Gestational Diabetes Mellitus Mice Research Articles

High levels of fucosylation and sialylation of milk N‐glycans from mothers with gestational diabetes mellitus alter the offspring gut microbiome and immune balance in mice

Gestational diabetes mellitus (GDM) is significantly associated with allergen sensitization in early childhood, and this may influence the gut microbiome and immune system of the children. In addition to mother-to-child transmission of microbes, milk glycans play a pivotal role in shaping the gut microbiome of infants. A previous study has demonstrated alterations in the major milk N-glycans of mothers with GDM. However, the impact of these changes on the gut microbiome and immune response of the neonates has yet to be studied. Here, we aimed to compare the glycosylation levels of various milk glycans between normal and GDM mice, and to characterize the intestinal microbiome and immune responses of the offspring after weaning. We found that GDM mouse milk contained significantly higher concentrations of fucosylated and sialylated N-glycans than control mice, but there was no difference in the concentration of milk oligosaccharides between the groups. The differences in milk N-glycans had direct effects on the intestinal microbiome of the offspring, which in turn affected their immune response upon challenge with ovalbumin (OVA), with disruptions in the Th1/Th2 and Th17/Treg cell balances. This study lays the foundation for further research and development of specific nutritional care for the offspring of GDM mothers.

TLR4/NF-κB Signaling Pathway Participates in the Protective Effects of Apocynin on Gestational Diabetes Mellitus Induced Placental Oxidative Stress and Inflammation.

Gestational diabetes mellitus (GDM) is a temporary form of diabetes during pregnancy which influences the health of both mother and child. Both inflammation and oxidative stress have been implicated in the pathophysiology of GDM. Apocynin, acetophenone with anti-oxidative and anti-inflammation activities, has been shown to protect against insulin resistance. In the current study, the effects of apocynin on GDM symptoms, productive outcomes, oxidative stress, and inflammation were evaluated and the underlying mechanisms were explored. We administrated apocynin to GDM mice and monitored the GDM symptoms including body weight, serum levels of glucose, insulin, lipid profile, and the fetal outcomes in GDM mice. We also evaluated the effects of apocynin on placental oxidative stress, inflammation, and activation of TLR4/NF-κB signaling pathway in GDM mice. Here, we reported that apocynin treatment significantly reduced serum levels of glucose, cholesterol, triglyceride, and low-density lipoprotein in GDM mice, while significantly increased serum level of insulin and high-density lipoprotein. Apocynin improved fetal outcomes in GDM mice. Apocynin ameliorated placental oxidative stress and inflammation and inhibited TLR4/NF-κB signaling pathway activation in GDM mice. We concluded that apocynin suppressed oxidative stress and inflammation in GDM by inhibiting the TLR4/NF-κB signaling pathway.

Exosomal MicroRNA Expression Profiling Analysis of the Effects of Lycium Barbarum Polysaccharide on Gestational Diabetes Mellitus Mice.

Objective Gestational diabetes mellitus (GDM) is a pathological condition, affecting an increasing number of pregnant women worldwide. Safe and effective treatment for GDM is very important for the public health. In this study, we utilized a high-fat diet-induced GDM model to evaluate the effects of LBP on GDM and examined the changes of exosomal microRNA expression profiling to decipher the potential underlying mechanism of LBP. Methods Female C57BL/6J mice were fed a control diet, HFD, or 150 mg/kg LBP-supplemented HFD for 6 weeks before conception and throughout gestation. Oral glucose tolerance test and plasma lipid levels were determined, and liver histopathology was assessed. Sequencing was used to define the microRNA expression profiling of plasma exosomes in the three groups of mice, and protein expression levels of the candidate target genes were analyzed. Results LBP significantly relieved glucose intolerance, abnormal plasma lipid levels, and pathomorphological changes of liver histopathology in HFD-induced GDM mice. Moreover, we found that this effect of LBP was mediated by downregulation of the increase of 6 miRNAs (miR-93-3p, miR-188-5p, miR-466k, miR-1188-5p, miR-7001-3p, and miR-7115-5p) and reversing the increase of the protein expression of CPT1A, which is the target gene of miR-188-5p. Conclusions Our findings provide novel insights into the biological activities of LBP in the treatment of GDM.

