A,Pietryga M,Brazert J,Wender M
Acta obstetricia et gynecologica Scandinavica
BACKGROUND:Several types of regulators (i.e. chemokines and metalloproteinases) are considered to play a crucial role in pregnancy by local modulation of the immune system at the level of peripheral leukocytes. The aim of this study was to determine whether changes in chemokines (interferon-gamma-inducible protein (IP-10), monocyte chemotactic peptide-1(MCP-1), cytokines regulated upon activation normal T cell expressed and secreted (RANTES) and matrix metalloproteinase-9 (MMP-9)) concentrations in diabetic patients could affect the course of pregnancy. METHODS:The study group consisted of 65 diabetics in the first trimester of pregnancy. Some 47 pregnancies were successfully continued to delivery, 18 were terminated with spontaneous miscarriages. Twenty healthy women matched for gestational age served as a control group. RESULTS:Glycated haemoglobin (HbA1C), vascular complications and lipoproteins (cholesterol, HDL-cholesterol, low density lipoprotein (LDL)-cholesterol and triglicerides) concentrations in maternal blood did not influence the chemokines concentrations. Lower RANTES level and higher MMP-9 concentrations were found in diabetic women. MCP-1 and RANTES levels differed significantly between pregnancies with good and poor perinatal outcome. A logistic regression model revealed that not only duration of diabetes, age of patients, HbA1C and insulin requirements, but also MMP-9,RANTES, MCP-1 and LDL-cholesterol levels seem to be involved in first trimester metabolism. CONCLUSIONS:Our results suggest the possible role of chemokines in early pregnancy development, especially in well-controlled diabetic patients, when hyperglycaemia is unlikely to be the main reason for an unfavourable outcome. Our results show that MCP-1 and RANTES might serve as predictive factors for an unfavourable outcome in diabetic pregnancy, whereas MMP-9 seems to be a marker of immunological changes related to mild hyperglycaemia. However, the open question of how the modulation of chemokines concentrations might be applied to prevent miscarriage in diabetic patients remains.
Epigenetics and cardiovascular risk in childhood.
Martino Francesco,Magenta Alessandra,Pannarale Giuseppe,Martino Eliana,Zanoni Cristina,Perla Francesco M,Puddu Paolo E,Barillà Francesco
Journal of cardiovascular medicine (Hagerstown, Md.)
Cardiovascular disease (CVD) can arise at the early stages of development and growth. Genetic and environmental factors may interact resulting in epigenetic modifications with abnormal phenotypic expression of genetic information without any change in the nucleotide sequence of DNA. Maternal dietary imbalance, inadequate to meet the nutritional needs of the fetus can lead to intrauterine growth retardation, decreased gestational age, low birth weight, excessive post-natal growth and metabolic alterations, with subsequent appearance of CVD risk factors. Fetal exposure to high cholesterol, diabetes and maternal obesity is associated with increased risk and progression of atherosclerosis. Maternal smoking during pregnancy and exposure to various environmental pollutants induce epigenetic alterations of gene expression relevant to the onset or progression of CVD. In children with hypercholesterolemia and/or obesity, oxidative stress activates platelets and monocytes, which release proinflammatory and proatherogenic substances, inducing endothelial dysfunction, decreased Doppler flow-mediated dilation and increased carotid intima-media thickness. Primary prevention of atherosclerosis should be implemented early. It is necessary to identify, through screening, high-risk apparently healthy children and take care of them enforcing healthy lifestyle (mainly consisting of Mediterranean diet and physical activity), prescribing nutraceuticals and eventual medications, if required by a high-risk profile. The key issue is the restoration of endothelial function in the reversible stage of atherosclerosis. Epigenetics may provide new markers for an early identification of children at risk and thereby develop innovative therapies and specific nutritional interventions in critical times.
Monocyte insulin receptors in infants of strictly controlled diabetic mothers.
Neufeld N D,Kaplan S A,Lippe B M
The Journal of clinical endocrinology and metabolism
Infants of diabetic mothers have hyperinsulinism at birth, presumably resulting from maternal hyperglycemia or some other derangement of maternal metabolism, and are extremely sensitive to insulin. Such infants have significantly greater numbers of insulin receptors on cord blood monocytes compared to normal infants. To assess the role of maternal diabetic control, nine infants of insulin-dependent diabetic mothers, who were intensively treated during pregnancy, were studied. Maternal blood glucose values were measured during weekly out-patient visits throughout pregnancy, and insulin therapy was given to maintain fasting blood glucose values below 100mg/dl. When necessary, the patients were hospitalized early in pregnancy in order to achieve glucose control, and all patients were hospitalized for up to 2 weeks before delivery for strict glucose control. The mean birth weight (+/- SD) of these infants (3.23 +/- 0.23 kg) was lower than that of nine infants of mothers with gestational diabetes not receiving insulin or intensive efforts at maintenance of normoglycemia (3.99 +/- 0.12; P less than 0.01) and was not significantly different from that of normal infants (3.51 +/- 0.37 kg). Mean cord blood C-peptide levels (+/- SD), determined by RIA, were 1.6 +/- 0.78 ng/ml for infants of these strictly controlled diabetic mothers and 1.4 0.1 ng/ml for normal infants. Scatchard analysis of insulin binding to cord blood monocytes yielded mean receptor numbers for infants of diabetic mothers of 22,500 vs. 105,000 sites/cell for infants of diabetic mothers (P less than 0.001) and 26,600 sites/cell for normal infants. We conclude that the strict control of maternal diabetes during the last trimester of pregnancy prevents fetal hyperinsulinemia and is associated with the development of normal numbers of insulin receptors on the infants' monocytes.
L-selectin is down-regulated in umbilical cord blood granulocytes and monocytes of newborn infants with acute bacterial infection.
Bührer C,Graulich J,Stibenz D,Dudenhausen J W,Obladen M
The leukocyte glycoprotein L-selectin mediates an early step in the recruitment of leukocytes to sites of inflammation. L-Selectin surface expression is rapidly down-regulated by inflammatory signals in vitro. In a prospective study, we found L-selectin expression on umbilical cord blood granulocytes and monocytes to be significantly decreased in newborn infants with acute bacterial infection compared with controls (p < 0.01). A significantly reduced L-selectin expression of both granulocytes and monocytes was also found to be associated with an increased neutrophil immature/total ratio (p < 0.01) but not with other laboratory markers of neonatal sepsis. There was no apparent impact of prematurity, low birth weight, gestational hypertension, or gestational diabetes on L-selectin expression. Although the mode of delivery did not affect granulocyte L-selectin expression, umbilical cord blood monocytes showed an increased L-selectin expression after emergency cesarean delivery compared with samples obtained after elective cesarean or vaginal delivery (p < 0.01). We conclude that acute systemic inflammation results in down-regulation of granulocyte and monocyte L-selectin expression in vivo similar to that observed in vitro.
The role of CXC chemokine ligand 16 in physiological and pathological pregnancies.
