Offspring Insulin Research Articles

1754-P: Prebiotic Early Intervention Improves Blood Glucose in Pup Mice

Maternal high fat (HF) during pregnancy is known to have numerous adverse effects on offspring, including increased adiposity and impaired glucose tolerance later in life. The aim of this study was to determine if prebiotic early intervention could mitigate some of the negative effects of maternal HF. C57BL mice were fed a HF diet, normal diet or a HF diet with prebiotic supplementation during pregnancy and lactation. At 3 weeks of age, glucose tolerance were measured in the offspring. And offspring livers were obtained. Hepatic DNA methylation and gene expression was assayed. Maternal HF diet led offspring glucose intolerance and insulin resistance. Prebiotic early intervention moderated glucose metabolism and insulin resistance in male pup mice. Maternal HF diet reduced phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alph (Pik3c2a), phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (Pik3c2b), and phosphoinositide-3-kinase regulatory subunit 2 (Pik3r2) gene expression in male pup mice (P<0.01). Prebiotic early intervention increased these gene expression in pup livers (P<0.01). Moreover, maternal HF diet led these three gene hypermethylated (P<0.01). These three genes were hypomethylated in prebiotic early intervention group (P<0.01). Prebiotic early intervention improved glucose intolerance by changing DNA methylation and gene expression of Pi3k in mice exposed to a maternal HF diet. Disclosure Q. Zhang: None. X. Xiao: None. M. Li: None. Funding National Natural Science Foundation of China (81870545, 81870579); Beijing Natural Science Foundation (7202163, 7172169)

No Association Between Maternal Dietary Protein Intake and Offspring Insulin Sensitivity Measures in the First Two Years of Life

Abstract Objectives Findings of an association between maternal dietary protein intake (1.1–1.7 g·kg−1·day−1) close to requirements for pregnant women throughout gestation (1.22–1.52 g·kg−1·day−1) and offspring insulin sensitivity are mixed, perhaps as a result of the small spread in protein intake and the large gap between measurements (∼9–40 years). Therefore, our objective was to evaluate the association between a wider spread of dietary protein intake during pregnancy and measurements of insulin sensitivity in the offspring in early life. Methods Healthy women (n = 182, mean ± SD; BMI: 26.2 ± 4.2 kg/m2) were recruited early in pregnancy (<10 weeks). Dietary protein intake was assessed using a 3-day food record in early (∼10 weeks, EP) and late (∼30 weeks, LP) pregnancy. Offspring blood was sampled at 12 and 24 months, and the updated homeostatic model assessment of insulin resistance (HOMA2-IR) was computed using fasting glucose and insulin. Body composition was measured using nuclear magnetic resonance. Two linear models were fitted to the data to estimate: 1) the unadjusted relationship of maternal protein intake to offspring HOMA2-IR and 2) the relationship of maternal protein intake to offspring HOMA2-IR adjusted for maternal plant protein intake and BMI, and offspring sex and body fat percentage. Values are mean ± SD. Results Habitual protein intake (average of early and late pregnancy measurements range: 0.5–1.9 g·kg−1·day−1) decreased throughout pregnancy (EP: 1.09 ± 0.36; vs. LP: 0.97 ± 0.28 g·kg−1·day−1, P = 0.0003). Offspring HOMA2-IR did not change from 12 (0.8 ± 0.8) to 24 (0.8 ± 0.9) months. Simple regression analysis: EP dietary protein intake did not associate with HOMA2-IR at 12 (β = 0.153, P = 0.429) and 24 (β = −0.349, P = 0.098) months. Similarly, LP dietary protein intake did not associate with offspring HOMA2-IR at 12 (β = 0.023, P = 0.916) and 24 (β = −0.442, P = 0.085) months. Results remained unchanged after multiple regression analyses were conducted. Conclusions Maternal dietary protein intake (amount or type) during pregnancy is not associated with indirect measurements of insulin sensitivity in offspring during the first two years of life. Funding Sources United States Department of Agriculture Agricultural Research Service Project 6026-51,000-012-06S, and NIH/NIDDK R01 DK107516.

