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

ABSTRACT: AIMS:To examine the associations of intrauterine exposure to maternal diabetes and obesity with offspring insulin resistance, ?-cell function and oral disposition index in a longitudinal observational study of ethnically diverse offspring. METHODS: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. RESULTS: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 ?-cell function (HOMA2-?), 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-?, 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 (?=1.12, P=0.03) and lower Matsuda index (?=0.83, P=0.01). Neither exposure was associated with early insulin response or oral disposition index. CONCLUSIONS: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.

SUBMITTER: Sauder KA

PROVIDER: S-EPMC5603388 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Sauder K A KA Hockett C W CW Ringham B M BM Glueck D H DH Dabelea D D

Diabetic medicine : a journal of the British Diabetic Association 20170721 10

<h4>Aims</h4>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.<h4>Methods</h4>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 tolera ...[more]

PMID: 28636758

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Project description:Maternal obesity can program metabolic syndrome in offspring but the mechanisms are not well characterized. Moreover, the consequences of maternal overnutrition in the absence of frank obesity remain poorly understood. This study aimed to determine the effects of maternal consumption of a high fat-sucrose diet on the skeletal muscle metabolic and transcriptional profiles of adult offspring. Female Sprague Dawley rats were fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. Although maternal weights were not different between groups at conception or weaning, HFD dams were ~22% heavier than chow fed dams from mid-pregnancy until 4 days post-partum. Adult male offspring of HFD dams were not heavier than controls but demonstrated features of insulin resistance including elevated plasma insulin concentration (+40%, P<0.05). Next Generation mRNA Sequencing was used to identify differentially expressed genes in the soleus muscle of offspring, and Gene Set Enrichment Analysis (GSEA) to detect coordinated changes that are characteristic of a biological function. GSEA identified 15 pathways enriched for up-regulated genes, including cytokine signaling (P<0.005), starch and sucrose metabolism (P<0.017), and inflammatory response (P<0.024). A further 8 pathways were significantly enriched for down-regulated genes including oxidative phosphorylation (P<0.004) and electron transport (P<0.022). Western blots confirmed a ~60% reduction in the phosphorylation of the insulin signaling protein Akt (P<0.05) and ~70% reduction in mitochondrial complexes II (P<0.05) and V expression (P<0.05). On a normal diet, offspring of HFD dams developed an insulin resistant phenotype, with transcriptional evidence of muscle cytokine activation, inflammation and mitochondrial dysfunction. These data indicate that maternal overnutrition, even in the absence of pre-pregnancy obesity can promote metabolic dysregulation and predispose offspring to type 2 diabetes. Messenger RNA profile of skeletal muscle of male offspring from female Sprague Dawley rats fed either a diet rich in saturated fat and sucrose (HFD, 23.5% fat, 20% sucrose wt/wt) or a standard chow diet (NFD, 7% fat, 10% sucrose w/w) for the 3 weeks prior to mating and throughout pregnancy and lactation. There were 5 HFD samples compared to 6 NFD control samples.

Project description:BackgroundThe developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis.Methods and findingsWe explored this hypothesis by comparing the associations of maternal and paternal pre-pregnancy body mass index (BMI) with offspring dual energy X-ray absorptiometry (DXA)-determined fat mass measured at 9 to 11 y (4,091 parent-offspring trios) and by using maternal FTO genotype, controlling for offspring FTO genotype, as an instrument for maternal adiposity. Both maternal and paternal BMI were positively associated with offspring fat mass, but the maternal association effect size was larger than that in the paternal association in all models: mean difference in offspring sex- and age-standardised fat mass z-score per 1 standard deviation BMI 0.24 (95% confidence interval [CI]: 0.22 to 0.26) for maternal BMI versus 0.13 (95% CI: 0.11, 0.15) for paternal BMI; p-value for difference in effect < 0.001. The stronger maternal association was robust to sensitivity analyses assuming levels of non-paternity up to 20%. When maternal FTO, controlling for offspring FTO, was used as an instrument for the effect of maternal adiposity, the mean difference in offspring fat mass z-score per 1 standard deviation maternal BMI was -0.08 (95% CI: -0.56 to 0.41), with no strong statistical evidence that this differed from the observational ordinary least squares analyses (p = 0.17).ConclusionsNeither our parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9-11 y. Developmental overnutrition related to greater maternal BMI is unlikely to have driven the recent obesity epidemic.

Dataset Information

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

Publications

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

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