Shi Jia-Wei,Yang Hui-Li,Fan Deng-Xuan,Yang Shao-Liang,Qiu Xue-Min,Wang Yan,Lai Zhen-Zhen,Ha Si-Yao,Ruan Lu-Yu,Shen Hui-Hui,Zhou Wen-Jie,Li Ming-Qing
American journal of reproductive immunology (New York, N.Y. : 1989)
The survival and development of a semi-allogeneic fetus during pregnancy require the involvement of a series of cytokines and immune cells. Chemokines are a type of special cytokine those were originally described as having a role in leukocyte trafficking. CXC chemokine ligand (CXCL) 16 is a member of the chemokine family, and CXC chemokine receptor (CXCR) 6 is its sole receptor. Emerging evidence has shown that CXCL16/CXCR6 is expressed at the maternal-fetal interface, by cell types that include trophoblast cells, decidual stroma cells, and decidual immune cells (eg, monocytes, γδT cells, and natural killer T (NKT) cells). The regulation of expression of CXCL16 is quite complex, and this process involves a multitude of factors. CXCL16 exerts a critical role in the establishment of a successful pregnancy through a series of molecular interactions at the maternal-fetal interface. However, an abnormal expression of CXCL16 is associated with certain pathological states associated with pregnancy, including recurrent miscarriage, pre-eclampsia, and gestational diabetes mellitus (GDM). In the present review, the expression and pleiotropic roles of CXCL16 under conditions of physiological and pathological pregnancy are systematically discussed.
Cell population data in neonates: differences by age group and associations with perinatal factors.
Lee J,Kim S Y,Lee W,Han K,Sung I K
International journal of laboratory hematology
INTRODUCTION:Cell population data (CPD) describe physical parameters of white blood cell subpopulations and are reported to be of some value in the diagnosis of sepsis in neonates. Before using the CPD for diagnosing sepsis, the baseline features of the CPD distribution in healthy neonates should be clarified. The aim of this study was to compare the CPD distributions of healthy neonates and other age groups and to identify perinatal factors that are associated with changes in the CPD distribution of healthy neonates. METHODS:The CPD distribution of 69 samples from term neonates was compared with adolescents and adults. The CPD distribution of 163 samples from healthy neonates was analyzed in association with perinatal factors, including gestational age, chronologic age, birthweight, delivery mode, premature rupture of membranes, diabetes, and pregnancy-induced hypertension. RESULTS:The CPD distribution for term neonates was significantly different from those in adolescents and adults. The mean lymphocyte volume showed a negative correlation with gestational age at birth (r = -0.305; P < 0.01). The mean neutrophil volume was smaller in the cesarean section group than in the normal delivery group. The small for gestational age (SGA) group had smaller mean neutrophil volume and mean monocyte volume than the appropriate for gestational age group. CONCLUSION:The CPD distribution of healthy neonates differed from those of adolescents or adults, and the differences were associated with gestational age, delivery mode, and being SGA.
Th2-Immune Polarizing and Anti-Inflammatory Properties of Insulin Are Not Effective in Type 2 Diabetic Pregnancy.
Fagninou Adnette,Nekoua Magloire Pandoua,Sossou Darius,Moutairou Kabirou,Fievet Nadine,Yessoufou Akadiri
Journal of immunology research
Background:The implication of the immune system in the physiopathology of pregnancy complicated by diabetes has been reported. Here, we investigated the effects of insulin treatment on the frequencies of immune cell subpopulations as well as T cell-derived cytokines in type 2 diabetic (T2D) pregnancy compared to gestational diabetes mellitus (GDM). Methods:Fifteen (15) women with GDM, twenty (20) insulin-treated T2D pregnant women, and twenty-five (25) pregnant controls were selected. Immune cell subpopulation frequencies were determined in blood using flow cytometry. The proliferative capacity of T cells was performed, and serum and cell culture supernatant cytokine levels were also quantified. Results:The frequencies of total CD3+ and CD4+ T cells and nonclassical monocytes significantly increased in insulin-treated T2D pregnant women compared to pregnant controls. The proportions of CD4+ T cells as well as B cells were significantly higher in women with GDM than in pregnant controls. GDM was associated with high frequencies of total CD3+ and CD4+ T cells and B cell expansion, suggesting a concomitant activation of cellular and humoral immunity. Concomitantly, Th1/Th2 ratio, determined as IFN-/IL-4, was shifted towards Th1 phenotype in women with GDM and insulin-treated T2D pregnant women. Besides, isolated T cells elicited similar proliferative capacity in the three groups of women. Insulin-treated T2D pregnant women and women with GDM exhibited a low serum IL-10 level, without any change in the number of Treg cells. Conclusion:Our study showed that, despite insulin treatment, pregnant women with T2D displayed a proinflammatory status consistent with high proportions of CD3+ and CD4+ T cells, upregulation of Th1 cytokines, and low IL-10 production, suggesting a reduced immune-suppressive activity of regulatory T cells. However, GDM, although associated with proinflammatory status, has shown increased humoral immunity consistent with high proportion of CD19+ B cells. Thus, the lack of response to insulin in diabetes during pregnancy and clinical implications of these immunological parameters deserves further investigations.
Nerve growth factor is closely related to glucose metabolism, insulin sensitivity and insulin secretion in the second trimester: a case-control study in Chinese.
Tang Mengyang,Luo Mingjuan,Lu Wenqian,Zhang Rong,Liang Wei,Gu Jianfen,Yu Xuemei,Zhang Xueli,Hu Cheng
Nutrition & metabolism
OBJECTIVE:Inflammation-related factors have been shown to play a significant role throughout pregnancy. In this study, we aimed to explore the relationships between selected inflammatory cytokines and gestational diabetes (GDM) in Chinese pregnant women. DESIGN AND METHODS:This was a 1:1 matched case-control study that included 200 pairs of subjects in the second trimester and 130 pairs of subjects in the third trimester. Serum levels of nerve growth factor (NGF), Interleukin-6 (IL-6), leptin, Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α) and Interleukin-1beta (IL-1β) were measured by enzyme immunoassay. The associations of these inflammatory factors with metabolic parameters were analysed. RESULTS:In the second trimester, GDM patients had higher NGF levels and lower IL-8 levels than did normal controls (P < 0.001 and P = 0.015, respectively). However, in the third trimester, only lower leptin levels were observed in the GDM group (P = 0.031). Additionally, in the second trimester, NGF levels were not only positively associated with fasting, 1-h and 2-h glucose levels and the area under curve of glucose, but also positively related to insulin sensitivity and secretion, as suggested by fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment index of β-cell secretion (HOMA-β) (all P < 0.05). Moreover, IL-6 and leptin levels were positively correlated with HOMA-IR and HOMA-β, and TNF-α levels were positively related to HOMA-IR (all P < 0.05). Except for the relationships between NGF and HOMA-β and TNF-α and HOMA-IR, the other correlations still existed even after adjusting for confounding factors (all P < 0.05). CONCLUSION:In addition to the positive associations of IL-6 and leptin with insulin resistance and secretion, NGF was higher in the GDM patients and strongly linked to glucose metabolism, insulin resistance and pancreatic β cell function in Chinese pregnant women in the second trimester.
Elevated Cholesteryl Ester Transfer Protein Activity Early in Pregnancy Predicts Prediabetes 5 Years Later.