Dietary Protein Intake during Pregnancy Is Not Associated with Offspring Insulin Sensitivity during the First Two Years of Life

Literature describing a relationship between dietary protein intake during pregnancy and offspring insulin resistance are equivocal perhaps because of the lapse between maternal and offspring measurements (~9–40 years). Thus, we evaluated protein intake in healthy women [n = 182, mean ± SD; body mass index (BMI): 26.2 ± 4.2 kg/m2] in early pregnancy (8.4 ± 1.6 weeks, EP), late pregnancy (30.1 ± 0.4 weeks, LP), and averaged throughout pregnancy, and determined the relationship between protein intake and offspring homeostatic model assessment of insulin resistance (HOMA2-IR) at 12 (12mo) and 24 (24mo) months. EP protein (g·kg−1·day−1) did not associate with HOMA2-IR at 12mo (β = 0.153, p = 0.429) or 24mo (β = −0.349, p = 0.098). LP protein did not associate with HOMA2-IR at 12mo (β = 0.023, p = 0.916) or 24mo (β = −0.442, p = 0.085). Finally, average protein did not associate with HOMA2-IR at 12mo (β = 0.711, p = 0.05) or 24mo (β = −0.445, p = 0.294). Results remained unchanged after adjusting for plant protein intake quartiles during pregnancy, maternal BMI, and offspring sex and body fat percentage. Additionally, these relationships did not change after quartile analysis of average protein intake, even after considering offspring fasting time and HOMA2-IR outliers, and maternal under-reporters of energy intake. Protein intake during pregnancy is not associated with indirect measurements of insulin sensitivity in offspring during the first two years of life.

Supplementation of polar lipids-enriched milk fat globule membrane in high-fat diet-fed rats during pregnancy and lactation promotes brown/beige adipocyte development and prevents obesity in male offspring.

Promoting brown adipose tissue (BAT) function or browning of white adipose tissue (WAT) provides a defense against obesity. The aim of the study was to investigate whether maternal polar lipids-enriched milk fat globule membrane (MFGM-PL) supplementation to high-fat diet (HFD) rats during pregnancy and lactation could promote brown/beige adipogenesis and protect against HFD-induced adiposity in offspring. Female SD rats were fed a HFD for 8weeks to induce obesity and, then, fed a HFD during pregnancy and lactation with or without MFGM-PL. Male offspring were weaned at postnatal Day 21 and then fed a HFD for 9weeks. MFGM-PL treatment to HFD dams decreased the body weight gain and WAT mass as well as lowered the serum levels of insulin and triglycerides in male offspring at weaning. MFGM-PL+HFD offspring showed promoted thermogenic function in BAT and inguinal WAT through the upregulation of UCP1 and other thermogenic genes. In adulthood, maternal MFGM-PL supplementation reduced adiposity and increased oxygen consumption, respiratory exchange ratio, and heat production in male offspring. The enhancement of energy expenditure was correlated with elevated BAT activity and inguinal WAT thermogenic program. In conclusion, maternal MFGM-PL treatment activated thermogenesis in offspring, which exerted long-term beneficial effects against HFD-induced obesity in later life.

Gestational Exposure to Bisphenol A and Bisphenol S Leads to Fetal Skeletal Muscle Hypertrophy Independent of Sex.

Gestational exposure to bisphenol A (BPA) can lead to offspring insulin resistance. However, despite the role that the skeletal muscle plays in glucose homeostasis, it remains unknown whether gestational exposure to BPA, or its analog bisphenol S (BPS), impairs skeletal muscle development. We hypothesized that gestational exposure to BPA or BPS will impair fetal muscle development and lead to muscle-specific insulin resistance. To test this, pregnant sheep (n = 7-8/group) were exposed to BPA or BPS from gestational day (GD) 30 to 100. At GD120, fetal skeletal muscle was harvested to evaluate fiber size, fiber type, and gene and protein expression related to myogenesis, fiber size, fiber type, and inflammation. Fetal primary myoblasts were isolated to evaluate proliferation and differentiation. In fetal skeletal muscle, myofibers were larger in BPA and BPS groups in both females and males. BPA females had higher MYH1 (reflective of type-IIX fast glycolytic fibers), whereas BPS females had higher MYH2 and MYH7, and higher myogenic regulatory factors (Myf5, MyoG, MyoD, and MRF4) mRNA expression. No differences were observed in males. Myoblast proliferation was not altered in gestationally BPA- or BPS-exposed myoblasts, but upon differentiation, area and diameter of myotubes were larger independent of sex. Females had larger myofibers and myotubes than males in all treatment groups. In conclusion, gestational exposure to BPA or BPS does not result in insulin resistance in fetal myoblasts but leads to fetal fiber hypertrophy in skeletal muscle independent of sex and alters fiber type distribution in a sex-specific manner.

