Offspring Glucose Research Articles

Maternal glucose homeostasis during pregnancy in women with overweight or obesity and offspring metabolic health

Gestational diabetes mellitus (GDM) adversely affects offspring glucose homeostasis and risk of developing obesity. Here, we examined the association between glycemia in pregnant women with overweight or obesity without GDM and offspring metabolic health. Maternal fasting glucose concentrations and glucose 2-h after an oral glucose tolerance test (OGTT) were measured in 208 women with a pre-pregnancy body mass index (BMI) of 28–45 kg/m2 without GDM. Offspring outcomes were collected at birth, 3, and 5 years of age. Linear mixed models with time as fixed factor and subject ID as random effects were used for analysis. No associations were found between maternal fasting or 2-h glucose concentrations with offspring glucose and insulin concentrations from birth to 5 years of age. However, maternal fasting glucose in GW 28 and 36, and 2-h OGTT glucose in GW 28 were positively associated with C-peptide concentration at birth. Maternal fasting glucose concentrations in GW 28 and 36 were positively associated with weight-for-length, and maternal fasting glucose in GW 36 was associated with BMI z-score at birth. In summary, blood glucose in pregnant women with overweight or obesity is positively associated with offspring C-peptide concentration, weight-for-length, and BMI z-score at birth, even in the absence of GDM.

Associations of Placental Inflammation and Oxidative Stress Biomarkers with Glucolipid Metabolism in Children: A Birth Cohort Study in China.

The maternal intrauterine immune environment may affect offspring long-term health. We aimed to investigate the association between the intrauterine placental immunological milieu and glycolipid metabolic health in children. This study enrolled 1803 mother-child pairs from the Ma'anshan birth cohort (2013-2014). Placental mRNA expression of inflammatory cytokines (interleukin-1β [IL-1β], IL-10, monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-4, IL-6, IL-8, C-reactive protein, and interferon-γ) and oxidative stress biomarkers (heme oxygenase-1, hypoxia-inducible factor-1alpha, and glucose-related protein 78) was quantified using real-time quantitative polymerase chain reaction. Fasting blood glucose, insulin, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol were assessed at 5 to 6 years old. Statistical analyses included multiple linear regression, binary logistic regression, restricted cubic spline model, and the Bayesian kernel machine regression model. Placental inflammatory cytokines (IL-1β, monocyte chemoattractant protein-1, C-reactive protein, IL-6, IL-8, IL-10) and oxidative stress biomarkers (heme oxygenase-1, hypoxia-inducible factor-1alpha, glucose-related protein 78) showed positive associations with children's fasting blood glucose levels. Heme oxygenase-1 and glucose-related protein 78 exhibited negative correlations with children's fasting insulin levels. Elevated IL-6, heme oxygenase-1, hypoxia-inducible factor-1alpha, and glucose-related protein 78 were associated with increased risk of prediabetes in children. Overall upregulation of placental proinflammatory cytokines and oxidative stress factors mRNA expression correlated with higher prediabetes risk in children. Bayesian kernel machine regression analysis indicated a joint positive effect of the 12 placental inflammation and oxidative stress mixtures on children's risk of high fasting blood glucose. This exploratory study underscores significant correlations between maternal intrauterine placental inflammation, oxidative stress markers, and offspring fasting blood glucose and insulin levels. These findings highlight the potential role of intrauterine holistic immunity in shaping offspring glucose metabolism health.

Maternal high fat diet induces circadian clock-independent endocrine alterations impacting the metabolism of the offspring

Maternal obesity has long-term effects on offspring metabolic health. Among the potential mechanisms, prior research has indicated potential disruptions in circadian rhythms and gut microbiota in the offspring. To challenge this hypothesis, we implemented a maternal high fat diet regimen before and during pregnancy, followed by a standard diet after birth. Our findings confirm that maternal obesity impacts offspring birth weight and glucose and lipid metabolisms. However, we found minimal impact on circadian rhythms and microbiota that are predominantly driven by the feeding/fasting cycle. Notably, maternal obesity altered rhythmic liver gene expression, affecting mitochondrial function and inflammatory response without disrupting the hepatic circadian clock. These changes could be explained by a masculinization of liver gene expression similar to the changes observed in polycystic ovarian syndrome. Intriguingly, such alterations seem to provide the first-generation offspring with a degree of protection against obesity when exposed to a high fat diet.

