Intrauterine Hyperglycemia Research Articles

Gestational Diabetes in Undernourished Women of KONKAN Region of State of Maharashtra, India (BKLWHANC-1)

Introduction: Offsprings exposed to intrauterine hyperglycaemia are at increased risk of obesity, type 2 diabetes in postnatal life. Little is known about gestational diabetes in KONKAN region of Maharashtra where women are undernourished across all stages of life. We estimated the prevalence of gestational diabetes among pregnant women visiting tertiary care hospital in KONKAN region. Methods: Between March 2020 and November 2020, 514 pregnant women registered in the antenatal clinic of BKL Walawalkar Hospital in KONKAN region. They underwent oral glucose tolerance test using the protocol set by Maternal & Child Health Division of Government of India. Results: Five hundred and six women completed oral glucose tolerance test. Mean age, gestation, weight and BMI at registration were 26.7 years, 23.1 weeks, 48.3 kg and 20.5 kg/m2 respectively. Prevalence of GDM was 20.3% and more than 50% of them were diagnosed before 24 weeks of gestation. Conclusion: Our results have shown that presence of GDM despite absence of overweight (high BMI). This is the first demonstration of hyperglycemia in pregnancy among undernourished women of KOKAN region. Offspring’s exposed to intrauterine hyperglycemia are at increased risk of obesity, type 2 diabetes in postnatal life hence long term implication of GDM in KONKAN can only be understood by systematic, community based study. Keywords: GDM; Rural; KONKAN; India; Malnutrition; Insulin resistance

Metabolic changes in female rats exposed to intrauterine hyperglycemia and postweaning consumption of high-fat diet†.

We evaluated the influence of the hyperglycemic intrauterine environment and postweaning consumption of a high-fat diet (HFD) on the glycemia, insulin, lipid, and immunological profile of rat offspring in adulthood. Female rats received citrate buffer (Control-C) or Streptozotocin (a beta cell-cytotoxic drug to induce diabetes-D) on postnatal day 5. In adulthood, these rats were mated to obtain female offspring, who were fed a standard diet (SD) or HFD from weaning to adulthood (n= 10 rats/group). OC/SD and OC/HFD represent female offspring of control mothers and received SD or HFD, respectively; OD/SD and OD/HFD represent female offspring of diabetic mothers and received SD or HFD, respectively. At adulthood, the oral glucose tolerance test (OGTT) was performed and, next, the rats were anesthetized and euthanized. Pancreas was collected and analyzed, and adipose tissue was weighted. Blood samples were collected to determine biochemical and immunological profiles. The food intake was lower in HFD-fed rats and visceral fat weight was increased in the OD/HFD group. OC/HFD, OD/SD, and OD/HFD groups presented glucose intolerance and lower insulin secretion during OGTT. An impaired pancreatic beta-cell function was shown in the adult offspring of diabetic rats, regardless of diet. Interleukin (IL)-6 and IL-10 concentrations were lower in the OD/HFD group and associated to a low-grade inflammatory condition. The fetal programming was responsible for impaired beta cell function in experimental animals. The association of maternal diabetes and postweaning HFD are responsible for greater glucose intolerance, impaired insulin secretion and immunological change.

Intrauterine Hyperglycemia Alters the Metabolomic Profile in Fetal Mouse Pancreas in a Gender-Specific Manner.

Mounting evidence has shown that intrauterine hyperglycemia exposure during critical stages of development may be contributing to the increasing prevalence of diabetes. However, little is known about the mechanisms responsible for offspring metabolic disorder. In this present study, we explored intrauterine hyperglycemia exposure on fetal pancreatic metabolome, and its potential link to impaired glucose tolerance in adult offspring. Here, using a GDM mouse model, we found the metabolome profiling of pancreas from male and female fetus showing altered metabolites in several important pathways, including 5-methylcytosine, α-KG, branched-chain amino acids, and cystine, which are associated with epigenetic modification, insulin secretion, and intracellular redox status, respectively. This finding suggests that intrauterine exposure to hyperglycemia could cause altered metabolome in pancreas, which might be a metabolism-mediated mechanism for GDM-induced intergenerational diabetes predisposition.