1395-P: Maternal Exercise during Pregnancy Affects Offspring Adiposity through One Carbon Metabolism Cycle

Maternal obesity during pregnancy can adversely affect adult offspring adiposity and insulin resistance. The goal of this study was to determine if maternal exercise mitigates the adverse effects of maternal obesity on offspring health. Female (C57BL/6NJ) mice were fed from weaning a control diet (10%kcal fat; MC n=18) or western diet (45% kcal fat; MW n=15) to induce excess adiposity. After 13 weeks, the mice were bred and maintained on the diets, with (E) and without (S) access to a running wheel (exercise), throughout pregnancy and lactation. Offspring were weaned onto the control diet and fed for 13 weeks; male offspring were studied. Offspring from MWE dams had greater (p<0.05) retroperitoneal and mesenteric adipose tissue than offspring from MWS dams. This was not observed in offspring from dams fed the control diet. Offspring from exercised dams had lower glucose-stimulated insulin secretion compared to those from sedentary dams, independent of maternal diet. No differences in glucose and insulin tolerance were observed. One carbon metabolism is required for several physiological processes including DNA synthesis, amino and lipid metabolism, and the generation of methyl groups. Disturbances in one carbon metabolism occur in obesity. We hypothesized that maternal exercise mitigates the adverse effects of maternal obesity on offspring adiposity through changes in one carbon metabolism. MCE offspring had lower serum total homocysteine (6.3μmol/L) compared to MCS offspring (9.4μmol/L). This was not observed in the offspring from western diet-fed dams. Offspring from western diet-fed dams had higher hepatic methylenetetrahydrofolate reductase (Mthfr) mRNA expression compared to offspring from control diet-fed dams. Offspring from dams that exercised also had higher hepatic Mthfr mRNA; the highest expression was observed in MWE offspring. The findings from this study suggest that one carbon metabolism may play a role in developmental programing of offspring adiposity. Disclosure N. Boonpattrawong: None. A. Mehran: None. I. Laher: None. A.M. Devlin: None. Funding Canadian Institutes of Health Research

The Association of Maternal Protein Intake during Pregnancy in Humans with Maternal and Offspring Insulin Sensitivity Measures

ABSTRACTThe purpose of this review is to critically evaluate the studies assessing the relations between protein intake during human pregnancy and insulin sensitivity measures in the mother and offspring, and to get a better understanding of the knowledge gaps that still exist. Overall, there is insufficient evidence to conclude about implications of higher amounts of protein intake during pregnancy on maternal or offspring insulin sensitivity. However, studies show a relation between protein quality and insulin sensitivity, such that animal protein may be associated with negative outcomes and plant protein may be associated with positive insulin sensitivity outcomes. There is an urgent need for standardized studies using comparable terminology to evaluate any potential relations between insulin sensitivity in mothers and offspring and truly low and high maternal protein intake while maintaining eucaloric balance to better inform about optimal protein dosage and quality during this period.

SAT-157 A Calcium-deficient Diet In Dams During Gestation Increases Insulin Resistance In Male Offspring