Tetramethylpyrazine attenuates placental oxidative stress, inflammatory responses and endoplasmic reticulum stress in a mouse model of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a disease characterized by insufficient insulin secretion and glucose metabolic disorder during pregnancy. Tetramethylpyrazine has been reported to inhibit endoplasmic reticulum (ER) stress and high glucose-induced inflammation, which are closely associated with GDM. This study aimed to investigate the effects of tetramethylpyrazine on inflammatory responses, ER stress and oxidative stress of the placenta in a mouse model of GDM. Our results showed that tetramethylpyrazine treatment significantly alleviated the GDM symptoms characterized by low body weight and serum insulin levels, high blood glucose, and decreased β-cell function in pregnant C57BL/KsJdb/+ mice. In addition, tetramethylpyrazine reduced the level of malondialdehyde, and increased the levels of superoxide dismutase, glutathione peroxidase and glutathione. Moreover, tetramethylpyrazine decreased the total serum cholesterol, serum triglyceride, and serum low-density lipoprotein levels and increased the high-density lipoprotein level. Further, tetramethylpyrazine regulated the levels of serum and placental inflammatory factors and the expression of ER stress related proteins. Taken together, the present study demonstrated that tetramethylpyrazine attenuated placental oxidative stress, inflammatory responses and ER stress in GDM mice.

Naringenin improves insulin sensitivity in gestational diabetes mellitus mice through AMPK

BackgroundGestational diabetes mellitus (GDM) is a temporary form of diabetes during pregnancy, which influences the health of maternal-child in clinical practice. It is still urgent to develop new effective treatment for GDM. Naringenin is a bioactive ingredient with multiple activities including anti-diabetic. In current study, the effects of naringenin on GDM symptoms, insulin tolerance, inflammation, and productive outcomes were evaluated and the underlying mechanisms were explored.MethodsWe administrated naringenin to GDM mice and monitored the GDM symptoms, glucose and insulin tolerance, inflammation and productive outcomes. We established tumor necrosis factor alpha (TNF-α)-induced insulin resistance skeletal muscle cell model and evaluated the effects of naringenin on reactive oxygen species (ROS) production, glucose uptake and glucose transporter type 4 (GLUT4) membrane translocation.ResultsWe found that naringenin ameliorated GDM symptoms, improved glucose and insulin tolerance, inhibited inflammation, and improved productive outcomes. It was further found that naringenin inhibited TNF-α-induced ROS production, enhanced GLUT4 membrane translocation, and glucose uptake, which were abolished by inhibition of AMP-activated protein kinase (AMPK).ConclusionNaringenin improves insulin sensitivity in gestational diabetes mellitus mice in an AMPK-dependent manner.

Upregulation Of Renal GLUT2 And SGLT2 Is Involved In High-Fat Diet-Induced Gestational Diabetes In Mice.

IntroductionGestational diabetes mellitus (GDM) is a metabolic disorder during mid- to late-pregnancy characterized by hyperglycemia, insulin resistance and fetal mal-development. Glucose transporter type 2 (GLUT2) and sodium-coupled glucose cotransporters 2 (SGLT2) in the proximal tubules play a critical role in the reabsorption of glucose and have been linked to the occurrence of type 2 diabetes mellitus (T2DM). Our study was designed to investigate the role of GLUT2 and SGLT2 in the pathogenesis of GDM, which is considered a forerunner of T2DM, and investigate the related molecular mechanism.MethodsHigh-fat diet (HFD) was utilized to build a GDM mouse model that closely induces metabolic abnormalities similar to human GDM. Body weight, blood glucose and serum insulin were recorded in the experimental process. Glucose tolerance was determined by the use of an intraperitoneal glucose tolerance test (IPGTT). In addition, levels of GLUT2 and SGLT2 were evaluated to further explore the underlying mechanism of GDM.ResultsHFD feeding induced abnormal glucose metabolism as manifested by increased levels of blood glucose and insulin and prominent glucose intolerance. Additionally, fetal mice from mother feed on HFD showed higher mean body weight. Furthermore, HFD feeding led to an increase in the number of positive cells of GLUT2 and SGLT2 in the renal proximal tubule and the expressions of renal GLUT2 and SGLT2 mRNA and proteins in mice. However, no obvious change was observed in renal morphology.ConclusionOur study demonstrates a potential involvement of renal GLUT2 and SGLT2 in GDM pathology in an HFD-induced GDM mouse model, which further supports the role of renal GLUT2 and SGLT2 not only in T1DM and T2DM but also in GDM.