Fetal Origin of Abnormal Glucose Tolerance in Adult Offspring Induced by Maternal Bisphenol A Analogs Exposure.

With the widespread use of bisphenol A (BPA) analogs, their health risks have attracted attention. The effects of maternal BPA analogs exposure on glucose homeostasis in adult offspring and the underlying fetal origins require further exploration. Herein, we exposed pregnant mice to two types of BPA analogs─BPB and BPAF; we evaluated glucose homeostasis in adult offspring and maternal-fetal glucose transport by testing intraperitoneal glucose tolerance, determining glucose and glycogen contents, conducting positron emission tomography (PET)/computed tomography (CT), detecting expression of placental nutrient transport factors, and assessing placental barrier status. We observed that adult female offspring maternally exposed to BPB and BPAF exhibited low fasting blood glucose in adulthood, with even abnormal glucose tolerance in the BPAF group. This phenomenon can be traced back to the elevated fetal glucose induced by the increased efficiency of placenta glucose transport in late pregnancy. On the other hand, the expression of genes associated with vascular development and glucose transport was significantly altered in the placenta in the BPAF group, potentially contributing to enhanced fetal glucose. These findings provide preliminary insights into potential mechanisms underlying the disturbance of glucose metabolism in adult female offspring mice induced by maternal exposure to BPA analogs.

Monitoring Blood Glucose in Mouse Offspring after Intracytoplasmic sperm injection - Embryo Transfer.

Human lifespan is considerably long, while mouse models can simulate the entire human lifespan in a relatively short period, with one year of mouse life roughly equivalent to 40 human years. Intracytoplasmic sperm injection (ICSI) is a commonly used assisted reproductive technology in clinical practice. However, given its relatively recent emergence about 30 years ago, the long-term effects of this technique on human development remain unclear. In this study, we established the ICSI combined with embryo transfer (ET) method using a mouse model. The results demonstrated that normal mouse sperm, after undergoing in vitro culture and subsequent ICSI, exhibited a fertilization rate of 89.57% and a two-cell rate of 87.38%. Following ET, the birth rate of offspring was approximately 42.50%. Furthermore, as the mice aged, fluctuations in glucose metabolism levels were observed, which may be associated with the application of the ICSI technique. These findings signify that the mouse ICSI-ET technique provides a valuable platform for evaluating the impact of sperm abnormalities on embryo development and their long-term effects on offspring health, particularly concerning glucose metabolism. This study provides important insights for further research on the potential effects of the ICSI technique on human development, emphasizing the necessity for in-depth investigation into the long-term implications of this technology.

Maternal Vitamin C Intake during Pregnancy Influences Long-Term Offspring Growth with Timing- and Sex-Specific Effects in Guinea Pigs.

Our previous work in guinea pigs revealed that low vitamin C intake during preconception and pregnancy adversely affects fertility, pregnancy outcomes, and foetal and neonatal growth in a sex-dependent manner. To investigate the long-term impact on offspring, we monitored their growth from birth to adolescence (four months), recorded organ weights at childhood equivalence (28 days) and adolescence, and assessed physiological parameters like oral glucose tolerance and basal cortisol concentrations. We also investigated the effects of the timing of maternal vitamin C restriction (early vs. late gestation) on pregnancy outcomes and the health consequences for offspring. Dunkin Hartley guinea pigs were fed an optimal (900 mg/kg feed) or low (100 mg/kg feed) vitamin C diet ad libitum during preconception. Pregnant dams were then randomised into four feeding regimens: consistently optimal, consistently low, low during early pregnancy, or low during late pregnancy. We found that low maternal vitamin C intake during early pregnancy accelerated foetal and neonatal growth in female offspring and altered glucose homeostasis in the offspring of both sexes at an age equivalent to early childhood. Conversely, low maternal vitamin C intake during late pregnancy resulted in foetal growth restriction and reduced weight gain in male offspring throughout their lifespan. We conclude that altered vitamin C during development has long-lasting, sex-specific consequences for offspring and that the timing of vitamin C depletion is also critical, with low levels during early development being associated with the development of a metabolic syndrome-related phenotype, while later deprivation appears to be linked to a growth-faltering phenotype.