Ueland Thor,Roland Marie Cecilie Paasche,Michelsen Annika E,Godang Kristin,Aukrust Pål,Henriksen Tore,Bollerslev Jens,Lekva Tove
The Journal of clinical endocrinology and metabolism
CONTEXT:Cholesteryl ester transfer protein (CETP) regulates high-density lipoprotein (HDL) cholesterol levels and interaction between glucose, and HDL metabolism is central in the development of diabetes. OBJECTIVE:We hypothesized that CETP levels would be regulated in diabetic pregnancies. We tested the hypothesis by evaluating CETP activity measured multiple times during pregnancy and at 5 years' follow-up in a prospective cohort (STORK) and investigated its association with gestational diabetes mellitus (GDM) during pregnancy or development of prediabetes 5 years after pregnancy. We also evaluated the strongest correlation of CETP activity among measures of adipocity and glucose metabolism, lipoproteins, adipokines, and monocyte/macrophage activation markers. DESIGN:A population-based longitudinal cohort study was conducted from 2001 to 2013. SETTING:The study setting was Oslo University Hospital. PATIENTS OR OTHER PARTICIPANTS:A total of 300 women during pregnancy and at 5 years postpartum participated in this study. MAIN OUTCOME MEASURES:CETP activity was measured at 14 to 16, 22 to 24, 30 to 32, and 36 to 38 weeks' gestation, and at 5 years' follow-up. RESULTS:We found higher CETP activity in pregnancy in women developing prediabetes but no association with GDM. CETP activity decreased throughout pregnancy and remained low at follow-up. High CETP activity was associated with sCD14 levels, in particular in women who developed prediabetes. These data show that enhanced CETP activity during pregnancy is associated with systemic indices of monocyte/macrophage activation, in particular in women who develop prediabetes later in life. CONCLUSIONS:CETP activity during pregnancy identifies women at risk for later diabetes development.
Elevated acetoacetate and monocyte chemotactic protein-1 levels in cord blood of infants of diabetic mothers.
Kurepa Dalibor,Pramanik Arun K,Kakkilaya Venkatakrishna,Caldito Gloria,Groome Lynn J,Bocchini Joseph A,Jain Sushil K
BACKGROUND:Infants of diabetic mothers (IDMs) are at increased risk for metabolic complications. Type 1 and some type 2 diabetic patients have elevated levels of the ketone bodies acetoacetate (AA) and β-hydroxybutyrate (BHB). OBJECTIVE:The aim of this study was to examine how hyperketonemia in diabetic mothers affects markers of inflammation and oxidative stress in their offspring. METHODS:Blood was obtained from 23 diabetic mothers and 13 healthy mothers and their infants' umbilical cords at delivery. Interleukin-8, monocyte chemotactic protein-1 (MCP-1) and protein carbonyl (protein oxidation) levels were determined by ELISA. U937 human monocyte cell culture was used to examine the effect of AA and BHB on secretion of MCP-1. RESULTS:There was a significant increase in the levels of AA in cord blood of IDMs compared with cord blood of infants of healthy mothers. A significant increase in the levels of protein oxidation (p < 0.05) and MCP-1 levels (p < 0.05) was observed in the cord blood of IDMs. The level of MCP-1 correlated significantly (r = 0.51, p = 0.01) with the concentration of AA in the IDMs. In further experiments with cultured monocytes treated with exogenous AA (0-4 mM), a significant increase in MCP-1 secretion was observed in AA- but not BHB-treated monocytes. CONCLUSION:Blood levels of AA and MCP-1 are elevated in IDMs, which may contribute to the development of the metabolic complications seen in IDMs.
Inflammatory markers in women with a recent history of gestational diabetes mellitus.
Di Benedetto A,Russo G T,Corrado F,Di Cesare E,Alessi E,Nicocia G,D'Anna R,Cucinotta D
Journal of endocrinological investigation
Gestational diabetes mellitus (GDM) is a risk factor for both Type 2 diabetes (DM2) and insulin-resistance syndrome (IRS). C-reactive protein (CRP), fibrinogen and leukocyte count are increased in the IRS and predict DM2 and cardiovascular disease (CVD). The chemochine monocyte chemoattractant protein-1 (MCP-1/CCL2) is also elevated in DM2 and CVD. Recent evidence suggests a relation between chronic inflammation and GDM, but post-delivery information on inflammatory markers in these high-risk women is lacking. Serum levels of CRP, fibrinogen, MCP-1/ CCL2, and leukocyte blood count have been assessed in 26 women with and 26 women without a recent history of GDM, matched for age, body mass index (BMI), post-partum duration and parity. DM2 was excluded in all the participants by an oral glucose tolerance test (OGTT). Women with previous GDM showed significantly higher CRP (p=0.007) and fibrinogen (p=0.02) serum concentrations, whereas MCP-1/CCL2 serum levels and leukocyte blood count were comparable in the two groups. Overall, CRP levels significantly correlated with BMI (r=0.40, p=0.03), waist-to-hip ratio (WHR) (r=0.44, p=0.001), fasting insulin (r=0.27, p=0.04), insulin-resistance assessed by means of the homeostatic model (HOMA) (r=0.28, p=0.04), and fibrinogen concentration (r=0.49, p=0.0001). At linear regression analysis, only WHR and fibrinogen were independently associated with CRP levels. In conclusion, the increase of inflammatory markers may be one of the first detectable disorders in healthy women at high risk of DM2 and IRS, like those with a GDM history.
Total adiponectin, but not inflammatory markers C-reactive protein, tumor necrosis factor-α, interluekin-6 and monocyte chemoattractant protein-1, correlates with increasing glucose intolerance in pregnant Chinese-Americans.
Kim So-Young,Sy Vanessa,Araki Takako,Babushkin Nicole,Huang Diana,Tan Doris,Liao Emilia,Liu George,Wan Stephen,Poretsky Leonid,Seto-Young Donna
Journal of diabetes
BACKGROUND:Elevated insulin, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 levels and decreased high molecular weight adiponectin (HMW-APN) levels have been reported in Caucasians with gestational diabetes mellitus (GDM). No similar studies have been performed in Chinese women. METHODS:Serum samples were obtained 1 h after a 50-g glucose challenge test (1HGCT) from Chinese-American women at 24-28 gestational weeks and total adiponectin (T-APN), HMW-APN, CRP, TNF-α, IL-6, and MCP-1 concentrations were measured. Correlation coefficients for glucose (1HGCT), HbA1c, insulin, and body mass index (BMI) were calculated against T-APN, HMW-APN, CRP, TNF-α, IL-6, and MCP-1. Significant P-values were determined using Bonferroni adjustments. RESULTS:Women with GDM had higher insulin and 1HGCT and lower T-APN. In addition, T-APN was lower in non-GDM subjects who had 1HGCT ≥135 mg/dL with no abnormal or one abnormal glucose value on the 3-h oral glucose tolerance test. There were no significant differences in HMW-APN and inflammatory marker levels between non-GDM and GDM groups. There were negative correlations between T-APN and 1HGCT, insulin, BMI, and HbA1c, as well as between HMW-APN and 1HGCT, insulin, and BMI. No significant correlations were observed between 1HGCT, HbA1c, insulin, or BMI and CRP, TNF-α, IL-6, or MCP-1. CONCLUSIONS:T-APN is reduced in Chinese women with GDM and those without GDM but with evidence of glucose intolerance. Unlike results reported for Caucasians, Chinese-American women with GDM do not exhibit elevated levels of CRP, TNF-α, IL-6, or MCP-1, possibly because Chinese women are relatively leaner compared with Caucasians.
The presence of gestational diabetes is associated with increased detection of anti-HLA-class II antibodies in the maternal circulation.
