Glucose Tolerance In Offspring Research Articles

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.

Intrauterine exposure of mice to arsenite induces abnormal and transgenerational glycometabolism

The adverse, transgenerational effects on health caused by environmental pollutants are receiving increasing attention. For humans and mice, inorganic arsenic (iAs), a widespread environmental contaminant, is associated with diabetic phenotypes. However, the transgenerational effects of arsenite-induced changes in glucose metabolism in mice have not been fully investigated. In the present study, F0 pregnant mice were exposed to arsenite via drinking water (0, 0.5, 5, or 50 ppm NaAsO2) from gestational day 0 (GD0) until parturition. We examined the effects of arsenite exposure on the metabolic phenotypes and the levels of proteins and genes related to glucose metabolism of dams and their offspring (F1∼F4). Arsenite exposure altered the glucose tolerance of offspring. Notably, glucose transporter-2 (GLUT2) and insulin receptor substrate-1 (IRS1), which are related to the maintenance of glucose homeostasis, were also changed. The homeostasis assessment-insulin resistance (HOMA-IR), an indicator of insulin resistance, was higher in the offspring from the F0 female mice exposed to arsenite. Furthermore, imprinted genes, insulin-like growth factor 2 (IGF2) and potassium voltage-gated channel subfamily Q member 1 (KCNQ1), related to glycometabolism across multiple generations, were lower in the offspring. In sum, arsenite exposure during pregnancy transgenerationally affects glucose metabolism, which is related to altered levels of IGF2 and KCNQ1.

Maternal hypothyroidism prolongs gestation period and impairs glucose tolerance in offspring of Wistar rats.

Pregnancy is a critical period keenly regulated by both maternal and foetal factors and a shift in these factors could result in severe complications manifesting in foetal and adult life. However, maternal hypothyroidism before and/or during pregnancy is a critical factor. This study investigated the effect of maternal hypothyroidism on glucose tolerance and thyroid function in male and female offspring. Fifteen adult female Wistar rats were divided intothree groups: Group 1 (sham-control), Group 2 (thyrodectomized) and Group 3 (thyroidectomised+L-thyroxine treated). Blood thyroxine (T4) level was measured on the day 10 after thyroidectomy in Groups 1 and 2, and day 35 inGroup 3. Males were introduced to the female rats after T4measurement. At PND-112, T4 levels of their offspring were measured. Oral Glucose Tolerance Test (OGTT) was measured in offspring at PND-133. Thyroxine reduced significantly in Group 2 and their offspring (male and female) compared to Group 3 while gestation period was prolonged significantly in Group 2 compared to Group 1. Hypothyroid male offspring showed depressed glucose tolerance, however, no effect was observed in female offspring. This study suggests that maternal hypothyroidism prolonged gestation period, induced foetal hypothyroidism in both genders and depressed glucose tolerance in male offspring.

Differential and Synergistic Effects of Low Birth Weight and Western Diet on Skeletal Muscle Vasculature, Mitochondrial Lipid Metabolism and Insulin Signaling in Male Guinea Pigs.

Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar “Western” diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose-tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male “lean” offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism, as reflected by increased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high-fat/high-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism, promoting mitochondrial overload.

GAD65 autoantibodies and glucose tolerance in offspring born to women with and without type 1 diabetes (The EPICOM study).