Intrauterine hyperglycemia impairs memory across two generations

Studies on humans and animals suggest associations between gestational diabetes mellitus (GDM) with increased susceptibility to develop neurological disorders in offspring. However, the molecular mechanisms underpinning the intergenerational effects remain unclear. Using a mouse model of diabetes during pregnancy, we found that intrauterine hyperglycemia exposure resulted in memory impairment in both the first filial (F1) males and the second filial (F2) males from the F1 male offspring. Transcriptome profiling of F1 and F2 hippocampi revealed that differentially expressed genes (DEGs) were enriched in neurodevelopment and synaptic plasticity. The reduced representation bisulfite sequencing (RRBS) of sperm in F1 adult males showed that the intrauterine hyperglycemia exposure caused altered methylated modification of F1 sperm, which is a potential epigenetic mechanism for the intergenerational neurocognitive effects of GDM.

Intrauterine hyperglycemia induces liver inflammation in mouse male offspring

Gestational diabetes mellitus (GDM) is a common complication of pregnancy characterized by intrauterine hyperglycemia, which is often associated with a high risk of obesity and diabetes in the offspring. In this study, we established a GDM mouse model by intraperitoneal injection of streptozotocin to investigate the immuno-inflammatory responses in the liver of adult offspring. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were employed to evaluate the glucose tolerance status. Hematoxylin-eosin staining was used to examine the histological changes in the liver. Quantitative real-timePCR (qRT-PCR) was applied to examine the mRNA expression of immune factors. Western blot and immunofluorescence analyses were used to examine the expression of target protein. Additionally, cell experiments were performed to validate the in vivo results. Compared to the control group, the area of fat vacuoles and the number of lymphocyte cells were significantly higher in the 20 weeks-old offspring of GDM mice. The elevated mRNA level of the pro-inflammatory cytokines IL-1β, IL-6, IL-33 and immune receptors CD3 and CD36 were found in the liver of F1-GDM. The protein level of IL-6r and the phosphorylation of JAK2 and STAT3 were significantly up-regulated. Moreover, the mRNA level of IL-6, IL-1β and IL-33 and the phosphorylation of JAK2 and STAT3 were also up-regulated in the hepatocyte treated with high concentration of glucose. Our results suggest that intrauterine hyperglycemia is associated with increased inflammation in the liver of adult male offspring.

Academic Performance in Adolescents Born to Mothers With Gestational Diabetes-A National Danish Cohort Study.

ContextThe prevalence of gestational diabetes mellitus (GDM) is increasing, and intrauterine hyperglycemia is suspected to affect offspring cognitive function.ObjectiveWe assessed academic performance by grade point average (GPA) in children aged 15 to 16 years at compulsory school graduation, comparing offspring exposed to GDM (O-GDM) with offspring from the background population (O-BP).MethodsThis register-based, cohort study comprised all singletons born in Denmark between 1994 and 2001 (O-GDM: n = 4286; O-BP: n = 501 045). Standardized and internationally comparable GPAs were compared in univariate and multivariable linear models. Main outcome measures included the adjusted mean difference in GPA. We also analyzed the probability of having a high GPA, a GPA below passing, and no GPA registered.ResultsO-GDM had a GPA of 6.29 (SD 2.52), whereas O-BP had a GPA of 6.78 (SD 2.50). The adjusted mean difference was –0.36 (95% CI, –0.44 to –0.29), corresponding to a Cohen’s D of 0.14. O-GDM had a lower probability of obtaining a high GPA (adjusted odds ratio [aOR] 0.68; 95% CI, 0.59 to 0.79), while their risk of obtaining a GPA below passing was similar to O-BP (aOR 1.20; 95% CI, 0.96 to 1.50). O-GDM had a higher risk of not having a GPA registered (aOR 1.38; 95% CI, 1.24 to 1.53).ConclusionAcademic performance in O-GDM was marginally lower than in O-BP. However, this difference is unlikely to be of clinical importance.

Umbilical cord blood metabolomics: association with intrauterine hyperglycemia.

