Dataset Information

Circulating milk fat globule-epidermal growth factor 8 levels are increased in pregnancy and gestational diabetes mellitus.

ABSTRACT:

Aims/introduction

Milk fat globule-epidermal growth factor 8 (MFG-E8) is the key mediator in anti-inflammatory responses that facilitate phagocytosis of apoptotic cells, and play an essential role in type 2 diabetes and pregnancy, both of which are under a low-grade inflammatory state. However, the action of MFG-E8 in gestational diabetes mellitus (GDM) is unclear. We measured plasma MFG-E8 levels in pregnancy and GDM for the first time, and elucidated possible relationships between its plasma levels and various metabolic parameters.

Materials and methods

Plasma MFG-E8 levels were quantified by enzyme-linked immunosorbent assay in 66 women with GDM, 70 with normal pregnancy (p-NGT) and 44 healthy non-pregnant controls (CON), who were matched for age and body mass index. Inflammatory factors tumor necrosis factor-? (TNF-?) and C-reactive protein levels were measured, oral glucose tolerance test was carried out and ?-cell function was evaluated.

Results

Plasma MFG-E8 levels were remarkably higher in p-NGT than in CON (P = 0.024), and were further elevated in GDM vs p-NGT (P = 0.016). MFG-E8 concentrations correlated positively with hemoglobin A1c, glucose levels and insulin resistance (homeostasis model assessment for insulin resistance), and correlated inversely with TNF-? and insulin secretion evaluated by disposition indices in pregnancies. Fasting glucose levels, disposition index of first phase insulin secretion and TNF-? were independent predictors of MFG-E8 levels in pregnancies. Logistic regression analyses showed that women in the third tertile of MFG-E8 levels had a markedly elevated risk of GDM.

Conclusions

Circulating MFG-E8 levels are dramatically elevated in pregnancy, and are significantly higher in GDM vs p-NGT. MFG-E8 concentrations are significantly associated with TNF-?, fasting glucose levels, homeostasis model assessment for insulin resistance and disposition indices. However, further studies are required to elucidate the regulation mechanism of MFG-E8 during pregnancy and GDM.

SUBMITTER: Li Y

PROVIDER: S-EPMC5497050 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

Circulating milk fat globule-epidermal growth factor 8 levels are increased in pregnancy and gestational diabetes mellitus.

Li Yuanyuan Y Ran Wenzhuo W Zhang Jiaqiang J Chen Shi S Li Yihang Y Luo Deng D Wang Chen C Jia Weiping W

Journal of diabetes investigation 20170215 4

<h4>Aims/introduction</h4>Milk fat globule-epidermal growth factor 8 (MFG-E8) is the key mediator in anti-inflammatory responses that facilitate phagocytosis of apoptotic cells, and play an essential role in type 2 diabetes and pregnancy, both of which are under a low-grade inflammatory state. However, the action of MFG-E8 in gestational diabetes mellitus (GDM) is unclear. We measured plasma MFG-E8 levels in pregnancy and GDM for the first time, and elucidated possible relationships between its ...[more]

PMID: 28035763

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Project description:BACKGROUND:Acute kidney injury (AKI) is most commonly caused by sepsis in critically ill patients, and it is associated with high morbidity and mortality. The pathophysiology of sepsis-induced AKI is generally accepted to include direct inflammatory injury, endothelial cell dysfunction, and apoptosis. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8) is a secretory glycoprotein with a known role in the enhancement of apoptotic cell clearance and regulation of inflammation. We hypothesize that administration of recombinant mouse MFG-E8 (rmMFG-E8) can protect mice from kidney injuries caused by sepsis. METHODS:Sepsis was induced in 8-wk-old male C57BL/6 mice by cecal ligation and puncture (CLP). rmMFG-E8 or phosphate-buffered saline (vehicle) was injected intravenously at a dosage of 20 ?g/kg body weight at time of CLP (n = 5-8 mice per group). After 20 h, serum and renal tissue were harvested for various analyses. The renal injury markers blood urea nitrogen (BUN) and creatinine were determined by enzymatic and chemical reactions, respectively. The gene expression analysis was carried out by real-time quantitative polymerase chain reaction. RESULTS:At 20 h after CLP, serum levels of BUN and creatinine were both significantly increased in the vehicle group compared with the sham group, whereas the mice treated with rmMFG-E8 had a significant reduction in BUN and creatinine levels by 28% and 24.1%, respectively (BUN: 197.7 ± 23.6 versus 142.3 ± 20.7 mg/dL; creatinine: 0.83 ± 0.12 versus 0.63 ± 0.06 mg/dL; P < 0.05). Expressions of novel biomarkers of renal tissue injury neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 were also significantly downregulated by 58.2% and 95%, respectively, after treatment with rmMFG-E8. Proinflammatory cytokine interleukin-6 and tumor necrosis factor-? messenger RNA (mRNA) were significantly reduced by 50.8% and 50.3%, respectively, in rmMFG-E8-treated mice compared with vehicle-treated mice. The mRNA levels of the chemokines keratinocyte chemoattractant and macrophage inhibitory protein-2 were reduced by 85.1% and 78%, respectively, in mice treated with rmMFG-E8 compared with the vehicle mice. In addition, the expression of intercellular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) mRNA was downregulated by 35.6% and 77.8%, respectively, in rmMFG-E8-treated mice compared with the vehicle animals (P < 0.05). CONCLUSIONS:Treatment with rmMFG-E8 reduces renal tissue injury induced by sepsis through inhibiting the production of proinflammatory cytokines and chemokine, as well as through the activation of endothelial cells. Thus, MFG-E8 may have a therapeutic potential for treating AKI induced by sepsis.