Effects of poor maternal diet during gestation are detected in F2 offspring.

Poor maternal nutrition of F0 ewes impairs F1 offspring growth, with minimal differences in glucose tolerance or select metabolic circulating factors, and independent of differences in residual feed intake (RFI). To determine if poor maternal nutrition in F0 ewes alters F2 offspring growth, circulating leptin, feed efficiency, or glucose tolerance, F0 ewes (n = 46) pregnant with twins were fed 100% (control), 60% (restricted), or 140% (over) of National Research Council requirements from days 30 ± 0.02 of gestation until parturition. At 16 to 19 mo of age, female F1 (n = 36) offspring were bred to generate F2 offspring [CON-F2 (n = 12 ewes; 6 rams), RES-F2 (n = 7 ewes; 13 rams), or OVER-F2 (n = 13 ewes; 9 rams) corresponding to diets of the granddam (F0)]. Lamb body weights (BW) and blood samples were collected weekly from days 0 to 28 and every 14 d until day 252 of age. Circulating leptin was measured in serum at days 0, 7, 14, 56, 210, and 252. An intravenous glucose tolerance test was performed at days 133 ± 0.28. At days 167 ± 0.33, individual daily intake was recorded over a 77-d feeding period to determine RFI. Rams were euthanized at days 285 ± 0.93, and body morphometrics, loin eye area (LEA), back fat thickness, and organ weights were collected and bone mineral density (BMD) and length were determined in the right hind leg. During gestation, OVER-F1 ewes tended to be 8.6% smaller than CON-F1 ewes (P ≤ 0.06). F2 offspring were of similar BW from birth to day 70 (P ≥ 0.20). However, from days 84 to 252, RES-F2 offspring tended to be 7.3% smaller than CON-F2 (P ≤ 0.10). Granddam diet did not influence F2 ram body morphometrics, organ or muscle weights, LEA, adipose deposition, or leg BMD (P ≥ 0.84). RES-F2 (-0.20) and CON-F2 (-0.45) rams tended to be more feed efficient than CON-F2 ewes (0.31; P ≤ 0.08). No effects of granddam diet were observed on glucose or insulin average or baseline concentrations, area under the curve, first-phase response, or ratio (P ≥ 0.52). However, CON-F2 rams (297mg/dL ± 16.5) had a greater glucose peak compared with RES-F2 rams (239mg/dL ± 11.2; P = 0.05). Peak insulin concentrations were not influenced by granddam diet (P = 0.75). At d 56, RES-F2 and OVER-F2 offspring had 53.5% and 61.8% less leptin compared with CON-F2 offspring, respectively (P ≤ 0.02). These data indicate that poor maternal nutrition impacts offspring growth into the second generation with minimal impacts on offspring RFI, glucose tolerance, and circulating leptin.

Intrauterine arsenic exposure induces glucose metabolism disorders in adult offspring by targeting TET2-mediated DNA hydroxymethylation reprogramming of HNF4α in developing livers, an effect alleviated by ascorbic acid

Exposure to arsenic during gestation has lasting health-related effects on the developing fetus, including an increase in the risk of metabolic disease later in life. Epigenetics is a potential mechanism involved in this process. Ten-eleven translocation 2 (TET2) has been widely considered as a transferase of 5-hydroxymethylcytosine (5hmC). Here, mice were exposed, via drinking water, to arsenic or arsenic combined with ascorbic acid (AA) during gestation. For adult offspring, intrauterine arsenic exposure exhibited disorders of glucose metabolism, which are associated with DNA hydroxymethylation reprogramming of hepatic nuclear factor 4 alpha (HNF4α). Further molecular structure analysis, by SEC-UV-DAD, SEC-ICP-MS, verified that arsenic binds to the cysteine domain of TET2. Mechanistically, arsenic reduces the stability of TET2 by binding to it, resulting in the decrease of 5hmC levels in Hnf4α and subsequently inhibiting its expression. This leads to the disorders of expression of its downstream key glucose metabolism genes. Supplementation with AA blocked the reduction of TET2 and normalized the 5hmC levels of Hnf4α, thus alleviating the glucose metabolism disorders. Our study provides targets and methods for the prevention of offspring glucose metabolism abnormalities caused by intrauterine arsenic exposure.