Intrauterine hyperglycemia can harm a fetus's growth and development, and this can be seen in the umbilical cord blood metabolism disorder. However, the metabolites and metabolic mechanisms involved in the condition remain unknown. Targeted metabolomics using liquid chromatography and MetaboAnalyst were conducted in this study to explore differences in metabolites and metabolic pathways between individuals with hyperglycemia or well-controlled gestational diabetes mellitus (GDM) and healthy controls. Univariate analysis found that the hyperglycemic and healthy control groups differed in 30 metabolites, while the well-controlled GDM and the healthy control groups differed only in three metabolites-ursodeoxycholic acid, docosahexaenoic acid, and 8,11,14-eicosatrienoic acid. Most of these metabolic variations were negatively associated with neonatal weights. Further research showed that the variations in the metabolites were primarily associated with the metabolic pathways of linoleic acid (LA) and alpha-linolenic acid (ALA). Gestational hyperglycemia and well-controlled GDM, which may play a major role by inhibiting the LA and ALA metabolic pathways, have detrimental effects on cord blood metabolism. The main point of this paper is that intrauterine hyperglycemia has a negative effect on cord blood metabolism mainly through the linoleic acid and alpha-linolenic acid metabolic pathways. This is a study to report a new association between well-controlled GDM and cord blood metabolism. This study provides a possible explanation for the association between intrauterine hyperglycemia and neonatal adverse birth outcomes.

Maternal Hyperglycemia during Pregnancy Increases Adiposity of Offspring.

BackgroundThe effect of intrauterine hyperglycemia on fat mass and regional fat proportion of the offspring of mothers with gestational diabetes mellitus (OGDM) remains to be determined.MethodsThe body composition of OGDM (n=25) and offspring of normoglycemic mothers (n=49) was compared using dualenergy X-ray absorptiometry at age 5 years. The relationship between maternal glucose concentration during a 100 g oral glucose tolerance test (OGTT) and regional fat mass or proportion was analyzed after adjusting for maternal prepregnancy body mass index (BMI).ResultsBMI was comparable between OGDM and control (median, 16.0 kg/m2 vs. 16.1 kg/m2). Total, truncal, and leg fat mass were higher in OGDM compared with control (3,769 g vs. 2,245 g, P=0.004; 1,289 g vs. 870 g, P=0.017; 1,638 g vs. 961 g, P=0.002, respectively), whereas total lean mass was lower in OGDM (15,688 g vs. 16,941 g, P=0.001). Among OGDM, total and truncal fat mass were correlated with fasting and 3-hour glucose concentrations of maternal 100 g OGTT during pregnancy (total fat mass, r=0.49, P=0.018 [fasting], r=0.473, P=0.023 [3-hour]; truncal fat mass, r=0.571, P=0.004 [fasting], r=0.558, P=0.006 [3-hour]), but there was no correlation between OGDM leg fat mass and maternal OGTT during pregnancy. Regional fat indices were not correlated with concurrent maternal 75 g OGTT values.ConclusionIntrauterine hyperglycemia is associated with increased fat mass, especially truncal fat, in OGDM aged 5 years.

Effect of glucose on Akt2 mRNA and methylation level and the association between early-pregnancy Akt2 mRNA level in peripheral blood and pre-pregnancy BMI and GDM

Objective: To explore the effect of glucose on Akt2 gene methylation and mRNA level in the trophoblast cell line HTR8/SVneo and the association between first-trimester Akt2 mRNA level in peripheral blood and pre-pregnancy body mass index (BMI) and gestational diabetes mellitus (GDM). Methods: The cell model of intrauterine hyperglycemia in pregnant women with GDM was established, and divided into 5 groups based on the different glucose concentrations (2.5, 5.0, 10.0, 25.0, and 40.0 mmol/L). The mRNA levels of Akt2 gene were detected by real-time quantitative PCR, and the methylation levels of Akt2 gene promoter region were detected by mass spectrometry. According to pre-pregnancy BMI and diagnosis of GDM, 60 pregnant women who had given birth at Peking University First Hospital during December 2014 to July 2016 were classified into overweight non-GDM group, overweight GDM group, obese non-GDM group and obese GDM group. Real-time quantitative PCR analyses were used to detect the levels of Akt2 mRNA in first-trimester peripheral blood of the 4 groups. Results: (1) Level of Akt2 mRNA significantly rose with the glucose concentration of medium increased, showing concentration dependency (all P<0.05). Compared with the 25.0 mmol/L group, the following methylation levels changed significantly (all P<0.05): cytosine-phosphate-guanine (CpG) 10, CpG23, and CpG24.5 of Akt2 gene promoter region in the 5.0 mmol/L group, CpG23 and CpG24.5 in the 2.5 mmol/L group, and CpG10 in the 10.0 mmol/L group. Compared with the 5.0 mmol/L group, CpG10 in the 40.0 mmol/L group showed methylation change (P<0.05). (2) Compared with the overweight non-GDM group [1.04(0.90~1.26)], overweight GDM group [2.10(1.85~2.28)] and obese GDM group [1.68(0.82~2.43)] all had higher Akt2 mRNA levels and the differences were statistically significant (all P<0.05). Compared to obese GDM group [1.68(0.82~2.43)], the level of Akt2 mRNA was higher in overweight GDM group [2.10(1.85~2.28)] and lower in obese non-GDM group [1.00(0.71~2.17)], but the differences were not statistically significant (all P>0.05). Conclusions: Glucose might affect Akt2 mRNA level by changing the methylation of Akt2 gene promoter region, and the change might appear in the first trimester of pregnant women with GDM, especially for women with lower pre-pregnancy BMI.