Steinborn Andrea,Saran Gaby,Schneider Andreas,Fersis Nicos,Sohn Christof,Schmitt Edgar
American journal of reproductive immunology (New York, N.Y. : 1989)
PROBLEM:Gestational diabetes (GD) may be associated with temporarily reduced immune tolerance toward alloantigens for the time of pregnancy. The aim of this study was to assess anti-HLA-class I and -II antibodies as markers for an aberrant immunostimulation in women with GD. METHOD OF STUDY:The percentage of anti-HLA-class I and -II antibodies was estimated in women with GD, normal term delivery and fetal distress, which was confirmed by demonstrating low cord blood pH for this patient group. These antibodies may cross the placental barrier and cause interleukin-6 (IL-6) release from fetal monocytes by cross-linking monocytes with antibody-loaded cells. Therefore we estimated the percentage of IL-6-positive monocytes in the fetal circulation of these three patient groups. RESULTS:We found a significantly increased percentage of anti-HLA-class II in the circulation of women with GD. In comparison with women with normal term delivery, a significantly increased percentage of IL-6-positive monocytes was detected for women with GD and for women with fetal distress. Significantly decreased cord blood pH were detected for neonates born in the presence of fetal distress but not for neonates born in the presence of GD. CONCLUSIONS:Our results suggest that GD is associated with an increased humoral immune response against HLA-class II antigens.
Circulating monocyte chemoattractant protein-1 in women with gestational diabetes.
Telejko Beata,Kuzmicki Mariusz,Zonenberg Anna,Niedziolko-Bagniuk Karolina,Nikolajuk Agnieszka,Szamatowicz Jacek,Gorska Maria
Folia histochemica et cytobiologica
Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a key factor in the recruitment and activation of peripheral blood leukocytes in atherosclerotic lesions and adipose tissue. Elevated levels of circulating MCP-1 have been found in patients with type 1 and type 2 diabetes, as well as with coronary artery disease. In this study we compared serum MCP-1 concentrations between pregnant women with normal glucose tolerance (NGT), gestational diabetes mellitus (GDM) and non-pregnant healthy women. The group studied consisted of 62 patients with GDM (mean age 30.1 +/- 5.0 years) at 29.0 +/- 3.5 week of gestation, 64 pregnant women with NGT (mean age 30.0 +/- 4.7 years) at 29.2 +/- 2.9 week of gestation and 34 non-pregnant healthy women (mean age 29.8 +/- 4.7 years). Serum MCP-1 concentration was measured using an enzyme - linked immunosorbent assay. Median MCP-1 concentrations did not differ significantly between women with GDM (median 342.3 [interquartile range 267.9-424.4] pg/ml) and NGT (338.0 [274.7-408.2] pg/ml), but were markedly lower than those found in non-pregnant women (485.2 [409.6-642.4] pg/ml, p<0.0001). After adjusting for glucose, the difference between pregnant and non-pregnant women remained highly significant (p<0.0001). In GDM patients MCP-1 levels correlated significantly with fasting glucose (r=0.2665, p=0.0363), insulin (r=0.4330, p=0.0004), HOMA-IR (r=0.4402, p=0.0003), ISQUICKI (r=-0.4402, p=0.0003), HbA1c (r=0.2724, p=0.0322), as well as with prepregnancy and current BMI (r=0.3501, p=0.0057 and r=0.3250, p=0.0106, respectively). Multiple regression analysis revealed that MCP1 concentrations were significantly predicted only by plasma glucose ( beta=0.3489, p=0.00004). Our results suggest that MCP1 levels are decreased in pregnant women, irrespective of their glucose tolerance status.
Maternal serum leptin, adiponectin, resistin and monocyte chemoattractant protein-1 levels in different types of diabetes mellitus.
Kapustin Roman V,Chepanov Sergey V,Babakov Vladimir N,Rogovskaya Nadezhda Y,Kopteeva Ekaterina V,Alekseenkova Elena N,Arzhanova Olga N
European journal of obstetrics, gynecology, and reproductive biology
OBJECTIVE:Evaluation of serum concentration of leptin, adiponectin, resistin, and MCP-1 in pregnant patients with different types of diabetes mellitus (DM) considering preconception planning and method of DM correction in 11-14th and 30-34th weeks of pregnancy. STUDY DESIGN:Longitudinal, prospective study included 130 pregnant women divided into the following comparison groups: type 1 DM (T1DM, n = 40), type 2 DM (T2DM, n = 35), GDM (n = 40), and the control group (n = 15). The ELISA method defined the levels of leptin, resistin, adiponectin, and MCP-1 concentration in serum, which was assessed in 11-14th and 30-34th weeks of pregnancy. Statistical analysis was accomplished using SPSS 23.0 and "Prism 8-GraphPad" software. RESULTS:The leptin level in the 1st trimester was the highest in T2DM insulin group compared to the control due to gestational age, hence in the 3rd trimester in all groups its serum concentrations appeared higher than in healthy patients (p = 0.0001). In the 1st trimester leptin levels directly correlated with women's BMI, newborns' weight and macrosomia rate, in the 3rd trimester - with OGTT levels, HbA1c, gestational hypertension, and preeclampsia rates. Resistin levels in the 1st and 3rd trimesters were increased in almost all DM groups compared to the control group (p = 0.0001). The study established direct positive correlation between resistin and HbA1c, birth weight, and preeclampsia. In the 1st trimester, adiponectin demonstrated the lowest levels in T2DM insulin compared to T1DM and the control group (p = 0.0001) while in the 3rd trimester, adiponectin levels declined alongside gestational age in DM patients and all the groups compared to the control group (p < 0.05). Adiponectin negatively correlated with BMI, OGTT levels, and preeclampsia rate. MCP-1 levels in T2DM appeared higher than in T1DM patients and the control group in the 1st trimester, whereas in the 3rd trimester MCP-1 declined, correlating with BMI, preeclampsia and OGTT levels. CONCLUSION:High rate of adverse perinatal outcomes in diabetic pregnancy might be developed due to more severe metabolic failures and further disturbances of adipokines expression.
Clinical significance of neutrophil-lymphocyte ratio and monocyte-lymphocyte ratio in women with hyperglycemia.
Wang Jing,Zhu Qing-Wen,Cheng Xiao-Yan,Sha Chun-Xiu,Cui Yu-Bao
: Abnormal pro-inflammatory regulation of the immune system might contribute to the pathogenesis of hyperglycemia during pregnancy. We examined the correlations of neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR) with disease severity and assessed their predictive values. : This retrospective case-control study included 311 cases of hyperglycemia first detected during pregnancy (HFDP) [153 with gestational diabetes mellitus (GDM) and 158 with diabetes in pregnancy (DIP)] and, as a control group, 172 pregnant women with normal glucose tolerance. The NLRs and MLRs were calculated from the blood test data. : The absolute leukocyte, neutrophil, monocyte, and lymphocyte counts as well as the NLR and MLR values of HFDP patients significantly differed from control values, but no significant differences were detected in the leukocyte, neutrophil, and monocyte counts of the GDM and DIP groups. Significantly different metrics were selected, binary analysis performed, and odds ratios calculated to identify risk factors. Age, BMI, NLR, and MLR were found to be risk factors for HFDP, and high systolic blood pressure (SBP) at triage and MLR related to the occurrence of DIP. Receiver operating characteristics curve analysis showed that NLR and MLR had better diagnostic accuracy in distinguishing HFDP from controls [NLR area under the curve (AUC) = 0.78; MLR AUC = 0.72] than age and BMI. Values for NLR > 4.394 or MLR > 0.309 correlated with the severity of maternal clinical symptoms and perinatal infant outcomes. MLR was the best predictor of DIP (AUC = 0.72) and MLR values > 0.299 could identify patients at risk for developing DIP and having poor fetal outcomes. : Metrics derived from peripheral blood neutrophil, monocyte, and lymphocyte counts are thought to reflect systemic immune-inflammation. Elevated MLR and NLR may be unfavorable prognostic factors for clinical outcomes in patients with hyperglycemia during pregnancy.