PSVIII-25 Investigating the Effects of Poor Maternal Nutrition on F2 Offspring Growth, Residual Feed Intake, and Glucose Tolerance

Abstract Poor maternal nutrition impairs F1 offspring growth independent of changes in feed efficiency and glucose tolerance. To determine if poor maternal nutrition in F0 ewes contributes to F2 offspring growth, feed efficiency, and glucose tolerance, multiparous Dorset ewes (F0; n = 46) pregnant with twins were fed 100% (control), 60% (restricted) or 140% (over) of NRC requirements from d 30 of gestation until parturition. At 16 to 19 mo of age, female F1 (n = 37) offspring were bred to one of two related Dorset rams to generate F2 offspring, identified as CON-F2 (n = 12 ewes; 6 rams), RES-F2 (n = 7 ewes; 13 rams), or OVER-F2 (n = 13 ewes; 9 rams), corresponding to diets of the granddam. F2 offspring body weight (BW) was measured weekly from birth (d 0) to d 28 and every 14 d until d 252. From d 0 to 70, granddam diet did not influence F2 BW (P ≥ 0.18). However, from d 84 to d 154, RES-F2 tended to be 9.42% lighter than CON-F2 with OVER-F2 intermediate (P ≤ 0.08), and from d 224 to d 252 RES-F2 tended to be 6.47% and 6.29% lighter than CON-F2 and OVER-F2, respectively (P ≤ 0.07). Overall, F2 rams were 8.36 kg heavier than F2 ewes (P < 0.0001). At d 133 ± 0.28 an intravenous glucose tolerance test (0.25 g/kg BW of a 50% dextrose solution) was performed. Glucose and insulin concentrations were determined using commercial kits. Granddam diet did not influence glucose or insulin average or baseline concentrations, area under the curve, first-phase response, or ratio (P ≥ 0.52). However, granddam diet influenced glucose peak response in rams, where CON-F2 rams (297 ± 16.5 mg/dL) had greater glucose peak compared with RES-F2 rams (239 ± 11.2 mg/dL; P = 0.05). At d 167 ± 0.33, daily intake of a complete pelleted feed was recorded using Super SmartFeeders over a 77-day feeding period. A treatment by sex interaction was detected for F2 offspring residual feed intake (RFI; P = 0.08) where CON-F2 ewes (0.31 ± 0.12 kg/d) tended to be less feed efficient than CON-F2 rams (-0.45 ± 0.20 kg/d) and RES-F2 rams (-0.20 ± 0.13 kg/d). Alternately, OVER-F2 ewes (0.16 ± 0.13 kg/d), OVER-F2 rams (0.02 ± 0.15 kg/d), RES-F2 ewes (-0.06 ± 0.18 kg/d), and RES-F2 rams were all of similar (P ≥ 0.34) feed efficiency. Rams were euthanized at d 285 ± 0.93 and body morphometrics, and organ weights were collected. No effect of granddam diet (P ≥ 0.25) on F2 ram morphometric measurements, organ weights, or muscle weights (P ≥ 0.15) were detected at time of necropsy. These data indicate that nutrient restriction during gestation decreases F2 offspring BW independent of RFI and glucose tolerance.

The Role of Gut Microbiota in Gestational Diabetes Mellitus Affecting Intergenerational Glucose Metabolism: Possible Mechanisms and Interventions

The incidence of type 2 diabetes is increasing every year and has become a serious public health problem. In addition to genetic factors, environmental factors in early life development are risk factors for diabetes. There is growing evidence that the gut microbiota plays an important role in glucose metabolism, and the gut microbiota of pregnant women with gestational diabetes mellitus (GDM) differs significantly from that of healthy pregnant women. This article reviews the role of maternal gut microbiota in offspring glucose metabolism. To explore the potential mechanisms by which the gut microbiota affects glucose metabolism in offspring, we summarize clinical studies and experimental animal models that support the hypothesis that the gut microbiota affects glucose metabolism in offspring from dams with GDM and discuss interventions that could improve glucose metabolism in offspring. Given that adverse pregnancy outcomes severely impact the quality of survival, reversing the deleterious effects of abnormal glucose metabolism in offspring through early intervention is important for both mothers and their offspring.