Astragaloside IV attenuates gestational diabetes mellitus via targeting NLRP3 inflammasome in genetic mice

BackgroundAs the most ordinary metabolic disorder during pregnancy, gestational diabetes mellitus (GDM) has become a severe risk for the health of both pregnant female and fetus. Astragaloside IV (AS-IV) is the dominant active component in Astragalus membranaceus. It has been proved that AS-IV has anti-inflammation and immune-regulation function. We aimed to demonstrate the function of AS-IV in the therapy of GDM and the molecular mechanism in this process.MethodsC57BL/KsJ-Lepdb/+ female mice were used as GDM model. The mRNA levels of relative genes in this research were detected by qRT-PCR. The protein levels of relative genes were analyzed by western blot. Serum concentration of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were analyzed by ELISA.ResultsGlucose and insulin levels in GDM mice model were decreased by AS-IV treatment. AS-IV down-regulated the expression of inflammatory gene IL-6 and TNF-α in GDM mice model. AS-IV treatment inhibited the expression of NLR family pyrin domain containing-3 (NLRP3) inflammasome relative proteins in the pancreas of GDM mice.ConclusionThis study demonstrated that AS-IV treatment has an effective therapeutic function of GDM in mice model through the inhibition of NLRP3 inflammasome in the pancreas.

Retinoic acid attenuates cardiac injury induced by hyperglycemia in pre- and post-delivery mice.

The aim of the present study is to explore the effect of retinoic acid (RA) on cardiac injury induced by gestational diabetes mellitus (GDM). GDM mice were given 3 mg/kg RA once daily until the 19th day of pregnancy or the 7th day of post-partum. Compared to normal control and normal pregnant control mice, GDM mice before and after delivery showed significantly cardiac injury. RA treatment attenuated cardiac injury as evidenced by decreased heart mass and left ventricular mass, mRNA expressions of ANP and BNP, and cardiac fibrosis compared with that in GDM mice. The protective effect of RA on GDM cardiomyopathy was related to the decreased MDA content and ROS generation, the increased GSH-Px and SOD content as well as the reduced TNF-α and IL-1β content and inhibition of NF-κB signaling. In addition, RA treatment delayed the continuous rise of blood glucose before delivery and decreased the higher level of glucose after delivery. In conclusion, RA treatment could increase the activity of the antioxidant enzyme and suppress the oxidative stress, inflammation response, and activation of NF-κB signaling, thereby improving blood glucose level and cardiac injury of GDM mice before and after delivery.

Anti-Diabetic, Anti-Inflammatory, and Anti-Oxidant Effects of Naringenin in an In Vitro Human Model and an In Vivo Murine Model of Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM), which affects up to 20% of pregnant women, is associated with maternal peripheral insulin resistance, low-grade inflammation, and oxidative stress. The flavonoid naringenin has potent anti-diabetic, anti-inflammatory, and anti-oxidative properties; however, its effects in GDM remain unknown. The study aimed to determine the effects of naringenin on glucose metabolism, inflammation, and oxidative stress associated with GDM both in vitro and in vivo. In vitro, human tissue samples obtained at term elective Caesarean section are stimulated with tumour necrosis factor alpha (TNF) to develop a GDM-like environment. Naringenin treatment significantly improves TNF-impaired glucose uptake in skeletal muscle. In placenta and visceral adipose tissue (VAT), naringenin significantly reduces expression of pro-inflammatory cytokines and chemokines and increases antioxidant mRNA expression. Mechanistically, naringenin suppresses nuclear factor κB activation. In vivo, pregnant heterozygous db/+ mice are used to model GDM. Daily intraperitoneal injections of GDM mice with naringenin from gestational day 10-17 significantly improve glucose tolerance, reduces IL1A mRNA expression, and increases antioxidant mRNA expression in placenta, VAT, and subcutaneous adipose tissue. Naringenin is shown to improve insulin sensitivity, inflammation, and oxidative stress associated with GDM and shows promise as a novel preventive therapeutic.