The aims of this study were to examine presence of GAD65 autoantibodies (GAD65aab) in offspring born to women with type 1 diabetes (T1D) and controls and if more were GAD65aab‐positive if diagnosed with diabetes or pre‐diabetes. This EPICOM study is a prospective follow‐up study focussing on pregnancies complicated by maternal T1D. The EPICOM study includes offspring (n = 278) born to mothers with pre‐gestational T1D between 1993 and 1999 and matched un‐exposed controls (n = 303). Age at the time of follow‐up was 16.7 years (13.0–20.4 years). GAD65aab was measured using the Glutamic Acid Decarboxylase Autoantibody RIA kit from RSR©. An Oral Glucose Tolerance Test (OGTT) was performed, and abnormal glucose tolerance was defined as having either diabetes, impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). GAD65aab could be measured in 561 participants. Of these, 17 (3%) were positive for GAD65aab (≥25 U/ml) with 11 (4%) offspring being born to women with T1D and 6 (2%) controls. The difference in GAD65aab status was not statistically significant (p = .2). One was diagnosed with GAD65aab‐negative diabetes during the study, 18 were diagnosed with IFG, and 44 with IGT. Overall, more were GAD65aab‐positive if diagnosed with abnormal glucose tolerance (p = .03). We found no association between GAD65aab status and HOMA‐IR, HOMA‐IS, birthweight, mode of delivery or maternal BMI prior to pregnancy. Our study found no overall difference in GAD65 status between offspring born to women with T1D and their matched controls. However, among the participants diagnosed with pre‐diabetes more were GAD65‐positive.

Effects of maternal controlled exercise on offspring adiposity and glucose tolerance.

While metabolic disorders such as obesity and diabetes are costly and deadly to the current population, they are also extremely detrimental to the next generation. Much of the current literature focuses on the negative impact of poor maternal choices on offspring disease, while there is little work examining maternal behaviors that may improve offspring health. Research has shown that voluntary maternal exercise in mouse models improves metabolic function in offspring. In this study, we hypothesized that controlled maternal exercise in a mouse model will effect positive change on offspring obesity and glucose homeostasis. Female mice were separated into three groups: home cage, sedentary, and exercise. The sedentary home cage group was not removed from the home cage, while the sedentary wheel group was removed from the cage and placed in an immobile wheel apparatus. The exercise group was removed from the home cage and run on the same wheel apparatus but with the motor activated at 5-10 m/min for 1 h/d prior to and during pregnancy. Offspring were subjected to oral glucose tolerance testing and body composition analysis. There was no significant difference in offspring glucose tolerance or body composition as a consequence of the maternal exercise intervention compared to the sedentary wheel group. There were no marked negative consequences of the maternal controlled exercise intervention. Further research should clarify the potential advantages of the controlled exercise model and improve experimental techniques to facilitate translation of this research to human applications.

Neonatal Milk Fat Globule Membrane Supplementation During Breastfeeding Ameliorates the Deleterious Effects of Maternal High-Fat Diet on Metabolism and Modulates Gut Microbiota in Adult Mice Offspring in a Sex-Specific Way.

Exposure to adverse events in early life increases the risk of chronic metabolic disease in adulthood. The objective of this study was to determine the significance of milk fat globule membrane (MFGM)-mediated alterations in the gut microbiome to the metabolic health of offspring in the long-term. Female C57BL/6 mice were fed either a high-fat diet (HFD) or a control diet for 3 weeks before pregnancy and throughout pregnancy and lactation. During lactation, pups from the HFD group were breast-fed with or without 1,000 mg/kg BW/day MFGM supplementation (HFD and HFD-MS group, respectively). After weaning, the offspring in each group were divided into male and female subgroups. The weaned mice were then shifted to a control diet for 8 weeks. At the eleventh week, stool samples were collected for 16S rRNA gene sequencing. Serum biochemical parameters were analyzed, and intraperitoneal glucose and insulin tolerance tests were performed. Neonatal supplementation with MFGM ameliorated metabolic disorder and improved glucose tolerance in offspring exposed to maternal HFD in a sex-specific manner. Furthermore, maternal HFD induced gut microbiota perturbation in offspring in adulthood. Neonatal MFGM supplementation significantly enriched g-Parabacteroides, g-Bifidobacterium, g-Faecalibaculum, and g-Lactobacillus in male offspring exposed to maternal HFD, while significantly enriched g-Parabacteroides and g-Alistipes in female offspring exposed to maternal HFD. These bacteria may be associated with the favorable changes in metabolism that occur in adulthood. Sex differences in the changes of metagenomic pathways related to oxidative phosphorylation, citrate cycle, electron transfer carries, and ubiquinone biosynthesis were also observed in the offspring. Maternal HFD has an adverse effect on the metabolism of offspring in later life. Neonatal MFGM supplementation could modulate the structure of gut microbiota communities and may have long-term protective effects on lipid and glucose metabolism, but these effects are sex dimorphic.