Project description:Background Age-associated aortic remodeling includes a marked increase in intimal medial thickness (IMT), associated with signs of inflammation. Although aortic wall milk fat globule-epidermal growth factor VIII (MFG-E8) increases with age, and is associated with aortic inflammation, it is not known whether MFG-E8 is required for the age-associated increase in aortic IMT. Here, we tested whether MFG-E8 is required for the age-associated increase in aortic IMT. Methods and Results To determine the role of MFG-E8 in the age-associated increase of IMT, we compared aortic remodeling in adult (20-week) and aged (96-week) MFG-E8 (-/-) knockout and age matched wild-type (WT) littermate mice. The average aortic IMT increased with age in the WT from 50±10 to 70±20 μm (P<0.0001) but did not significantly increase with age in MFG-E8 knockout mice. Because angiotensin II signaling is implicated as a driver of age-associated increase in IMT, we infused 30-week-old MFG-E8 knockout and age-matched littermate WT mice with angiotensin II or saline via osmotic mini-pumps to determine whether MFG-E8 is required for angiotensin II-induced aortic remodeling. (1) In WT mice, angiotensin II infusion substantially increased IMT, elastic lamina degradation, collagen deposition, and the proliferation of vascular smooth muscle cells; in contrast, these effects were significantly reduced in MFG-E8 KO mice; (2) On a molecular level, angiotensin II treatment significantly increased the activation and expression of matrix metalloproteinase type 2, transforming growth factor beta 1, and its downstream signaling molecule phosphorylated mother against decapentaplegic homolog 2, and collagen type I production in WT mice; however, in the MFG-E8 knockout mice, these molecular effects were significantly reduced; and (3) in WT mice, angiotensin II increased levels of aortic inflammatory markers phosphorylated nuclear factor-kappa beta p65, monocyte chemoattractant protein 1, tumor necrosis factor alpha, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 molecular expression, while in contrast, these inflammatory markers did not change in knockout mice. Conclusions Thus, MFG-E8 is required for both age-associated proinflammatory aortic remodeling and also for the angiotensin II-dependent induction in younger mice of an aortic inflammatory phenotype observed in advanced age. Targeting MFG-E8 would be a novel molecular approach to curb adverse arterial remodeling.

Project description:BackgroundGestational diabetes mellitus (GDM) is a common complication of pregnancy. It may predispose offspring to increased fat mass (FM) and the development of obesity, however few data from Latin America exist.ObjectiveTo investigate the influence of GDM on newborn FM in mother-newborn pairs recruited from a public maternity care center in São Paulo, Brazil.MethodsData were collected cross-sectionally in 2013-2014 from 72 mothers diagnosed with GDM, and 211 mothers with normal glucose tolerance (NGT). Newborn FM was evaluated by air-displacement plethysmography (PEA POD), and relevant demographic and obstetric data were collected from hospital records. Associations between maternal GDM status and newborn FM were investigated by multiple linear regression analysis, with adjustment for maternal age, pre-pregnancy BMI, gestational weight gain, type of delivery, sex of the child, and gestational age.ResultsFM was greater in GDM versus NGT newborns in a bivariable model (Median (IQR), GDM: 0.35 (0.3) kg vs. NGT: 0.27 (0.2) kg, p = 0.02), however GDM status was not a significant predictor of FM with adjustment for other variables. Rather, pre-pregnancy BMI (coefficient (?) 1.46; 95% confidence interval (CI) 0.66, 2.27), gestational weight gain (? 1.32; 95% CI 0.49, 2.15), and male sex (? -17.8; 95% CI -27.2, -8.29) predicted newborn FM. Analyzing GDM and NGT groups separately, pre-pregnancy BMI (? 6.75; 95% CI 2.36, 11.1) and gestational weight gain (? 5.64; 95% CI 1.16, 10.1) predicted FM in the GDM group, while male sex alone predicted FM in the NGT group (? -12.3; 95% CI -18.3, -6.34).ConclusionsCombined model results suggest that in our cohort, pre-pregnancy BMI and gestational weight gain are more important risk factors for increased neonatal FM than GDM. However, group-specific model results suggest that GDM status may contribute to variation in the relationship between maternal/offspring factors and FM. Our use of a binary GDM variable in the combined model may have precluded clearer results on this point. Prospective cohort studies including data on maternal pre-pregnancy BMI, GWG, and glycemic profile are needed to better understand associations among these variables and their relative influence on offspring FM.