Centella asiatica and lipoic acid, or a combination thereof, inhibit monocyte adhesion to endothelial cells from umbilical cords of gestational diabetic women.
Di Tomo P,Di Silvestre S,Cordone V G P,Giardinelli A,Faricelli B,Pipino C,Lanuti P,Peng T,Formoso G,Yang D,Arduini A,Chiarelli F,Pandolfi A,Di Pietro N
Nutrition, metabolism, and cardiovascular diseases : NMCD
BACKGROUND AND AIMS:Diabetes mellitus is associated with inflammatory endothelial activation and increased vascular leukocyte adhesion molecule expression, both playing a prominent role in the development of vascular complications. Centella asiatica (CA) and Lipoic Acid (LA) have shown anti-inflammatory and anti-oxidant properties in a variety of experimental models; however, their action on human umbilical vein endothelial cells (HUVECs), chronically exposed to hyperglycemia and pro-inflammatory environment during pregnancy, is still unknown. METHODS AND RESULTS:In HUVECs from umbilical cords of gestational diabetic (GD) or healthy (C) women, both CA and LA affected tumor necrosis factor-α (TNF-α)-induced inflammation, being associated with a significant decrease in vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression (western blot) and exposure (flow cytometry), as well as monocyte-HUVECs interaction (adhesion assay). Notably, this was associated with a significant reduction of an index of nitro-oxidative stress, such as the intracellular peroxynitrite levels (fluorescence detection by cytometric analysis), Mitogen-Activated Protein kinase (p44/42 MAPK) expression/phosphorylation levels and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB p65) cytoplasm-nucleus translocation (flow cytometry). Overall our results indicate that both CA and LA used separately, and even better when combined, are effective to reduce the inflammatory response in TNF-α-treated HUVECs. Notably, this was more significant in GD than in C-HUVECs and also evident at baseline. CONCLUSION:In conclusion, our in vitro study demonstrates that both CA and LA, or a combination thereof, are able to mitigate the potentially dangerous effects on the endothelium of chronic exposure to hyperglycemia in vivo.
Circulating levels of MCP-1 are increased in women with gestational diabetes.
Klein Katharina,Satler Miriam,Elhenicky Marie,Brix Johanna,Krzyzanowska Katarzyna,Schernthaner Guntram,Husslein Peter W,Schernthaner Gerit-Holger
OBJECTIVE:We investigated whether gestational diabetes mellitus is associated with monocyte-chemoattractant-protein-1 (MCP-1) and soluble CD40 ligand (sCD40L), the functional relevant proteins in the inflammatory process. METHODS:In all 32 women with gestational diabetes mellitus, 18 women without gestational diabetes mellitus and 40 nonpregnant women were included. MCP-1 and sCD40L were measured at the time of the oral glucose tolerance test (second trimester), in the third trimester and postpartum. RESULTS:MCP-1 was higher in pregnant women (women with gestational diabetes mellitus and without) than in nonpregnant women (p < 0.001) in the third trimester, and also in the second trimester and postpartum. MCP-1 was elevated in patients with gestational diabetes mellitus in the third trimester compared to healthy pregnant women (p = 0.007). In gestational diabetes mellitus, MCP-1 increased from the second to the third trimester (p = 0.003). We found no association of sCD40L and gestational diabetes mellitus. CONCLUSION:The elevation of MCP-1 in the third trimester in gestational diabetes mellitus suggests an association between inflammation and GDM.
Association of oxidative stress biomarkers with gestational diabetes mellitus in pregnant women: a case-control study.
Zhu Chunyan,Yang Hongling,Geng Qingshan,Ma Qingling,Long Yan,Zhou Cheng,Chen Ming
OBJECTIVE:The relationship between gestational diabetes mellitus (GDM) and oxidative stress has not been fully elucidated. This study examined the association between biomarkers of oxidative stress and GDM. METHODS:We conducted a case-control study which included 36 women presenting with GDM and 36 asymptomatic matched control subjects who visited Guangzhou Women and Children's Medical Centre, China, from June 2012 to December 2012. Pregnant women were prospectively recruited to the study, and blood samples were collected at the time of a routine oral glucose tolerance test. These samples were then analyzed for levels of endocrine and surrogate markers of oxidative stress. RESULTS:Compared to control subjects, women with GDM exhibited elevated values for plasma glucose, insulin, and insulin resistance (IR), and showed reduced HOMA pancreatic β-cell function (HOMA-B), insulin sensitivity index (ISI), insulinogenic index, and corrected insulin response at 24-28 weeks gestation. A bivariate logistic regression analysis showed that levels of high-sensitivity C reactive protein (hs-CRP) and high fluorescence reticulocytes at fasting, and hs-CRP in a 1-h OGTT, were significantly associated with GDM. A linear regression analysis showed that levels of hs-CRP (P = 0.003) and reticulocytes (P = 0.029) at fasting were associated with IR, and levels of hs-CRP (P = 0.002) and monocytes (P = 0.006) in a 1-h OGTT were associated with ISI. CONCLUSIONS:Pregnant women with GDM developed a pathological IR and exhibited β-cell dysfunction. Their decreased ability to compensate for oxidative stress was associated with increased IR and a reduced ISI, which might be important factors in GDM.
Identifying common and specific microRNAs expressed in peripheral blood mononuclear cell of type 1, type 2, and gestational diabetes mellitus patients.
Collares Cristhianna V A,Evangelista Adriane F,Xavier Danilo J,Rassi Diane M,Arns Thais,Foss-Freitas Maria C,Foss Milton C,Puthier Denis,Sakamoto-Hojo Elza T,Passos Geraldo A,Donadi Eduardo A
BMC research notes
BACKGROUND:Regardless the regulatory function of microRNAs (miRNA), their differential expression pattern has been used to define miRNA signatures and to disclose disease biomarkers. To address the question of whether patients presenting the different types of diabetes mellitus could be distinguished on the basis of their miRNA and mRNA expression profiling, we obtained peripheral blood mononuclear cell (PBMC) RNAs from 7 type 1 (T1D), 7 type 2 (T2D), and 6 gestational diabetes (GDM) patients, which were hybridized to Agilent miRNA and mRNA microarrays. Data quantification and quality control were obtained using the Feature Extraction software, and data distribution was normalized using quantile function implemented in the Aroma light package. Differentially expressed miRNAs/mRNAs were identified using Rank products, comparing T1DxGDM, T2DxGDM and T1DxT2D. Hierarchical clustering was performed using the average linkage criterion with Pearson uncentered distance as metrics. RESULTS:The use of the same microarrays platform permitted the identification of sets of shared or specific miRNAs/mRNA interaction for each type of diabetes. Nine miRNAs (hsa-miR-126, hsa-miR-1307, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-144, hsa-miR-199a-5p, hsa-miR-27a, hsa-miR-29b, and hsa-miR-342-3p) were shared among T1D, T2D and GDM, and additional specific miRNAs were identified for T1D (20 miRNAs), T2D (14) and GDM (19) patients. ROC curves allowed the identification of specific and relevant (greater AUC values) miRNAs for each type of diabetes, including: i) hsa-miR-1274a, hsa-miR-1274b and hsa-let-7f for T1D; ii) hsa-miR-222, hsa-miR-30e and hsa-miR-140-3p for T2D, and iii) hsa-miR-181a and hsa-miR-1268 for GDM. Many of these miRNAs targeted mRNAs associated with diabetes pathogenesis. CONCLUSIONS:These results indicate that PBMC can be used as reporter cells to characterize the miRNA expression profiling disclosed by the different diabetes mellitus manifestations. Shared miRNAs may characterize diabetes as a metabolic and inflammatory disorder, whereas specific miRNAs may represent biological markers for each type of diabetes, deserving further attention.