Backgrounds: Maternal malnutrition and the resulting low birth weight predispose offspring to various diseases, including adult-onset insulin resistance syndrome. Several lines of evidence demonstrate that calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome and obesity, suggesting that hypocalcemia is a risk factor for developing these conditions. We previously reported that maternal Ca deficiency during pregnancy can affect regulation of non-imprinted genes by altering epigenetic regulation of gene expression, thereby inducing different metabolic phenotypes. On the other hand, osteocalcin (OC), a bone formation biomarker, acts directly on β-cells to increase their mass and proliferation and, therefore, increases insulin secretion. Aims: We studied whether alterations in insulin resistance and secretion were induced in offspring by feeding dams a Ca-deficient diet during pregnancy and lactation, and to explore the association between bone and glucose metabolism. Methods: Female Wistar rats consumed either a Ca-deficient (0.008% Ca) or control (0.90% Ca) diet ad libitum from 3 weeks preconception to 21 days postparturition. Pups were allowed to nurse their original mothers until weaning. The offspring were fed a control diet beginning at weaning (day 21) and were killed on day 180 ± 10. Serum carboxylated OC (Gla-OC) and undercarboxylated OC (Glu-OC), insulin and adipokines in offspring were measured using enzyme-linked immunosorbent assay kits. Ionized calcium (iCa) and magnesium (iMg) were measured by ion-selective electrodes. Results: In males, mean levels of insulin, glucose, and Homeostasis Model Assessment of Insulin Resistance were higher in the Ca-deficient group than in the control group. Mean adiponectin levels and iMg in Ca-deficient male offspring were higher than those in control male offspring. The serum ionized Ca/Mg ratio in Ca-deficient male offspring was lower than that in control male offspring. In addition, iCa was inversely associated with serum Glu-OC and adiponectin in males. In females, mean levels of Glu-OC and Gla-OC in the Ca-deficient group were higher than in the control group, whereas no significant difference was observed in these measures between the two groups in male offspring. In all offspring, serum leptin levels were correlated with iMg (p=0.0039, R=0.436) and serum insulin levels (p<0.0001, R=0.62), and inversely correlated with iCa (p=0.0025, R=-0.454). Conclusion: Maternal Ca restriction during pregnancy alters postnatal growth and insulin resistance in a sex- and window of exposure-specific manner. Increased Glu-OC may mitigate insulin resistance in female Ca-deficient offspring. The present study provided further support for the hypothesis that early postnatal lactation plays a sexually divergent role in programming the phenotype later in life.

OR31-4 Neonatal Vitamin D Deficiency and Insulin Resistance

Background: Vitamin D deficiency is prevalent in pregnant women and their offspring. Maternal vitamin D deficiency is associated with insulin resistance in children and can induce a proinflammatory macrophage phenotype [1, 2]. Purpose: We hypothesized that maternal vitamin D deficiency induces immune cell reprogramming that promotes adipose insulin resistance in the offspring and is detectable in the newborn period. Methods: We enrolled 32 normal pregnant women prior to delivery of AGA, term infants. Cord blood was obtained and used to determine vitamin D [25(OH)D] levels and qPCR of microRNA levels. Cord blood monocytes were co-cultured with 3T3L1 adipocytes for insulin-stimulated 2-deoxyglucose uptake studies, and the monocyte media and co-cultured adipocytes were analyzed for microRNA expression. 3T3L1 adipocytes were transfected with miR106b mimic and antagonist to confirm the effect of the 2-deoxyglucose results. Results: 83% of the newborn’s venous cord blood showed vitamin D deficiency with 25(OH)D <20 ng/mL (n=24, total n=29). Adipocytes co-cultured with cord blood monocytes showed an inverse correlation between insulin stimulated 2-deoxyglucose uptake and cord blood 25(OH)D levels (n=29, Spearman r=0.43, p=0.02). Adipocytes exposed to monocytes or to monocyte media elevated miR106b by 7 to 12-fold (n=8, p<0.01). Interestingly, cord blood plasma miR106b levels were found to inversely correlate with 25(OH)D levels (n=27, Spearman r=-0.41, p<0.04). Transfection of adipocytes with miR106b mimic reduced the 2-deoxyglucose uptake after insulin stimulation, whereas transfection with anti-miR-106b increased 2-deoxyglucose uptake after insulin stimulation, suggesting that monocyte secretion of miR106b induced adipose insulin resistance (n=8, p<0.05). Conclusions: This study provides evidence of a novel intercellular miRNA communication mechanism enabling monocytes programmed in utero by vitamin D deficiency to induce adipose insulin resistance. Identification of circulating miR106b as a mechanism of insulin resistance in offspring born with vitamin D deficiency is a potential advance toward precision medicine as it allows for optimal targeting of those at risk for diabetes later in life within a heterogeneous population. These findings serve as background for interventional studies evaluating the effect of maternal vitamin D supplementation on offspring insulin resistance later in life.

A Calcium-Deficient Diet in Dams during Gestation Increases Insulin Resistance in Male Offspring.

Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Osteocalcin (OC), a bone formation biomarker, acts directly on β-cells and increases insulin secretion. We determined the effects of Ca deficiency during pregnancy and/or lactation on insulin resistance in offspring. Female Wistar rats consumed either a Ca-deficient or control diet ad libitum from three weeks preconception to 21 days postparturition. Pups were allowed to nurse their original mothers until weaning. The offspring were fed a control diet beginning at weaning and were killed on day 180. Serum carboxylated OC (Gla-OC) and undercarboxylated OC (Glu-OC), insulin and adipokines in offspring were measured. In males, mean levels of insulin, glucose, and HOMA-IR were higher in the Ca-deficient group than in the control group. In addition, ionized Ca (iCa) was inversely associated with serum Glu-OC and adiponectin in males. In females, mean levels of Glu-OC and Gla-OC in the Ca-deficient group were higher than in the control group. In all offspring, serum leptin levels were correlated with serum insulin levels, and inversely correlated with iCa. In conclusion, maternal Ca restriction during pregnancy and/or lactation influences postnatal offspring Ca metabolism and insulin resistance in a sex-specific manner.

Lactational Programming of Offspring Glucose Homeostasis and Body Composition by Early Postnatal Metformin Exposure

Background: The early postnatal period is a critical window for programming of long-term metabolic health. Our previous studies have shown that gestational metformin exposure increases pancreatic beta-cell fraction at birth and improves glucose homeostasis in adulthood. Hypothesis: We hypothesized that metformin administration to dams during the critical window of lactation would alter neonatal nutrient exposure and the acquisition of the gut microbiome from the mother leading to a permanent change in offspring metabolic tissues. Methods: We used C57BL/6J mice for the developmental programming studies in this experiment. Metformin was delivered in drinking water to dams from postnatal day 1 (P1) and continued through the lactation period to P21 (Met PN group). Offspring were examined during lactation and as adults. Dams were examined during lactation and upon weaning. Gut microbe composition was determined by 16s sequencing in dams and offspring. Results: Dams on metformin showed improved glucose tolerance at weaning. Met PN pups had lower body weights that began during the first 3 weeks of life and persisted to 6 months. On intraperitoneal glucose tolerance testing male but not female offspring had improved glucose responses at 2 months and increased glucose stimulated insulin secretion. Met PN offspring had a lower body fat percentage at necropsy. Stool microbiome studies showed that Met PN pups had an altered intestinal colonization that persisted into adulthood with an increase in the bacteroidetes:firmicutes ratio at the time the lower weight trajectory was established. A lower bacteroidetes:firmicutes ratio has been associated with obesity. Conclusions: These findings suggest that limited early postnatal exposure to a dam on metformin results in long-term programming of offspring weight, insulin secretion and intestinal microbiome. Disclosure B. Gregg: None.

Paternal high-fat diet enhances offspring whole-body insulin sensitivity and skeletal muscle insulin signaling early in life.

Evidence suggests that paternal diet can predispose offspring to metabolic dysfunction. Despite this knowledge, little is known regarding the effects of paternal high‐fat feeding on offspring insulin sensitivity. The purpose of this study was to investigate for the first time the effects of paternal high‐fat feeding on whole‐body and skeletal muscle insulin action in young and adult offspring. At 4 weeks of age, founder C57BL6/N males (F0) were fed a high‐fat diet or control diet for 12 weeks and then bred with females on a control diet. Offspring (F1) were euthanized at 6 weeks, 6 months, or 12 months and insulin‐stimulated insulin signaling was measured ex vivo in isolated soleus muscle. At 6 weeks of age, paternal high fat offspring (HFO) had enhanced whole‐body insulin sensitivity (35%, P < 0.05), as well as, increased insulin‐stimulated skeletal muscle phosphorylation of Akt threonine 308 (70%, P < 0.05) and AS160 threonine 642 (80%, P < 0.05) compared to paternal control fed offspring (CFO), despite both offspring groups consuming standard chow. At 6 months of age, HFO had increased percent body fat compared to CFO (74%, P < 0.005) and whole‐body and skeletal muscle insulin signaling normalized to CFO. Body fat was inversely related with insulin signaling in HFO, but not CFO. These findings suggest that paternal high‐fat feeding contributes to enhanced whole‐body and skeletal muscle insulin sensitivity in HFO early in life; however, these benefits are lost by early adulthood, potentially due to premature increases in body fat.