DNA methylation regulates pancreatic gene expression and links maternal high-fat diet to the offspring glucose metabolism

Maternal high-fat diet (HFD) is related to an increased risk of glucose metabolism disorders throughout the whole life of offspring. The pancreas is a glucose homeostasis regulator. Accumulating evidence has revealed that maternal HFD affects offspring pancreas structure and function. However, the potential mechanism remains unclear. In this study, the mouse dam was fed with HFD or control diet (CD) during prepregnancy, pregnancy and lactation. The pancreatic insulin secretion function and islet genome methylome of offspring were analyzed. Pancreatic islet specific gene methylation was detected by using MeDIP qPCR. The results showed that body weight, blood glucose after oral glucose loads, fasting serum insulin, and HOMA-IR index values were significantly higher in male 12-week-old offspring from HFD dams than in the offspring from CD dams. Maternal HFD induced insulin secretion defects in male offspring. Compared with that in maternal CD group, methylation of the Abcc8 and Kcnj11 genes was increased in maternal HFD group in male offspring pancreatic islets. Furthermore, the expression levels of Abcc8 and Kcnj11 were downregulated by intrauterine exposure to a maternal HFD. In summary, maternal HFD results in a long-term functional disorder of the pancreas that is involved in insulin secretion-related gene DNA hypermethylation.

High-fat diet impairs glucose homeostasis by increased p16 beta-cell expression and alters glucose homeostasis of the progeny in a parental-sex dependent manner.

Obesity consists in the accumulation of adipose tissue accompanied by low grade chronic inflammation and is considered a pandemic disease. Recent studies have observed that obesity affects females and males in a sex-dependent manner. In addition, several works have demonstrated that parental obesity increases the risk to develop obesity, insulin resistance, diabetes, and reproductive disorders. Considering that intergenerational effects of obesity may occur in a sex-dependent manner, we studied male Wistar rat progeny (F1) obtained from mothers or fathers (F0) fed on a high-fat diet (HFD). Five-week-old female and male Wistar rats were fed on a HFD (with 60% of calories provided by fat) for 18 weeks (F0). At the end of the treatment, animals were mated with young rats to obtain their progeny (F1). After weaning, F1 animals were fed on standard chow until 18 weeks of age. Body weight gain, fasting plasma glucose, insulin and leptin levels, glucose tolerance, insulin sensitivity, and adiposity were evaluated. In addition, beta-cell expression of nuclear p16 was assessed by immunofluorescence. HFD altered plasma fasting glucose, insulin and leptin levels, glucose tolerance, adiposity, and beta-cell expression of p16 in F0 rats. Particularly, HFD showed sexual dimorphic effects on body weight gain and insulin sensitivity. Moreover, we observed that parental HFD feeding exerts parental-sex-specific metabolic impairment in the male progeny. Finally, parental metabolic dysfunction could be in part attributed to the increased beta-cell expression of p16; other mechanisms could be involved in the offspring glucose homeostasis.

Altered expression of long noncoding RNA MEG3 in the offspring of gestational diabetes mellitus induces impaired glucose tolerance in adulthood.