Expression of toll-like receptor 4 in maternal monocytes of patients with gestational diabetes mellitus.
Xie Bao-Guo,Jin Song,Zhu Wei-Jie
Experimental and therapeutic medicine
Toll-like receptors (TLRs) are pattern recognition receptors and play an important role in innate immune responses and the occurrence of inflammatory disease. TLR4 is a member of the TLR family and its activation is capable of inducing inflammatory responses, reflecting a relationship between the innate and adaptive immune systems. However, whether TLR4 is expressed in patients with gestational diabetes mellitus (GDM) has not been elucidated. The aim of the present study was to investigate whether TLR4 is expressed in maternal peripheral blood monocytes of patients with GDM. A case-control study, using standard quantitative polymerase chain reaction and western blotting, was performed to assess the TLR4 expression in 30 females with GDM and 32 healthy pregnant females at similar gestational ages. Serum tumor necrosis factor (TNF)-α levels were assessed using ELISA in all the females. The TLR4 expression levels in the maternal peripheral blood monocytes and the serum TNF-α levels were increased in females with GDM compared with healthy pregnant females (P<0.05). Additionally, there was a positive correlation between the TLR4 expression level in peripheral blood monocytes and serum TNF-α levels in all the females. These results indicate that TLR4-mediated release of inflammatory cytokines may represent one factor leading to increased glucose levels in patients with GDM. In addition, TLR4 may be involved in the pathogenesis of GDM.
Hyperglycemia aggravates monocyte-endothelial adhesion in human umbilical vein endothelial cells from women with gestational diabetes mellitus by inducing Cx43 overexpression.
Zhang Qian,Wu Shan,Sun Guoliang,Zhang Rui,Li Xianlong,Zhang Yanling,Huang Fei,Yuan Dongdong
Annals of translational medicine
Background:Gestational diabetes mellitus (GDM) is among the most common metabolic diseases during pregnancy and inevitably leads to maternal and fetal complications. Hyperglycemia results in injury to vascular endothelial cells, including monocyte-endothelial adhesion, which is considered to be the initiating factor of vascular endothelial cell injury. Connexin 43 (Cx43) plays a key role in this adhesion process. Therefore, this study aimed to explore the effects of Cx43 on monocyte-endothelial adhesion in GDM-induced injury of vascular endothelial cells. Methods:Human umbilical vein endothelial cells (HUVECs) were isolated from umbilical cords from pregnant women with and without GDM. THP-1 cells (a human leukemia monocytic cell line) adhering to HUVECs, related molecules [intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)], and the activity of the phosphoinositide 3-kinase/protein kinase B/Nuclear factor- kappa B (PI3K/AKT/NF-κB) signaling pathway were compared between the normal and GDM-HUVECs. Oleamide and specific small interfering ribonucleic acids (siRNAs) were used to inhibit Cx43 expression in GDM-HUVECs to observe the effects of Cx43 on the adhesion of THP-1 cells and HUVECs. Results:A much higher number of THP-1 cells adhered to GDM-HUVECs than to normal HUVECs. This was accompanied by an increased expression of Cx43, ICAM-1, and VCAM-1, as well as activation of the PI3K/AKT/NF-κB signaling pathway. After the inhibition of Cx43 expression in GDM-HUVECs with oleamide and specific siRNA, THP-1-HUVEC adhesion, ICAM-1 and VCAM-1 expression, and activation of PI3K/AKT/NF-κB signaling pathway were all attenuated. Hyperglycemia was able to increase expression of Cx43 in HUVECs. Conclusions:For the first time, Cx43 expression was found to be substantially higher in GDM-HUVECs than in normal HUVECs. Hyperglycemia caused the overexpression of Cx43 in HUVECs, which resulted in the activation of the PI3K/AKT/NF-κB signaling pathway and the increase of its downstream adhesion molecules, including ICAM-1 and VCAM-1, ultimately leading to increased monocyte-endothelial adhesion.
Unveiling the pathophysiology of gestational diabetes: Studies on local and peripheral immune cells.
De Luccia Thiago P B,Pendeloski Karen P T,Ono Erika,Mattar Rosiane,Pares David B S,Yazaki Sun Sue,Daher Silvia
Scandinavian journal of immunology
Gestational diabetes mellitus (GDM) has been associated with impaired maternal immune response. Our aim was to review the available literature linking immune cells profile to GDM, in order to comprehend the role that different subpopulations play in the development of this pathology. We searched in PubMed for studies published in the last decade on circulating levels and placenta expression of immune cells on GDM. We identified 18 studies with several differences regarding the study design, clinical characteristics, number of participants, cell subpopulation and type of sample. Most studies assessed only one subpopulation either in peripheral blood or placenta and did not analyse functional properties of the cells. The most frequently evaluated immune cells were T lymphocytes, especially regulatory T (Tregs), and natural killer (NK) cells in the peripheral blood, and placental macrophages. No studies analysing B cells were identified, and only one study each evaluating γδT cells, dendritic cell (DC) and monocytes was found. Although there are controversies, at least one study reported positive association between GDM and CD4 (activated), Tregs, Th17 and γδT cells; neutrophil/lymphocyte; NK cell (cytotoxic); macrophages; and monocytes. The number of studies is still small, so caution should be exercised in interpreting the data, and further research is required to validate these findings and establish the role of adaptive and innate immune cells in GDM pathophysiology.
Characterization of maternal plasma biomarkers associated with delivery of small and large for gestational age infants in the MIREC study cohort.