A maternal high-fat, high-sucrose diet alters insulin sensitivity and expression of insulin signalling and lipid metabolism genes and proteins in male rat offspring: effect of folic acid supplementation.

A maternal high-fat, high-sucrose (HFS) diet alters offspring glucose and lipid homoeostasis through unknown mechanisms and may be modulated by folic acid. We investigated the effect of a maternal HFS diet on glucose homoeostasis, expression of genes and proteins associated with insulin signalling and lipid metabolism and the effect of prenatal folic acid supplementation (HFS/F) in male rat offspring. Pregnant Sprague-Dawley rats were randomly fed control (CON), HFS or HFS/F diets. Offspring were weaned on CON; at postnatal day 70, fasting plasma insulin and glucose and liver and skeletal muscle gene and protein expression were measured. Treatment effects were assessed by one-way ANOVA. Maternal HFS diet induced higher fasting glucose in offspring v. HFS/F (P=0·027) and down-regulation (P<0·05) of genes coding for v-Akt murine thymoma viral oncogene homolog 2, resistin and v-Raf-1 murine leukaemia viral oncogene homolog 1 (Raf1) in offspring skeletal muscle and acetyl-CoA carboxylase (Acaca), fatty acid synthase and phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit β in offspring liver. Skeletal muscle neuropeptide Y and hepatic Kruppel-like factor 10 were up-regulated in HFS v. CON offspring (P<0·05). Compared with CON, Acaca and Raf1 protein expression levels were significantly lower in HFS offspring. Maternal HFS induced higher homoeostasis model of assessment index of insulin resistance v. CON (P=0·030) and HFS/F was associated with higher insulin (P=0·016) and lower glucose (P=0·025). Maternal HFS diet alters offspring insulin sensitivity and de novo hepatic lipogenesis via altered gene and protein expression, which appears to be potentiated by folate supplementation.

Regulation of malonyl-CoA-acyl carrier protein transacylase network in umbilical cord blood affected by intrauterine hyperglycemia.

BackgroundGestational diabetes mellitus (GDM) has been shown to be associated with high risk of diabetes in offspring. However, the mechanisms involved in the insulin resistance in offspring are still unclear. Mitochondrial dysfunction is related with insulin resistance. In mitochondria, malonyl-CoA-acyl carrier protein transacylase (MCAT) is the key enzyme of mitochondrial fatty acid synthesis and is estimated to contribute to insulin resistance. In this study, we aimed to examine the role of MCAT and its network in the umbilical cord blood in GDM-induced offspring insulin resistance.MethodsWe isolated lymphocytes from umbilical cord vein blood in 6 GDM patients and 6 controls and examined the differences of RNA by RNA sequencing. qRT-PCR and western blot were used to measure mRNA and protein changes. Bisulfite genomic sequencing PCR was applied to detect DNA methylation.ResultsWe found more than 400 genes were differentially regulated in the lymphocytes of umbilical cord blood from GDM patients and these genes were mainly enriched in immune system and endocrine system, which relate to mitochondrial dysfunction and insulin resistance. MCAT closely related with PTPN1 (Protein Tyrosine Phosphatase, Non-Receptor Type1) and STAT5A (Signal Transducer And Activator of Transcription 5A), which were all increased in umbilical cord blood from GDM patients. Increase in MCAT may be due to decreased MCAT DNA methylation.ConclusionMCAT and its network with PTPN1, STAT5A are regulated in umbilical cord blood affected by maternal intrauterine hyperglycemia.

EP17.08: The association between maternal vitamin B12 insufficiency and obesity: a systematic review