Gestational diabetes mellitus (GDM) affects a significant number of women worldwide and has been associated with lifelong health consequences for their offspring, including increased susceptibility to obesity, insulin resistance, and type II diabetes. Recent studies have suggested that aberrant expression of the long non-coding RNA Meg3 in the liver may contribute to impaired glucose metabolism in individuals. In this study, we aimed to investigate whether intrauterine exposure to hyperglycemia affects glucose intolerance in puberty by mediating the overexpression of LncMeg3 in the liver. To test our hypothesis, we established an animal model of intrauterine hyperglycemia to mimic GDM. The progeny was observed for phenotypic changes, and intraperitoneal glucose tolerance tests, insulin tolerance tests, and pyruvate tolerance tests were conducted to assess glucose and insulin tolerance. We also measured LncMeg3 expression in the liver using real-time quantitative PCR and examined differential methylation areas (DMRs) in the Meg3 gene using pyrophosphoric sequencing. To investigate the role of LncMeg3 in glucose tolerance, we conducted Meg3 intervention by vein tail and analyzed the changes in the phenotype and transcriptome of the progeny using bioinformatics analysis. We found that intrauterine exposure to hyperglycemia led to impaired glucose and insulin tolerance in the progeny, with a tendency toward increased fasting blood glucose in fat offspring at 16weeks (P = 0.0004). LncMeg3 expression was significantly upregulated (P = 0.0061), DNMT3B expression downregulated (P = 0.0226), and DNMT3A (P = 0.0026), TET2 (P = 0.0180) expression upregulated in the liver. Pyrophosphoric sequencing showed hypomethylation in Meg3-DMRs (P = 0.0005). Meg3 intervention by vein tail led to a decrease in the percentage of obese and emaciated offspring (emaciation: 44% vs. 23%; obesity: 25% vs. 15%) and attenuated glucose intolerance. Bioinformatics analysis revealed significant differences in the transcriptome of the progeny, particularly in circadian rhythm and PPAR signaling pathways. In conclusion, our study suggests that hypomethylation of Meg3-DMRs increases the expression of the imprinted gene Meg3 in the liver of males, which is associated with impaired glucose tolerance in GDM-F1. MEG3 interference may attenuate glucose intolerance, which may be related to transcriptional changes. Our findings provide new insights into the mechanisms underlying the long-term effects of intrauterine hyperglycemia on progeny health and highlight the potential of Meg3 as an intervention target for glucose intolerance.

Abstract 029: Hypertensive Disorder Of Pregnancy Results In Loss Of Pancreatic Beta Cell Area In Female Rat Offspring Without Development Of Glucose Intolerance

Hypertensive disorders of pregnancy can result in increased risk for type 2 diabetes (T2D) in offspring. Reduced pancreatic beta cell area can also influence development of glucose intolerance or T2D. Using a rat model of reduced uterine perfusion pressure (RUPP) which leads to hypertension during pregnancy and intrauterine growth restriction, we previously demonstrated reduced beta cell area in female RUPP offspring vs Sham at embryonic day 19 persisting to postnatal day (PD)13. To determine if this alteration in beta cell area is associated with phenotypic changes in glucose handling as offspring mature, we assessed IPGTT (intraperitoneal glucose tolerance test), OGTT (oral glucose tolerance test) and ITT (insulin tolerance test) in PD14, PD28, 8 week and 6 month female offspring (n=5-11/group). Our results demonstrate no change in fasting blood glucose and no alteration in glucose handling with IP glucose administration at any age. However, peak glucose following oral glucose administration was significantly less in RUPP offspring at PD14 (196.3+/-8.6 mg/dl, RUPP; 218.3+/-9.5 mg/dl, Sham; p=0.05), PD28 (220.0+/-4.1 mg/dl, RUPP; 280.0+/-12.8 mg/dl, Sham; p<0.05) and 6 months (139.6+/-3.8 mg/dl, RUPP; 150.9+/-4.5 mg/dl, Sham; p<0.05) compared to Sham, suggesting the incretin effect on pancreas and non-pancreas tissues is more effective in controlling blood glucose in RUPP offspring vs Sham. In addition, the decrease in glucose level in response to insulin injection in ITT was significantly greater in RUPP offspring vs Sham at PD28 (58.9+/-5.0 mg/dl, RUPP; 78.3+/-8.9 mg/dl, Sham; p<0.05) suggesting increased insulin sensitivity in non-pancreatic tissues in RUPP compared to Sham offspring. Our studies demonstrate female offspring of hypertensive pregnancies are not glucose intolerant by 6 months of age. Despite reduced pancreatic beta cell area in female RUPP offspring early in development, glucose handling was maintained and even improved after oral glucose challenge in older RUPP offspring. Overall, these data suggest that increased peripheral insulin sensitivity may reduce the demand for beta cell function, and our studies reinforce the idea that adverse pregnancy can have a lasting effect on development and function of the pancreas.