Kumarathasan Premkumari,Williams Gabriela,Bielecki Agnieszka,Blais Erica,Hemmings Denise G,Smith Graeme,von Dadelszen Peter,Fisher Mandy,Arbuckle Tye E,Fraser William D,Vincent Renaud
OBJECTIVE:Neonatal morbidity and mortality can be influenced by maternal health status. Information on maternal and fetal biomarkers of adverse health outcomes is limited. This work aims at identifying maternal biomarkers associated with low and high birth weight for gestational age groups. DESIGN AND SETTINGS:Population-based prospective cohort study of the potential adverse health effects of exposure to environmental contaminants on pregnancy and infant health. METHODS:Third trimester maternal plasma samples (n = 1588) from a pregnancy cohort (Maternal-Infant Research on Environmental Chemicals Study, MIREC) were analyzed for changes in a target spectrum of biomarkers of vascular health (e.g., matrix metalloproteinases MMPs, vascular endothelial cell growth factor VEGF), inflammation (e.g. cellular adhesion molecules CAMs, cytokines, chemokines) by affinity-based multiplex protein array analyses. Multivariate logistic regression analyses were done to examine associations between target plasma biomarkers, maternal-infant characteristics, and birth weight outcomes assessed as small for gestational age (SGA) ≤10th percentile and large for gestational age (LGA) ≥90th percentile groups. RESULTS AND OUTCOMES:Our results revealed that maternal plasma biomarkers monocyte chemoattractant protein-1 MCP-1 (p<0.05, +ve) and VEGF (p<0.05, -ve) along with parity = 1 (p<0.01, -ve) and gestational hypertension (p<0.05, +ve) were associated with SGA births. Meanwhile, LGA was associated with maternal plasma VEGF (p<0.05, +ve) and MMP-9 (p<0.05, -ve) and gestational hypertension (p<0.01, +ve), pre-pregnancy body mass index (p<0.01, +ve), parity (p<0.05, +ve) and education (p<0.05, -ve). CONCLUSIONS:Third trimester maternal plasma biomarkers in combination with maternal health and socioeconomic characteristics can be useful in predicting SGA and LGA outcomes. Maternal vascular health and inflammatory status may contribute to both SGA and LGA births through distinct molecular mechanisms.
Changes in VEGF-related factors are associated with presence of inflammatory factors in carbohydrate metabolism disorders during pregnancy.
Sugimoto Masahiko,Kondo Mineo,Kamimoto Yuki,Ikeda Tomoaki,Cutler Alecia,Mariya Ali,Anand-Apte Bela
The aim of this study was to determine the action of molecules in carbohydrate metabolism disorders during pregnancy. The concentration of different types of cytokines and vascular endothelial growth factor (VEGF) in the plasma were measured in 4 groups of women: Group I, normal pregnancy (n = 10); Group II, patients with gestational DM (n = 12); Group III, pregnant patients with preexisting DM (n = 16); and Group IV, diabetic non-pregnant women (n = 22). The plasma VEGF concentration was significantly higher in the women in Group IV than in other groups (P <0.01). The concentration of the soluble form of the VEGF receptor-1 (sVEGFR-1) was significantly higher in Group I than in other groups (P <0.01). The concentration of soluble form of the VEGF receptor-2 (sVEGFR-2) was significantly lower in Groups I than in other groups (P <0.05). The concentrations of monocyte chemotactic protein-1 (MCP-1) and eotaxin were significantly lower in Group I than in Groups III and IV. The levels of interleukin (IL)-8, IL-6, and tumor necrosis factor-α (TNF-α) were significantly higher in Group I than in Group IV. Both the VEGF-related molecules and the Inflammatory cytokines are altered in pregnant women with the carbohydrate metabolism disorders.
Diabetic pregnancy activates the innate immune response through TLR5 or TLR1/2 on neonatal monocyte.
Yanai Sakika,Tokuhara Daisuke,Tachibana Daisuke,Saito Mika,Sakashita Yuko,Shintaku Haruo,Koyama Masayasu
Journal of reproductive immunology
Diabetes mellitus (DM) during pregnancy causes congenital malformation, macrosomia, respiratory distress syndrome, and other abnormalities in neonates, but whether maternal DM affects the neonatal innate immune system is unknown. Therefore we aimed to reveal the influence of DM in pregnancy on the toll-like receptor (TLR)-mediated innate immune response in neonates. Cord blood was collected after full-term vaginal or cesarean delivery and classified into a DM group (n=8) and non-DM (control) group (n=7). Mononuclear cells were harvested from cord blood by using density gradient centrifugation, after which anti-CD14 magnetic beads were used to isolate monocytes from the mononuclear population. After monocytes were cultured with lipopolysaccharide (TLR4 ligand), flagellin (TLR5 ligand), Pam3CSK4 (TLR1/TLR2 ligand), zymosan (TLR2/TLR6 ligand), or macrophage-activating lipopeptide (TLR2/TLR6 ligand) for 12h, the cytokine levels (interleukin [IL]-8, IL-6, IL-1β, IL-10, tumor necrosis factor alpha and IL-12) in the culture supernatants were measured. Compared with the control group, the DM group had higher concentrations of IL-8 (P=0.01) and tumor necrosis factor alpha (P=0.02) after monocyte cultures were stimulated with Pam3CSK4 and higher concentrations of IL-8 (P=0.01) after flagellin treatment. In contrast, stimulation with lipopolysaccharide, zymosan, or macrophage-activating lipopeptide did not lead to any difference in cytokine profiles between the two groups. These data indicate that maternal DM induces excessive inflammatory activation in neonates via a TLR5- or TLR1/2-mediated innate immune response.
Increased GPR120 level is associated with gestational diabetes mellitus.
He Qingwen,Zhu Shenglong,Lin Mengyuan,Yang Qin,Wei Lengyun,Zhang Jingwei,Jiang Xuan,Zhu Doudou,Lu Xuyang,Chen Yong Q
Biochemical and biophysical research communications
G-protein coupled receptor 120 (GPR120 or FFAR4) functions as a receptor for free fatty acids and plays a critical role in lipid metabolism. Studies have shown a close relationship between GDM and lipid metabolism disorders, whether GPR120 participates in the metabolic regulation of GDM remains unclear. In this study, 29 women with GDM and 33 normal pregnant women were enrolled. Lipid profiles were determined by lipidomics, expression of GPR120 and FGF21 was measured in the white blood cells, and regulation of FGF21 by GPR120 was investigated in THP-1 cells as well as human peripheral blood monocytes. Lipidomics reveal altered lipid metabolism in patients with GDM. The expression of both GPR120 and FGF21 is significantly higher in the GDM than in the control at the 32nd and 37th weeks of pregnancy, but the differences disappear by the 2nd day post-delivery. Generally positive correlations are found between the total amount of lipids and expression levels of GPR120 and FGF21 in GDM patients. FGF21 expression is induced by GPR120 activation in THP-1 cells and WBCs. GPR120 may act as a metabolic regulator, through the induction of FGF21, to control lipid metabolism, and GDM patients may manifest a GPR120 insensitivity.
The association between dysregulated adipocytokines in early pregnancy and development of gestational diabetes.
Abell Sally K,Shorakae Soulmaz,Harrison Cheryce L,Hiam Danielle,Moreno-Asso Alba,Stepto Nigel K,De Courten Barbora,Teede Helena J
Diabetes/metabolism research and reviews
BACKGROUND:To investigate the association of adipocytokines and other inflammatory markers with development of GDM. METHODS:Serum adipocytokines and inflammatory markers were studied at 12 to 15 weeks gestation using biobanked control samples from a randomised trial. Study participants were identified as high risk for GDM using a validated clinical risk prediction tool. Markers were tested using commercial ELISA kits for high molecular weight (HMW) adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1, visfatin, omentin-1, sex-hormone binding globulin, monocyte chemoattractant protein, and asymmetrical dimethylarginine. The association between each biomarker and development of GDM at 24 to 28 weeks was evaluated using multivariable logistic regression analysis adjusted for maternal factors. RESULTS:There were no differences in age, parity, country of birth, smoking, body mass index, or family history of diabetes in women with normal glucose tolerance (n = 78) and women who developed GDM (n = 25). Women with GDM were more likely to have a past history of GDM (P = 0.004). HMW adiponectin (odds ratio OR 0.37 [95% confidence interval 0.19-0.74]), omentin-1 (0.97 [0.94-0.99]), and IL-6 (1.87[1.03-3.37]) were associated with development of GDM, after adjustment for maternal age, body mass index, and past history of GDM. The other markers were not associated with GDM development. CONCLUSIONS:Decreased high molecular weight adiponectin and omentin-1 and increased IL-6 may enhance sensitivity of early risk prediction tools for women at high risk of GDM. This may allow early identification and opportunities for prevention of GDM and adverse outcomes. Further research is required in large validation studies to confirm these results.