The rising rates of obesity in pregnancy together with the paradox of nutritional deficiencies in these women have important implications for maternal and fetal well being. Specifically, the micronutrients B12 and folate are required to support the increased demands of the fetus in pregnancy. Deficiencies in these micronutrients can lead to increased maternal adiposity, maternal and offspring insulin resistance and adverse lipid profile in neonates. This review aims to assess existing evidence linking maternal vitamin B12 deficiency with obesity. Inclusion criteria was body mass index (BMI) greater than or equal to 30 kg/m2, non diabetic, pregnant population. The outcome was vitamin B12 level measured at any gestational age. We considered observational studies, randomised control trials and case control studies. We searched Medline, Embase, CINAHL and The Cochrane Library database. Two reviewers independently extracted data from relevant studies. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement. Of 366 articles identified, seven met inclusion criteria. Most studies were observational, with one case control study. There was consistent evidence linking maternal obesity with low vitamin B12 levels (defined as <150 pmol/L). Most studies adjusted for potential confounders, such as maternal demographics, lifestyle factors, pregnancy related factors and hemodilution. BMI remained a significant negative predictor of low vitamin B12. In the case control study, third trimester vitamin B12 insufficiency was associated with a 2.4 times increased odds of first trimester obesity. As the prevalence of maternal obesity is rapidly increasing, the implications of low vitamin B12 on maternal and fetal health need to be considered. Further longitudinal cohort studies are needed to understand the mechanisms between vitamin B12 and obesity, to identify any possible causal relationship and therefore potentially offer simple interventions to improve maternal and offspring health.

Fetal overnutrition and offspring insulin resistance and β-cell function: the Exploring Perinatal Outcomes among Children (EPOCH) study.

To examine the associations of intrauterine exposure to maternal diabetes and obesity with offspring insulin resistance, β-cell function and oral disposition index in a longitudinal observational study of ethnically diverse offspring. A total of 445 offspring who were exposed (n=81) or not exposed (n=364) to maternal diabetes in utero completed two fasting blood measurements at mean (sd) ages of 10.5 (1.5) and 16.5 (1.2) years, respectively, and an oral glucose tolerance test at the second visit. We used linear mixed models and general linear univariate models to evaluate the associations of maternal diabetes and pre-pregnancy BMI with offspring outcomes. Maternal diabetes in utero predicted increased insulin resistance [18% higher updated homeostatic model assessment of insulin resistance (HOMA2-IR), P=0.01; 19% lower Matsuda index, P=0.01 and 9% greater updated homeostatic model assessment of β-cell function (HOMA2-β), P=0.04]. Each 5-kg/m2 increase in pre-pregnancy BMI predicted increased insulin resistance (11% greater HOMA2-IR, P<0.001; 10% lower Matsuda index, P<0.001; 6% greater HOMA2-β, P<0.001). Similar results were obtained in a combined model with both exposures. After adjustment for offspring BMI, only maternal diabetes was associated with higher HOMA2-IR (β=1.12, P=0.03) and lower Matsuda index (β=0.83, P=0.01). Neither exposure was associated with early insulin response or oral disposition index. Intrauterine exposure to diabetes or obesity is associated with greater offspring insulin resistance than non-exposure, supporting the hypothesis that fetal overnutrition results in metabolic abnormalities during childhood and adolescence.

A post-weaning obesogenic diet exacerbates the detrimental effects of maternal obesity on offspring insulin signaling in adipose tissue

Previous studies have shown that maternal diet-induced obesity leads to increased risk of type 2 diabetes in offspring. The current study investigated if weaning onto an obesogenic diet exaggerated the detrimental effects of maternal diet-induced obesity in adipose tissue. Maternal obesity and offspring obesity led to reduced expression of key insulin signalling proteins, including insulin receptor substrate-1 (IRS-1). The effects of maternal obesity and offspring obesity were, generally, independent and additive. Irs1 mRNA levels were similar between all four groups of offspring, suggesting that in both cases post-transcriptional regulation was involved. Maternal diet-induced obesity increased miR-126 expression however levels of this miR were not influenced by a post-weaning obesogenic diet. In contrast, a post-weaning obesogenic diet was associated with increased levels of suppressor of cytokine signaling-1, implicating increased degradation of IRS-1 as an underlying mechanism. Our results suggest that whilst programmed reductions in IRS-1 are associated with increased levels of miR-126 and consequently reduced translation of Irs1 mRNA, the effects of a post-weaning obesogenic diet on IRS-1 are mediated by miR-126 independent mechanisms, including increased IRS-1 protein degradation. These divergent mechanisms explain why the combination of maternal obesity and offspring obesity leads to the most pronounced effects on offspring metabolism.