MicroRNA-351 eases insulin resistance and liver gluconeogenesis via the PI3K/AKT pathway by inhibiting FLOT2 in mice of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is known as different degree glucose intolerance that is initially identified during pregnancy. MicroRNAs (miRs) may be a potential candidate for treatment of GDM. Herein, we suggested that miR‐351 could be an inhibitor in the progression of GDM via the phosphoinositide 3‐kinase/protein kinase B (PI3K/AKT) pathway. Microarray analysis was used to identify differentially expressed genes and predict miRs regulating flotillin 2 (FLOT2). Target relationship between miR‐351 and FLOT2 was verified. Gestational diabetes mellitus mice were treated with a series of mimic, inhibitor and small interfering RNA to explore the effect of miR‐351 on insulin resistance (IR), cell apoptosis in pancreatic tissues and liver gluconeogenesis through evaluating GDM‐related biochemical indexes, as well as expression of miR‐351, FLOT2, PI3K/AKT pathway‐, IR‐ and liver gluconeogenesis‐related genes. MiR‐351 and FLOT2 were reported to be involved in GDM. FLOT2 was the target gene of miR‐351. Gestational diabetes mellitus mice exhibited IR and liver gluconeogenesis, up‐regulated FLOT2, activated PI3K/AKT pathway and down‐regulated miR‐351 in liver tissues. Additionally, miR‐351 overexpression and FLOT2 silencing decreased the levels of FLOT2, phosphoenolpyruvate carboxykinase, glucose‐6‐phosphatase, fasting blood glucose, fasting insulin, total cholesterol, triglyceride, glyeosylated haemoglobin and homeostasis model of assessment for IR index (HOMA‐IR), extent of PI3K and AKT phosphorylation, yet increased the levels of HOMA for islet β‐cell function, HOMA for insulin sensitivity index and glucose transporter 2 expression, indicating reduced cell apoptosis in pancreatic tissues and alleviated IR and liver gluconeogenesis. Our results reveal that up‐regulation of miR‐351 protects against IR and liver gluconeogenesis by repressing the PI3K/AKT pathway through regulating FLOT2 in GDM mice, which identifies miR‐351 as a potential therapeutic target for the clinical management of GDM.

Mangiferin ameliorates gestational diabetes mellitus-induced placental oxidative stress, inflammation and endoplasmic reticulum stress and improves fetal outcomes in mice

Gestational diabetes mellitus (GDM) is a temporary form of diabetes during pregnancy, which causes maternal diabetic symptoms and abnormal fetal development, and influence the health of maternal-child in clinical practice. Mangiferin is a bioactive ingredient with anti-inflammation, anti-oxidation and anti-endoplasmic reticulum stress activities. In current study, the effects of mangiferin on GDM were evaluated. We reported that mangiferin greatly improved altered glucose and lipid profile, insulin tolerance, and reproductive outcomes of the GDM mice. Mangiferin ameliorated placental oxidative stress, inflammation and ER stress in GDM mice. Therefore, we demonstrated that mangiferin displayed protective effects on gestational diabetes mellitus symptoms by suppressing placental oxidative stress, inflammation and endoplasmic reticulum stress in GDM mice.

Tertiary butylhydroquinone alleviates gestational diabetes mellitus in C57BL/KsJ-Lep db/+ mice by suppression of oxidative stress.