Hyperglycaemia in Pregnancy and Anthropometric Parameters in the Offspring at 10 Years: A Community-Based Retrospective Cohort Study in Sri Lanka.

Background Studies of developmental origins of health and disease have highlighted the possible role of intrauterine hyperglycaemia, increasing the future risk of obesity, diabetes, and cardiovascular diseases in the offspring. There is limited evidence from South Asian populations for risk estimates for childhood obesity that are attributable to maternal diabetes in utero. Objective The aim of this study was to determine the association between hyperglycaemia in pregnancy (HIP) and anthropometric parameters in the offspring at 10-11 years of age. Methods A community-based retrospective cohort study was conducted in Colombo district, Sri Lanka. In the first stage, children born in 2005 were identified, and the availability of antenatal records was assessed. In the second stage, the exposure status of participants was ascertained based on antenatal records and predefined criteria. In the third stage, height, weight, waist circumference, and triceps skinfold thickness (TSFT) of eligible participants were measured to ascertain the outcome status. Background characteristics were collected by interviewing mothers. A 24-hour dietary recall and a 3-day diet diary were recorded. Results 159 children of mothers with HIP (exposed) and 253 children of mothers with no HIP (nonexposed) participated. Mean ages (SD) of exposed and unexposed groups were 10.9 (0.3) and 10.8 (0.3) years, respectively. The median BMI (17.6 vs 16.1, p < 0.001), waist circumference (63 cm vs 59.3 cm, p < 0.001), and triceps skinfold thickness (13.7 mm vs 11.2 mm, p < 0.001) were significantly higher in the exposed group. Offspring of women with HIP were more likely to be overweight (aOR = 2.6, 95% CI 1.4–4.9) and have abdominal obesity (aOR = 2.7, 95% CI 1.1–6.5) and high TSFT (aOR = 2.2, 95% CI 1.06–4.7) at 10-11 years than children who were not exposed after adjusting for maternal BMI, maternal age at delivery, and birth order. Conclusions Intrauterine exposure to HIP is a significant determinant of overweight, high TSFT, and abdominal obesity in the offspring.

169-LB: Is It Time for Country-Specific Glucose Cut-Off Values for Diagnosing Gestational Diabetes Mellitus in the Indian Population?

Background: Gestational diabetes mellitus (GDM) affects nearly 5 million pregnancies in India and is associated with multiple adverse pregnancy outcomes. Exposure to intrauterine hyperglycemia predisposes infants to increased risk obesity and diabetes. Indian phenotype tends to deposit excess central fat, which is linked to insulin resistance. Our study aimed to determine the effect of varying plasma glucose concentrations in predicting adverse maternal and infant outcomes in participants of a birth cohort in India. Methods: We examined a prospective cohort of pregnant women in the public hospitals of Bengaluru. We conducted a 2-hour 75g Oral glucose Tolerance Test (OGTT) in 1847, pregnant women between 24 to 36 weeks. We followed up women and children at delivery, and recorded skinfold thickness of babies at biceps, triceps, and subscapular region. We fitted 240 robust Poisson models to estimate the risk of the sum of skinfold thickness (SSFT) infants and caesarian section delivery with the FBS and PPBS. With one-unit increase beginning from FBS≥87 up to 92 mg/dL and PPBS ≥134 up to 153 mg/dL were tested with the sum of skinfold Thickness (SSST) and C section delivery. Results: We found that 10.65% (95% CI 9.19%, 12.30%) of 1847 infants had SSFT above 90th percentile, and 46.91% (95% CI 44.45%, 49.38%) of the women underwent caesarian section. The results indicate that FBS≥87 mg/dL and PPBS of ≥134mg/dl was associated with risk of increased SSST in infants [adjusted RR 1.70 (95% CI 1.06, 2.74)] and caesarian section delivery [Adjusted RR 1.19 (1.07,1.32)] after adjusting for age, parity, socioeconomic status, height and adiposity in mothers. Discussion: The pregnant women in India are at a higher risk of adverse birth outcomes with lower glucose cut-off values, compared to the international classification systems. These findings offer insights to revise the cut off points based on contextual settings in LMIC countries. Disclosure G.R. Babu: None. M.G. Lewis: None. D. R: None. E. Lobo: None. S. Kinra: None. G.V. Murthy: None. Funding UK Wellcome Trust/DBT India Alliance Fellowship (IA/CPHI/14/1/501499 to G.R.B.)