Project description:ObjectivesRenal ischemia-reperfusion injury causes acute renal failure, and the hallmarks of renal ischemia-reperfusion injury are inflammation, apoptosis, necrosis, and capillary dysfunction. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8), a membrane-associated secretory glycoprotein, is produced by immune cells and reported to participate in multiple physiologic processes associated with tissue remodeling. We have recently shown that MFG-E8 treatment attenuates organ injury, inflammatory responses, and survival after sepsis through the enhancement of phagocytosis of apoptotic cells. The purpose of this study was to determine whether administration of MFG-E8 attenuates renal ischemia-reperfusion injury.DesignProspective, controlled, and randomized animal study.Setting: A research institute laboratory.SubjectsMale C57BL/6J mice (20-25 g).Interventions: Renal ischemia-reperfusion injury with bilateral renal pedicle clamping for 45 mins, followed by reperfusion. A recombinant murine MFG-E8 (0.4 μg/20 g) was given intraperitoneally at the beginning of reperfusion.Measurements and main resultsMFG-E8 levels, organ injury variables, inflammatory responses, histology, apoptosis, and capillary functions were assessed at 1.5 and 20 hrs after reperfusion. A 60-hr survival study was conducted in MFG-E8 and recombinant murine MFG-E8-treated wild-type mice. After renal ischemia-reperfusion injury, MFG-E8 mRNA and protein expressions were significantly decreased in the kidneys and spleen. Treatment with recombinant murine MFG-E8 recovered renal dysfunction, significantly suppressed inflammatory responses, apoptosis, necrosis, and improved capillary functions in the kidneys. In the survival study, MFG-E8 mice showed a significant deterioration and, in contrast, recombinant murine MFG-E8-treated wild-type mice showed a significant improvement of survival compared with vehicle-treated wild-type mice.ConclusionsMFG-E8 can be developed as novel treatment for renal ischemia-reperfusion injury. This protective effect appears to be mediated through the enhancement of apoptotic cell clearance and improvement of capillary functions in the kidneys.

Project description:BackgroundMilk fat globule-epidermal growth factor-factor VIII (MFG-E8) is a secretory glycoprotein with a known role in inflammation. In sepsis, interleukin (IL)-17 acts as a proinflammatory cytokine to exaggerate systemic inflammation. We hypothesize that MFG-E8 downregulates IL-17 expression in sepsis.MethodsSepsis was induced in 8-week-old male C57BL/6 mice by cecal ligation and puncture (CLP). Recombinant mouse MFG-E8 (rmMFG-E8) at a dosage of 20 μg/kg body weight or phosphate-buffered saline was concurrently injected. After 10 hours, blood and spleen samples were harvested for analysis. For in vitro studies, splenocytes isolated from healthy mice pretreated with rmMFG-E8 and splenocytes from MFG-E8 knockout (mfge8(-/-)) mice were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, followed by measurement of IL-17 expression with either quantitative PCR or enzyme-linked immunosorbent assay.ResultsAt 10 hours after CLP, rmMFG-E8 inhibited the elevated levels of IL-17 protein in serum by 31%, compared with the vehicle. In the spleen, rmMFG-E8 reduced the upregulated IL-17 mRNA and protein levels by 81% and 51%, respectively. This correlated with a significant reduction in organ injury markers AST and ALT in sepsis after administration of rmMFG-E8. In vitro treatment of splenocytes isolated from healthy mice with rmMFG-E8 showed significant downregulation in PMA/ionomycin-induced IL-17 expression. In contrast, CD4 T-cells from mfge8(-/-) mice showed significant upregulation of IL-17 compared with wild-type mice. The phosphorylated level of signal transducer and activator of transcription 3 (STAT3) was downregulated in spleen tissue of septic mice treated with rmMFG-E8. Conversely, mfge8(-/-) mice showed increased phosphorylated STAT3 compared with wild-type mice after sepsis.ConclusionOur findings demonstrate MFG-E8-mediated downregulation of IL-17 expression, implicating its potential as a novel therapeutic agent against sepsis.

Dataset Information

Circulating milk fat globule-epidermal growth factor 8 levels are increased in pregnancy and gestational diabetes mellitus.

Aims/introduction

Materials and methods

Results

Conclusions

Publications

Circulating milk fat globule-epidermal growth factor 8 levels are increased in pregnancy and gestational diabetes mellitus.

Similar Datasets

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