Maternal exercise and vitamin D feeding cooperatively regulate the offspring glucose metabolism

Maternal exercise and vitamin D feeding cooperatively regulate the offspring glucose metabolism

Like father, like daughter:Paternal cadmium exposure causes hepatic glucose metabolic disorder and phospholipids accumulation in adult female offspring

Cadmium (Cd), is a well-known reproductive toxicant. The impacts of paternal Cd exposure on offspring glucose and lipid metabolism remain unclear, despite the abundance of adverse reports following early exposure from the mother. Here, we assessed paternally acquired metabolic derailment using a mouse model. LC-MS/MS, transcriptomics and molecular experimental techniques were subsequently applied in this study to explore the potential mechanism. We found that paternal Cd exposure caused glucose intolerance, lower insulin sensitivity and abnormal hepatic glycogen storage in adult female offspring, but not in males. LC-MS/MS data showed that hepatic phospholipids accumulation was also only observed in adult female offspring after paternal Cd exposure. Gene expression data showed that the level of insulin signaling and lipid transport-related genes was decreased in Cd-treated adult female offspring livers. Meanwhile, AHR, a transcription factor that combines with phospholipids to promote insulin resistance, was increased in Cd-treated adult female offspring livers. In addition, the escalation of the afore-mentioned lipid metabolites in the liver occurred as early as fetal stages in the female pups following paternal Cd exposure, suggesting the potential for these lipid species to be selected as early markers of disease for metabolic derailment later in life. Altogether, paternal Cd exposure causes offspring glucose metabolism disorder and phospholipids accumulation in a sex-dependent manner. This study provides a theoretical framework for future understanding of paternal-originated metabolic diseases.

177-LB: Association of Pregnancy and Childhood C-Peptide Levels—Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO-FUS)

Physiological insulin resistance partitions glucose for the growing fetus during the 2nd and 3rd trimester of pregnancy. The HAPO study has demonstrated that pregnancy hyperglycemia is associated with offspring adiposity, hyperglycemia, and glucose intolerance. Maternal insulin is a key regulator of the glucose physiology but does not cross the placenta. The goal of this study was to identify the association of pregnancy and offspring c-peptide levels, measured during oral glucose tolerance test (OGTT). Method: Using HAPO-FUS data from the NIH-NIDDK repository, multiple linear regression assessed the association of scaled pregnancy fasting and 1-hour c-peptide with cord c-peptide (at birth), and child c-peptide from OGTT at the follow-up visit (ages 10-14 years). Maternal covariates include pregnancy gestational age, BMI, glucose level and field center. Child covariates include age, sex, tanner stage, BMI z-score and glucose level. Multiple imputation was performed using missing at random assumption. Results: A total of 4,802 mother-child pairs were included. Pregnancy c-peptide was associated with cord c-peptide (fasting 0.02 [0.01-0.03], p <.001, 1-hour 0.01 [0.002-0.02], p =.006). Pregnancy fasting c-peptide was also associated with child OGTT c-peptide (fasting 0.03 [0.02-0.04], p <.001; 1-hour 0.11 [0.08-0.15], p <.001; 2-hour 0.01 [0.007-0.02], p <.001) and pregnancy 1-hour c-peptide (fasting 0.01 [0.007-0.02], p <.001; 1-hour 0.15 [0.12-0.17], p <.001; 2-hour 0.11 [0.09-0.14], p <.001). Similar associations were observed with child insulin levels. Pregnancy c-peptide levels were positively associated with HOMA-IR and negatively with child insulin sensitivity and Matsuda index while adjusting for child BMI z-score and pubertal stage. Conclusion: Pregnancy insulin levels are strongly associated with the child insulin response during OGTT. This suggests a role in the offspring pancreas developmental programming. Disclosure H. Zheng: None. A. Rajamoorthi: None. A. Skowronski: None. R. Salem: Other Relationship; Travere Inc. C. A. Leduc: None. V. V. Thaker: None. Funding National Institutes of Health (K23DK110539)

Lactational retrorsine exposure changes maternal milk components and disturbs metabolism homeostasis of offspring rats