Gestational diabetes mellitus (GDM) is a common disorder characterized by abnormal glucose metabolism during pregnancy, affecting 2% to 5% of pregnant women. Currently, clinical treatment for GDM is very limited. The present study was designed to investigate the effect and underlying molecular mechanism of tertiary butylhydroquinone (TBHQ) in a pregnant C57BL/KsJ-Lep db/+ (referred to as db+) GDM mouse model. The results showed that nonpregnant db/+ mice did not show a diabetic phenotype, and TBHQ had no effect on glucose and insulin tolerance in these mice. Moreover, in db/+ pregnant mice exhibiting typical diabetes symptoms, such as hyperglycemia and hypoinsulinemia, TBHQ could remarkably decrease the blood glucose level, increase insulin level, and improve glucose and insulin intolerance. The results also revealed that TBHQ could inhibit oxidative stress in pregnant db/+ mice. Furthermore, TBHQ greatly improved offspring survival rate, glucose metabolism, and insulin tolerance. In addition, TBHQ inhibited oxidative stress by reducing malondialdehyde (MDA) and reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Moreover, we found that TBHQ activated the nuclear factor erythroid 2-related factor 2 (Nrf2), thereby increasing the levels of Nrf2, and ultimately upregulating the expression of heme oxygenase 1 (NO-1) and superoxide dismutase 2 (SOD2). In conclusion, our findings demonstrated that TBHQ alleviated GDM via Nrf2 activation.

Renal dysfunction in a mouse model of GDM is prevented by metformin through MAPKs.

Gestational diabetes mellitus (GDM) incidence is increasing worldwide. In the present study, the effects of metformin on high fat diet (HFD)‑induced renal dysfunction were investigated in GDM mice. In addition, the molecular mechanisms underlying metformin function were examined. GDM was induced by feeding pregnant mice a HFD, and mice were treated with two different doses of metformin (300 and 600mg/kg/day) or PBS between embryonic day 11.5 (E11.5) and E17.5. The pregnant mice at E18.5 were utilized to analyze the effects of metformin on renal dysfunction. Renal function and the protein expression levels of inflammatory cytokines and factors of the mitogen‑activated protein kinase (MAPK) signaling pathway in the kidneys of pregnant mice were assessed by ELISA and western blotting. Data obtained during late pregnancy suggested that metformin significantly decreased body weight and the levels of blood glucose in GDM mice, as assessed by the glucose tolerance test and the homeostatic model assessment for insulin resistance. The levels of microalbumin and serum β2‑microglobulin in GDM mice during late pregnancy were decreased following treatment with metformin. Furthermore, serum levels of interleukin (IL)‑6 and tumor necrosis factor (TNF)‑α, and phosphorylation of MAPK1/3, MAPK14 and MAPK8 in the kidneys were decreased in GDM mice following metformin treatment at E18.5, compared with the untreated GDM group. The present study suggested that inflammation may be associated with renal dysfunction in GDM mice, and that the MAPK signaling pathway may be involved in the protective effect of metformin on renal dysfunction in GDM mice.

Gestational diabetes mellitus alters DNA methylation profiles in pancreas of the offspring mice

Gestational diabetes mellitus (GDM), which has an increasing global prevalence, contributes to the susceptibility to metabolic dysregulation and obesity in the offspring via epigenetic modifications. However, the underlying mechanism remains largely obscure. The current study established a GDM mice model to investigate the alternations in the metabolic phenotypes and genomic DNA methylation in the pancreas of the offspring. We found that in the GDM offspring, intrauterine hyperglycemia induced dyslipidemia, insulin resistance, and glucose intolerance. Meanwhile, altered DNA methylation patterns were exhibited in the pancreas and many differentially methylated regions (DMRs)-related genes were involved in glycolipids metabolism and related signaling pathways, including Agap2, Plcbr, Hnf1b, Gnas, Fbp2, Cdh13, Wnt2, Kcnq1, Lhcgr, Irx3, etc. Additionally, the overall hypermethylation of Agap2, verified by bisulfite sequencing PCR (BSP), was negatively correlated with its mRNA expression level. In conclusion, these findings suggest that the DNA methylation changes in the pancreatic genome of the GDM offspring may be associated with the glycolipid metabolism abnormalities, T2DM susceptibility, and obesity in the adult GDM offspring.

MiR-335-5p induces insulin resistance and pancreatic islet β-cell secretion in gestational diabetes mellitus mice through VASH1-mediated TGF-β signaling pathway.