Transgenerational Obesity and Alteration of ARHGEF11 in the Rat Liver Induced by Intrauterine Hyperglycemia.

It is understood that intrauterine hyperglycemia increases the risk of obesity and diabetes in offspring of consecutive generations but its mechanisms remain obscure. This study is aimed at establishing an intrauterine hyperglycemia rat model to investigate the growth and glycolipid metabolic characteristics in transgenerational offspring and discuss the effects of Rho guanine nucleotide exchange factor 11 (ARHGEF11) and the PI3K/AKT signaling pathway in offspring development. The severe intrauterine hyperglycemia rat model was caused by STZ injection before mating, while offspring development and glycolipid metabolism were observed for the following two generations. The expression of ARHGEF11, ROCK1, PI3K, and AKT was tested in the liver and muscle tissue of F2 offspring. The results showed severe growth restriction in F1 offspring and obesity, fatty liver, and insulin resistance in female F2 offspring, especially the offspring of female intrauterine hyperglycemia-exposed parents (F2G♀C♂) and both (F2G♀G♂). The expression of ARHGEF11 and ROCK1 was significantly elevated; PI3K and phosphorylation of AKT were significantly decreased in liver tissues of F2G♀C♂ and F2G♀G♂. Our study revealed that intrauterine hyperglycemia could cause obesity and abnormal glycolipid metabolism in female transgenerational offspring; the programming effect of the intrauterine environment could cause a more obvious phenotype in the maternal line. Further exploration suggested that increased expression of ARHGEF11 and ROCK1 and the decreased expression of PI3K and phosphorylation of AKT in the liver could be responsible for the abnormal development in F2 offspring.

The impact of the intrauterine hyperglycaemia on the expression of genes related to cardio-metabolic diseases in human umbilical vein endothelial cells: results from a randomised, controlled study of different glycaemic targets during gestational diabetes treatment

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Epigenetic alteration of Rho guanine nucleotide exchange Factor 11 (ARHGEF11) in cord blood samples in macrosomia exposed to intrauterine hyperglycemia

Background: Macrosomia at birth is associated with maternal hyperglycemia and leads to subsequent susceptibility to obesity, abnormal glucose metabolism, hypertension, and dyslipidemia in offspring. Epigenetic reprogramming has been reported to be involved in the development of human diseases caused by suboptimal environmental or nutritional factors. The study was aiming to explore epigenetic mechanism influences on macrosomic infants exposed to intrauterine hyperglycemia. We performed a genome-wide analysis of DNA methylation in cord blood from macrosomic infants born to women with gestational diabetes in order to identify genes related to fetal growth or early adipose tissue development.Methods: To analyze the epigenetic patterns in umbilical cord blood in gestational diabetes mellitus (GDM), we collected umbilical cord blood from women with GDM (mean pregestational BMI of 24.4 kg/m2 and mean neonatal birth weight of 4366 g) and normal glucose-tolerant women (mean pregestational BMI of 19.8 kg/m2 and mean neonatal birth weight of 3166 g). Differentially methylated genes in the GDM group were identified using the Infinium HumanMethylation450 BeadChip array.Results: A total of 1251 genes were differentially methylated compared to the controls (p < .01). The methylation microarray data showed that two specific CpG sites (cg12604331 and cg08480098) in the gene body of ARHGEF11 were significantly hypomethylated in the cord blood in macrosomic infants. Altered DNA methylation levels of ARHGEF11 were negatively correlated with glucose levels and neonatal birth weight.Conclusions: Exposure to adverse intrauterine environments can alter fetal development, such as by affecting the nutritional status of the fetus. Such exposure can also result in significant epigenetic modifications, including DNA methylation, which could serve as a potential marker for nutrition and metabolic conditions at the neonatal stage or even in the adult.

Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue.

Brown adipose tissue (BAT) is an exclusive tissue of nonshivering thermogenesis. It is fueled by lipids and glucose and involved in energy and metabolic homeostasis. Intrauterine exposure to hyperglycemia during gestational diabetes mellitus may result in abnormal fetal development and metabolic phenotypes in adulthood. However, whether intrauterine hyperglycemia influences the development of BAT is unknown. In this study, mouse embryos were exposed to the intrauterine hyperglycemia environment by injecting streptozocin into pregnant mice at 1 d post coitum (dpc). The structure of BAT was examined by hematoxylin and eosin staining and immunohistochemical analysis. The glucose uptake in BAT was measured in vivo by [18F]-fluoro-2-deoxyglucose-micro-positron emission tomography. The gene expression in BAT was determined by real-time PCR, and the 5'-C-phosphate-G-3' site-specific methylation was quantitatively analyzed. Intrauterine hyperglycemia exposure resulted in the impaired structure of BAT and decreased glucose uptake function in BAT in adulthood. The expressions of the genes involved in thermogenesis and mitochondrial respiratory chain in BAT, such as Ucp1, Cox5b, and Elovl3, were down-regulated by intrauterine hyperglycemia exposure at 18.5 dpc and at 16 wk of age. Furthermore, higher methylation levels of Ucp1, Cox5b, and Elovl3 were found in offspring of mothers with streptozotocin-induced diabetes. Our results provide the evidence for enduring inhibitory effects of intrauterine hyperglycemia on BAT development in offspring. Intrauterine hyperglycemia is associated with increased DNA methylation of the BAT specific genes in offspring, which support an epigenetic involvement.-Yu, D.-Q., Lv, P.-P., Yan, Y.-S., Xu, G.-X., Sadhukhan, A., Dong, S., Shen, Y., Ren, J., Zhang, X.-Y., Feng, C., Huang, Y.-T., Tian, S., Zhou, Y., Cai, Y.-T., Ming, Z.-H., Ding, G.-L., Zhu, H., Sheng, J.-Z., Jin, M., Huang, H.-F. Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue.

MCSEA: detecting subtle differentially methylated regions.

The identification of differentially methylated regions (DMRs) among phenotypes is one of the main goals of epigenetic analysis. Although there are several methods developed to detect DMRs, most of them are focused on detecting relatively large differences in methylation levels and fail to detect moderate, but consistent, methylation changes that might be associated to complex disorders. We present mCSEA, an R package that implements a Gene Set Enrichment Analysis method to identify DMRs from Illumina450K and EPIC array data. It is especially useful for detecting subtle, but consistent, methylation differences in complex phenotypes. mCSEA also implements functions to integrate gene expression data and to detect genes with significant correlations among methylation and gene expression patterns. Using simulated datasets we show that mCSEA outperforms other tools in detecting DMRs. In addition, we applied mCSEA to a previously published dataset of sibling pairs discordant for intrauterine hyperglycemia exposure. We found several differentially methylated promoters in genes related to metabolic disorders like obesity and diabetes, demonstrating the potential of mCSEA to identify DMRs not detected by other methods. mCSEA is freely available from the Bioconductor repository. Supplementary data are available at Bioinformatics online.

Programming of Vascular Dysfunction in the Intrauterine Milieu of Diabetic Pregnancies.

With the rising global tide of obesity, gestational diabetes mellitus (GDM) burgeoned into one of the most common antenatal disorders worldwide. Macrosomic babies born to diabetic mothers are more likely to develop risk factors for cardiovascular disease (CVD) before they reach adulthood. Rodent studies in offspring born to hyperglycemic pregnancies show vascular dysfunction characterized by impaired nitric oxide (NO)-mediated vasodilation and increased production of contractile prostanoids by cyclooxygenase 2 (COX-2). Vascular dysfunction is a key pathogenic event in the progression of diabetes-related vascular disease, primarily attributable to glucotoxicity. Therefore, glucose-induced vascular injury may stem directly from the hyperglycemic intrauterine environment of GDM pregnancy, as evinced by studies showing endothelial activation and inflammation at birth or in childhood in offspring born to GDM mothers. This review discusses potential mechanisms by which intrauterine hyperglycemia programs dysfunction in the developing vasculature.