Pyrrolizidine alkaloids (PAs) are a type of plant-derived environmental toxins, which pose a health hazard to human and livestock via contaminating soil, water, plants and food. In this study, we aimed to investigate the effect of lactational retrorsine (RTS, a typical toxic PA) exposure on breastmilk components and glucose-lipid metabolism of offspring rats. Dams were intragastrically administered with 5 mg/(kg·d) RTS during lactation. After metabolomic analyses, 114 differential constituents were identified in breastmilk between control and RTS groups, featured by reduction of lipids and lipid-like molecules, while presence of abundant RTS and its derivative in RTS-exposed milk. RTS exposure induced liver injury in pups, but the leakage of transaminases in serum recovered in their adulthood. Serum glucose levels were lower in pups but higher in male adult offspring from RTS group. RTS exposure also induced hypertriglyceridemia, hepatic steatosis and decreased glycogen content in both pups and adult offspring. Additionally, suppression of PPARα-FGF21 axis persisted in offspring liver after RTS exposure. These data indicated that inhibition of PPARα-FGF21 axis induced by milk deficient in lipid contents, together with hepatotoxic injury caused by RTS in breastmilk, may disrupt glucose and lipid metabolism of pups, and the persistent suppression of PPARα-FGF21 axis may program metabolic disorder of glucose and lipid in adult offspring.

Altered local RAS in the liver increased the risk of NAFLD in male mouse offspring produced by in vitro fertilization

BackgroundAssisted reproductive technology (ART) is associated with an increased risk of adverse metabolic health in offspring, and these findings have been demonstrated in animal models without parental infertility issues. However, it is unclear what changes lead to abnormal metabolism. The activation of the renin-angiotensin system (RAS) has been related to various aspects of metabolic syndrome. Thus, we focused on the local RAS of the liver, which is the central organ for glucose and lipid metabolism in offspring conceived by in vitro fertilization (IVF), and studied the role of local liver RAS in metabolic diseases.MethodsMale C57BL/6 mouse offspring obtained by natural pregnancy and IVF were fed a standard chow diet or a high-fat diet (HFD) from 4 weeks of age through 16 weeks of age. We assessed glucose and lipid metabolism, hepatic histopathology, and the gene and protein expression of key RAS components. In addition, the blocker losartan was used from 4 weeks of age through 16 weeks of age to investigate the regulatory mechanisms of abnormal local RAS on metabolic activity in the IVF offspring liver.ResultsThe growth trajectories of IVF offspring body and liver weights were different from those of naturally pregnant offspring. Impaired glucose tolerance (IGT) and insulin resistance (IR) occurred in IVF-conceived male offspring. After continuous HFD feeding, male offspring in the IVF group underwent earlier and more severe IR. Furthermore, there was a trend of lipid accumulation in the livers of chow-fed IVF offspring. Hepatic steatosis was also more serious in the IVF offspring after HFD treatment. Type 1 receptor (AT1R), which is the primary receptor mediating the action of angiotensin (Ang) II, has been confirmed to be upregulated in IVF offspring livers. Losartan reduced or even eliminated most of the significant differences between the IVF and NC groups after HFD consumption.ConclusionsThe upregulation of AT1R expression in the liver increased the activity of the local RAS, resulting in abnormal glucose and lipid metabolism and lipid accumulation in the liver, significantly increasing the risk of nonalcoholic fatty liver disease (NAFLD) in IVF offspring.

Exposure to PCB126 during the nursing period reversibly impacts early-life glucose tolerance.

Polychlorinated biphenyls (PCBs) are persistent environmental organic pollutants known to have detrimental health effects. Using a mouse model, we previously demonstrated that PCB126 exposure before and during pregnancy and throughout the perinatal period adversely affected offspring glucose tolerance and/or body composition profiles. The purpose of this study was to investigate the glucose tolerance and body composition of offspring born to dams exposed to PCB126 during the nursing period only. Female ICR mice were bred, and half of the dams were exposed to either vehicle (safflower oil) or 1 µmole PCB126 per kg of body weight via oral gavage on postnatal days (PND) 3, 10, and 17 (n = 9 per group). Offspring body weight, lean and fat mass, and glucose tolerance were recorded every three weeks. PCB126 treatment did not alter dam nor offspring body weight (p > 0.05). PCB126-exposed male and female offspring displayed normal body composition (p > 0.05) relative to vehicle-exposed offspring. However, both male and female offspring that were exposed to PCB126 during the nursing period had significantly impaired glucose tolerance at 3 and 9 weeks of age (p < 0.05). At 6 and 12 weeks of age, no impairments in glucose tolerance existed in offspring (p > 0.05). Our current study demonstrates that exposure to PCB126 through the mother's milk does not affect short- or long-term body composition but impairs glucose tolerance in the short-term.