Multiple studies have reported different methods in treating gestational diabetes mellitus (GDM); however, the relationship between miR-335-5p and GDM still remains unclear. Here, this study explores the effect of miR-335-5p on insulin resistance and pancreatic islet β-cell secretion via activation of the TGFβ signaling pathway by downregulating VASH1 expression in GDM mice. The GDM mouse model was established and mainly treated with miR-335-5p mimic, miR-335-5p inhibitor, si-VASH1, and miR-335-5p inhibitor + si-VASH1. Oral glucose tolerance test (OGTT) was conducted to detect fasting blood glucose (FBG) fasting insulin (FINS). The OGTT was also used to calculate a homeostasis model assessment of insulin resistance (HOMA-IR). A hyperglycemic clamp was performed to measure the glucose infusion rate (GIR), which estimated β-cell function. Expressions of miR-335-5p, VASH1, TGF-β1, and c-Myc in pancreatic islet β-cells were determined by RT-qPCR, western blot analysis, and insulin release by ELISA. The miR-335-5p mimic and si-VASH1 groups showed elevated blood glucose levels, glucose area under the curve (GAUC), and HOMA-IR, but a reduced GIR and positive expression of VASH1. Overexpression of miR-335-5p and inhibition of VASH1 contributed to activated TGFβ1 pathway, higher c-Myc, and lower VASH1 expressions, in addition to downregulated insulin and insulin release levels. These findings provided evidence that miR-335-5p enhanced insulin resistance and suppressed pancreatic islet β-cell secretion by inhibiting VASH1, eventually activating the TGF-β pathway in GDM mice, which provides more clinical insight on the GDM treatment.

Maternal Choline and Betaine Supplementation Modifies the Placental Response to Hyperglycemia in Mice and Human Trophoblasts.

Gestational diabetes mellitus (GDM) is characterized by excessive placental fat and glucose transport, resulting in fetal overgrowth. Earlier we demonstrated that maternal choline supplementation normalizes fetal growth in GDM mice at mid-gestation. In this study, we further assess how choline and its oxidation product betaine influence determinants of placental nutrient transport in GDM mice and human trophoblasts. C57BL/6J mice were fed a high-fat (HF) diet 4 weeks prior to and during pregnancy to induce GDM or fed a control normal fat (NF) diet. The HF mice also received 25 mM choline, 85 mM betaine, or control drinking water. We observed that GDM mice had an expanded placental junctional zone with an increased area of glycogen cells, while the thickness of the placental labyrinth zone was decreased at E17.5 compared to NF control mice (p < 0.05). Choline and betaine supplementation alleviated these morphological changes in GDM placentas. In parallel, both choline and betaine supplementation significantly reduced glucose accretion (p < 0.05) in in vitro assays where the human choriocarcinoma BeWo cells were cultured in high (35.5 mM) or normal (5.5 mM) glucose conditions. Expression of angiogenic genes was minimally altered by choline or betaine supplementation in either model. In conclusion, both choline and betaine modified some but not all determinants of placental transport in response to hyperglycemia in mouse and in vitro human cell line models.

Mogroside IIIE attenuates gestational diabetes mellitus through activating of AMPK signaling pathway in mice

As one kind of complications of pregnancy, gestational diabetes mellitus (GDM) can influence the health of maternal-child in clinical practice. The C57 BL/KsJdb/+(db/+) mice, genetic GDM model, and C57 BL/KsJ+/+ (wild-type) mice were purchased and classified into three groups: normal pregnancy (C57 BL/KsJ+/+), GDM (C57 BL/KsJdb/+), and GDM plus Mogroside IIIE (20.0 mg/kg) group. GDM symptoms (maternal body weight, serum glucose, and insulin levels), glucose and insulin tolerance, and reproductive outcome (body weight at birth and litter size of offspring) were investigated. The inflammatory factors such as IL-1β, IL-6, and TNF-α in the serum and the pancreas were detected by ELISA and qRT-PCR, while the expression of pAMPK, AMPK, pHDAC4, HDAC4, and G6Pase in the livers were analyzed by Western Blot. Mogroside IIIE greatly improved glucose metabolism, insulin tolerance, and reproductive outcome of the GDM mice. Moreover, Mogroside IIIE treatment significantly decreased inflammatory factors expression and relieved GDM symptoms through enhanced AMPK activation, inhibited HDAC4 expression, and reduced production of G6Pase. The alleviation of GDM by Mogroside IIIE was mediated by elevated AMPK activation, which in turn inhibited HDAC4 phosphorylation, and eventually down-regulated G6Pase expression and activity.