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.

Fish Intake in Pregnancy and Offspring Metabolic Parameters at Age 9⁻16-Does Gestational Diabetes Modify the Risk?

Oily fish, an important source of marine n-3 long-chain polyunsaturated fatty acids (LCPUFA), has shown to reduce cardiometabolic risk in adults. Whether maternal fish intake affects offspring metabolic health is less established, especially among high-risk pregnancies. We aimed to examine the association of fish intake in pregnancy with offspring metabolic health who were either exposed or unexposed to gestational diabetes mellitus (GDM). Our study included 1234 mother-offspring dyads (608 with a GDM index pregnancy and 626 control dyads) nested within the Danish National Birth Cohort, which is a prebirth cohort. Maternal seafood and marine n-3 LCPUFA consumption was quantified by a food frequency questionnaire (gestational week 25) and a sub-sample with interview data (weeks 12 and 30). The offspring were clinically examined at 9–16 years, including a Dual energy X-ray Absorptiometry (DXA) scan and a fasting blood sample. We calculated multivariable effect estimates and 95% confidence intervals (CI) for anthropometric, adiposity, and metabolic parameters. The median (IQR) intake of total seafood was 23(24) g/day. We found largely no association for total seafood and marine n-3 LCPUFA with offspring metabolic parameters in either group. Using interview data, GDM-exposed women reporting no fish in week 12 and 30 (versus intake >2 times/week) had offspring with a higher Body Mass Index (BMI) (ratio of geometric means (RGM): 1.28, 95% CI: 1.06, 1.55), waist circumference (RGM: 1.22, 95% CI: 1.05, 1.40), triglycerides (RGM: 1.77, 95% CI: 1.03, 3.03), and homeostatic model assessment of insulin resistance HOMA-IR (RGM: 2.16, 95% CI: 1.17, 3.97). We found no associations of n-3 LCPUFA and seafood intake with offspring metabolic outcomes. However, GDM-exposed women who consistently reported eating no fish had offspring with a poorer metabolic profile. Fish intake in pregnancy may mitigate some adverse effects of intrauterine hyperglycemia, however, these findings need replication in better powered studies.

Intrauterine hyperglycemia exposure results in intergenerational inheritance via DNA methylation reprogramming on F1 PGCs

BackgroundThe existing reports about intergenerational or transgenerational effects of intrauterine hyperglycemia have included both intrauterine and postnatal metabolic exposure factors, while the impact of intrauterine hyperglycemia per se has not been assessed alone. A number of studies suggest DNA methylation reprogramming of gametes plays a crucial role in the metabolic inheritance, but it is unclear when and how DNA methylation patterns are altered when exposed to intrauterine hyperglycemia. In this study, we selected nondiabetic F1- and F2-gestational diabetes mellitus (GDM) male mice as founders to examine metabolic changes in the next generation and performed methylome sequencing of day 13.5 primordial germ cells (PGCs) from F1-GDM to explore the underlying epigenetic mechanism.ResultsWe found that intrauterine hyperglycemia exposure resulted in obesity, insulin resistance, and/or glucose intolerance in F2 male mice, but no metabolic changes in F3 male mice at 8 weeks. Using reduced representation bisulfite sequencing, we found DNA methylome of day 13.5 PGCs from F1-GDM fetuses revealed differently methylated genes enriched in obesity and diabetes. Methylation validation of the insulin resistance and fat accumulation gene Fyn showed a consistent hypomethylation status in F1 PGCs, F1 fetal testes, sperm from F1/C-GDM mice, and somatic cells from F2-GDM male mice. In contrast, no methylation alteration was observed in F2-GDM male germ cells and F3-GDM somatic cells.ConclusionWe provide evidence that intrauterine hyperglycemia exposure per se contributes to intergenerational metabolic changes in the F2 but not F3 generation. And the aberrant DNA methylation reprogramming occurs as early as day 13.5 in PGCs of the F1 generation. Our findings suggest that intrauterine exposure alone is sufficient to cause the epigenetic inheritance in F2 offspring, and the epigenetic memory carried by DNA methylation pattern could be erased by the second wave of methylation reprogramming in F2 PGCs during fetal development.