Adipokines and macrophage markers during pregnancy-Possible role for sCD163 in prediction and progression of gestational diabetes mellitus.
Ueland Thor,Michelsen Annika E,Aukrust Pål,Henriksen Tore,Bollerslev Jens,Lekva Tove
Diabetes/metabolism research and reviews
AIMS:The risk of gestational diabetes mellitus (GDM) is increased in overweight and obese women potentially involving secreted mediators from adipose tissue. Our main aim was to evaluate if circulating adipokines and monocyte/macrophage markers were dysregulated in GDM and the influence body mass and indices of glucose metabolism had on this association. We further explored if early detection of these markers improved prediction of GDM and if they remained modified during long-term follow-up. MATERIALS AND METHODS:Population-based prospective cohort study in 273 pregnant women with markers measured four times during pregnancy and at 5-year follow-up. RESULTS:sCD163 was higher (25% at 14-16 weeks, P < 0.001) and adiponectin lower (-17% at 14-16 weeks, P < 0.01) early in pregnancy and at 5-year follow-up in GDM women, independent of BMI, and other GDM risk factors. Leptin, adiponectin, and chemerin were robustly associated with glucose metabolism throughout pregnancy while sCD163 was inversely associated with β-cell function early in pregnancy in women with increased BMI. Finally, the markers at 14 to 16 weeks displayed modest discriminatory properties with regard to prediction of GDM (AUC < 0.7). Using a combination of fasting glucose and sCD163, 53% of GDM could be identified when 25% of the population scored positive suggesting some merit in a multimarker approach. CONCLUSIONS:sCD163 and adiponectin were dysregulated in GDM, independent of body mass. None of the adipokines or monocyte/macrophage activation markers displayed clinically useful properties alone for early detection of GDM. Activation of monocytes/macrophages may be an important event in the early development of GDM.
High glucose induces dysfunction of human umbilical vein endothelial cells by upregulating miR-137 in gestational diabetes mellitus.
Peng Hai-Yan,Li Hua-Ping,Li Ming-Qing
Recent studies have revealed considerable dysfunction of vascular endothelial cells (VECs) and abnormal expression of microRNA (miR)-137 in women with gestational diabetes mellitus (GDM), and the aim of this study was to clarify the underlying mechanism and possible role of microRNA (miR)-137 in dysfunction of VECs during GDM. We found increased levels of miR-137 in the plasma of GDM women and high-glucose (HG)-exposed HUVECs. Upregulating miR-137 in HUVECs elevated the chemokine (C-C motif) ligand 2 (CCL2) secretion and enhanced the chemotaxis and adhesion of U937 and THP-1 (two human acute monocytic leukemia cell lines) cells to HUVECs in a co-culture system. Moreover, HG stimulation and/or overexpression of miR-137 inhibited the viability, upregulated the expression levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), E-selectin, and inflammatory cytokine interleukin (IL)-6, and downregulated the production of IL-8, vascular endothelial growth factor (VEGF), and angiogenesis of HUVECs in vitro. These results imply that up-regulated miR-137 by HG can restrict the viability and angiogenesis, promote the activation and inflammatory cytokine secretion of VECs, and stimulate the monocyte chemotaxis and adhesion to VECs. Ultimately, we have concluded that miR-137 is crucial to HG-induced VEC dysfunction and may be involved in pathology of GDM.
Association of downregulated HDAC 2 with the impaired mitochondrial function and cytokine secretion in the monocytes/macrophages from gestational diabetes mellitus patients.
Qu Xin,Yu Hongna,Jia Bei,Yu Xiaoyan,Cui Qing,Liu Zhifen,Sun Chengming,Chu Yongli
Cell biology international
Gestational diabetes mellitus (GDM) is associated with an increased risk of type 2 diabetes (T2DM) and cardiovascular diseases in later life, yet with underlying mechanisms unclear. The present study was to explore the association of upregulated histone deacetylase 2 (HDAC 2) with the impaired mitochondrial function and the cytokine secretion in the monocytes/macrophages from GDM patients. In this study, we examined the mitochondrial function, proinflamatory cytokine secretion and the HDAC 2 level in the serum or in the monocytes/macrophages from GDM patients, investigated the influence by HDAC 2 inhibitor, AR-42 (N-hydroxy-4-[[(2S)-3-methyl-2-phenylbutanoyl]amino]benzamide), on the mitochondrial function and cytokine secretion in the isolated GDM monocytes/macrophages. Results demonstrated an increased mitochondria size, mitochondrial superoxide and reactive oxygen species (ROS) production, and an undermined mitochondria membrane potential (MMP) in the GDM monocytes/macrophages. And the serum levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6 were also markedly higher in the GDM pregnancies, while the expression and activity of HDAC 2 was downregulated. Moreover, AR-42-mediated HDAC 2 inhibition in vitro contributed to the impaired mitochondrial function and the proinflamatory cytokine secretion. In conclusion, this study suggests an association of the impaired mitochondrial function and the promoted proinflamatory cytokine secretion with the reduced HDAC 2 activity in GDM. These findings may present HDAC 2 as a target for GDM treatment.
Monocyte profile in peripheral blood of gestational diabetes mellitus patients.
Angelo Ana G S,Neves Carla T C,Lobo Thalita F,Godoy Ramon V C,Ono Érika,Mattar Rosiane,Daher Silvia
OBJECTIVE:Gestational diabetes Mellitus has been considered an inflammatory disease involving different cells and mediators in its development. The role of innate immune cells in GDM physiopathology remains unclear, therefore this study was conducted to assess monocyte profile in GDM patients. DESIGN:This was a case-control study including 20 glucose-tolerant pregnant women (controls) and 18 GDM patients. METHODS:Flow cytometry was used to assess peripheral blood monocytes subsets (classical, intermediate, non-classical), the expression of TLR4 and CCR2 chemokine receptor (CD192) and cytokines (TNFA, IL6, IL10) secretion by monocytes subsets. In addition, sCD14 serum levels were evaluated by ELISA. RESULTS:We observed increased percentage of CD14 cells, decreased frequency of intermediate monocytes (CD14CD16), and lower percentage of circulating monocytes (classical, intermediate and non-classical) that express TLR4 in the diabetic group compared to controls. Soluble CD14 serum levels were higher in GDM patients compared to controls. There were no differences in the expression of the CCR2 chemokine receptor and cytokines (TNFA, IL6 and IL10) secretion between the studied groups. CONCLUSIONS:Our results demonstrated that GDM patients present impaired monocyte profile in the peripheral blood, suggesting that these cells are involved in GDM physiopathology.