Combined intervention of swimming plus metformin ameliorates the insulin resistance and impaired lipid metabolism in murine gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) has short- and long- term influence on pregnant women and fetus. Swimming, as an aerobic exercise, can effectively improve the blood glucose level in GDM, but the effect of mild swimming alone was not very substantial. Metformin, as an oral antidiabetic drug, has obvious hypoglycemic effect, and is economic also, but the long-term effect on pregnant women and fetus has not been completely clear. We hypothesize that combined intervention of mild swimming and low dose of metformin, may effectively reduce blood glucose, improve the pregnancy outcomes in GDM dams, but simultaneously avoiding the adverse effects caused by overdose of drug and impotence of mild swimming. The streptozotocin was used to stimulate C57BL/6J mice to develop GDM, by which serum glucose, TC, TG, LDL-C were increased significantly, meanwhile HDL-C was decreased significantly in the GDM control (DC) group compared with the normal control group. Swimming or metformin intervention slightly or moderately improves hyperglycemia, insulin sensitivity and lipid metabolism both in liver and skeletal muscle from GDM mice, while combined therapy of swimming plus metformin markedly ameliorated hyperglycemia (FPG, decreased by 22.2–59.5% from G10 to G18 versus DC group), insulin sensitivity (2.1 and 2.8 fold increase, respectively, in AKT activity versus DC group) and de novo lipogenesis (3.2 and 7.0 fold decrease, respectively, in ACC activity, and 1.94 and 5.1 fold decrease, respectively, in SREBP2 level, versus DC group) both in liver and skeletal muscle from GDM mice. We conclude that the combined intervention by metformin plus swimming may be more effective than single action to ameliorate glucose and lipid metabolism via improving insulin sensitivity in GDM mice.

Naringenin enhances the efficacy of human embryonic stem cell-derived pancreatic endoderm in treating gestational diabetes mellitus mice

Gestational diabetes mellitus (GDM) is a disease commonly occurs during mid to late pregnancy with pathologies such as hyperglycemia, hyperinsulinemia and mal-development of fetus. We have previously demonstrated that pancreatic endoderm (PE) derived from human embryonic stem cells (hESCs) effectively alleviated diabetic symptoms in a mouse model of GDM, although the clinical efficacy was limited due to oxidative stress. In this study, using the anti-oxidant agent naringenin, we aimed to further enhance the efficacy of hESC-derived PE transplant. Insulin-secreting PE was differentiated from hESCs, which were then transplanted into GDM mice. Naringenin was administered to mice receiving the PE transplant, with sham operated mice serving as negative control, to assess its effect on alleviation of GDM symptoms. We found that naringenin supplement further improved insulin response, glucose metabolism and reproductive outcome of the PE-transplanted female mice. Our new findings further potentiates the feasibility of using differentiated hESCs to treat GDM, in which anti-oxidative agent such as naringenin could greatly enhance the clinical efficacy of stem cell based therapies.

Resveratrol relieves gestational diabetes mellitus in mice through activating AMPK.

BackgroundGestational diabetes mellitus (GDM) is a disease often manifests in mid to late pregnancy with symptoms including hyperglycemia, insulin resistance and fetal mal-development. The C57BL/KsJ-Lepdb/+ (db/+) mouse is a genetic GDM model that closely mimicked human GDM symptoms. Resveratrol (RV) is a naturally existing compound that has been reported to exhibit beneficial effects in treating type-2 diabetes.MethodsIn this study, we investigated the effect of RV on the pregnant db/+ GDM mouse model, and the underlying molecular mechanism.ResultsRV greatly improved glucose metabolism, insulin tolerance and reproductive outcome of the pregnant db/+ females. Moreover, we found that RV relieved GDM symptoms through enhancing AMPK activation, which in turn reduced production and activity of glucose-6-phosphatase in both pregnant db/+ females and their offspring.ConclusionsOur findings further supported the potential therapeutic effect of RV on not only diabetes, but also alleviating GDM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-015-0114-0) contains supplementary material, which is available to authorized users.