Exercise rescues obese mothers\u2019 insulin sensitivity, placental hypoxia and male offspring insulin sensitivity

The prevalence of obesity during pregnancy continues to increase at alarming rates. This is concerning as in addition to immediate impacts on maternal wellbeing, obesity during pregnancy has detrimental effects on the long-term health of the offspring through non-genetic mechanisms. A major knowledge gap limiting our capacity to develop intervention strategies is the lack of understanding of the factors in the obese mother that mediate these epigenetic effects on the offspring. We used a mouse model of maternal-diet induced obesity to define predictive correlations between maternal factors and offspring insulin resistance. Maternal hyperinsulinemia (independent of maternal body weight and composition) strongly associated with offspring insulin resistance. To test causality, we implemented an exercise intervention that improved maternal insulin sensitivity without changing maternal body weight or composition. This maternal intervention prevented excess placental lipid deposition and hypoxia (independent of sex) and insulin resistance in male offspring. We conclude that hyperinsulinemia is a key programming factor and therefore an important interventional target during obese pregnancy, and propose moderate exercise as a promising strategy to improve metabolic outcome in both the obese mother and her offspring.

Maternal age at childbirth is associated with offspring insulin sensitivity: a cross-sectional study in adult male siblings.

Maternal age at childbirth is increasing worldwide, but studies investigating the consequences of this trend on offspring metabolic health are scarce. We investigated the associations of maternal age at childbirth with metabolic outcomes in adult male siblings. We used data from 586 men aged 25-45 participating in a cross-sectional, population-based sibling-pair study, including maternal age at childbirth and offspring birthweight, adult weight, height, dual-energy X-ray absorptiometry (DXA)-derived body composition, blood pressure, and total cholesterol, glucose and insulin levels from fasting serum samples. Insulin sensitivity was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). Maternal age at childbirth was 27·1 ± 4·7 years and was inversely associated with glucose levels (β = -0·10, P = 0·022) and HOMA-IR (β = -0·06, P = 0·065) in age- and body composition-adjusted analyses. Moreover, sons of younger (aged <25 and 25-29) and older (aged ≥35) mothers had higher HOMA-IR values than sons of mothers aged 30-34 (1·39, 1·35 and 1·42 vs 1·19, P = 0·028). Additional adjustment for birthweight did not substantially alter these results. Maternal age was inversely associated with cholesterol levels in unadjusted (β = -0·09, P = 0·032), but not in age- and body composition-adjusted analyses. No associations of maternal age were observed with blood pressure, leptin, or adiponectin levels or with any of the body composition measurements. Increasing maternal age at childbirth is associated with lower fasting glucose levels and higher insulin sensitivity in adult male offspring. However, this association might not hold true in offspring of women aged ≥35 years at childbirth.

Maternal Hyperleptinemia Improves Offspring Insulin Sensitivity in Mice.

Maternal obesity and gestational diabetes are prevalent worldwide. Offspring of mothers with these conditions weigh more and are predisposed to metabolic syndrome. A hallmark of both conditions is maternal hyperleptinemia, but the role of elevated leptin levels during pregnancy on developmental programming is largely unknown. We previously found that offspring of hyperleptinemic mothers weighed less and had increased activity. The goal of this study was to determine whether maternal leptin affects offspring insulin sensitivity by investigating offspring glucose metabolism and lipid accumulation. Offspring from two maternal hyperleptinemic models were compared. The first model of hyperleptinemia is the Lepr(db/+) mouse, which has a mutation in one copy of the gene that encodes the leptin receptor, resulting in a truncated long form of the receptor, and hyperleptinemia. Wild-type females served as the control for the Lepr(db/+) females. For the second hyperleptinemic model, wild-type females were implanted with miniosmotic pumps, which released leptin (350 ng/h) or saline (as the control) just prior to mating and throughout gestation. In the offspring of these dams, we measured glucose tolerance; serum leptin, insulin, and triglyceride levels; liver triglycerides; pancreatic α- and β-cell numbers; body composition; incidence of nonalcoholic fatty liver disease; and the expression of key metabolic genes in the liver and adipose tissue. We found that the offspring of hyperleptinemic dams exhibited improved glucose tolerance, reduced insulin and leptin concentrations, reduced liver triglycerides, and a lower incidence of nonalcoholic fatty liver disease. Overall, maternal hyperleptinemia was beneficial for offspring glucose and lipid metabolism.