700-P: Mechanism for the Beneficial Effects of Maternal Exercise to Improve Offspring Metabolic Health

Poor maternal diet and obesity increase the risk of obesity and type 2 diabetes in offspring, fueling the worldwide epidemic of these diseases. Recent animal studies have shown that maternal exercise (MatEx) improves the metabolic phenotype of offspring in adulthood, including improved glucose tolerance and liver function. Here, we determined the molecular mechanisms responsible for these critical effects of MatEx. Female mice were fed a chow or high fat diet and housed in cages with (Trained) or without (Sedentary) running wheels for 2 wks prior to breeding and during gestation. Offspring were sedentary and chow-fed. MatEx improved glucose tolerance and liver function in adult offspring. Beginning at embryonic day 13.5, MatEx increased expression of TCA cycle and fatty acid oxidation genes in offspring liver, and increased DNA demethylation at promoters of these hepatic genes. Next, we identified a novel MatEx-induced AMPK/isocitrate dehydrogenase/αketoglutarate/Tet axis in offspring liver controlling DNA demethylation. Primary hepatoblasts treated with serum from trained dams, but not sedentary dams or trained non-pregnant females stimulated this pathway, suggesting the effects of MatEx on offspring stem from a placenta-derived serum factor(s). LC-MS/MS of serum and RNAseq of placenta from trained dams identified this factor as superoxide dismutase 3 (Sod3), and recombinant SOD3 treatment of hepatoblasts increased AMPK-Tet signaling and hepatic gene expression. The effects of MatEx to increase liver AMPK-Tet signal, alter liver DNA methylation and gene expression, and improve offspring glucose tolerance in vivo were ablated in placenta-specific Sod3 KO mice. Finally, SOD3 was increased in serum and placenta from highly physically active pregnant women. Sod3 is an exercise-induced, placenta-derived protein that improves glucose homeostasis via epigenetic changes in offspring liver, defining a novel paradigm for the beneficial effects of exercise on metabolic health. Disclosure J. Kusuyama: None. A.B. Wagner: None. R.H. Conlin: None. N.S. Makarewicz: None. M. Møller: None. E.M. Miele: None. R. Middelbeek: None. N. Jessen: None. P.G. Ovesen: None. M.F. Hirshman: Stock/Shareholder; Self; Abbott Laboratories, AbbVie Inc., Amgen, Colgate-Palmolive, Eli Lilly and Company, Medtronic. K.B. Adamo: None. E.N. Grayck: None. L.J. Goodyear: None. Funding National Institutes of Health (DK101043)

Role of metformin in epigenetic regulation of placental mitochondrial biogenesis in maternal diabetes

Adverse maternal environments, such as diabetes and obesity, impair placental mitochondrial function, which affects fetal development and offspring long-term health. The underlying mechanisms and effective interventions to abrogate such effect remain unclear. Our previous studies demonstrated impaired mitochondrial biogenesis in male human placenta of diabetic mothers. In the present studies, epigenetic marks possibly related to mitochondrial biogenesis in placentae of women with diabetes (n = 23) and controls (n = 23) were analyzed. Effects of metformin were examined in human placental explants from a subgroup of diabetic women and in a mouse model of maternal high fat diet feeding. We found that maternal diabetes was associated with epigenetic regulation of mitochondrial biogenesis in human placenta in a fetal sex-dependent manner, including decreased histone acetylation (H3K27 acetylation) and increased promoter methylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In male placenta, the levels of H3K27 acetylation and PGC-1α promoter methylation correlated significantly with the activity of AMP-activated protein kinase (AMPK). Metformin treatment on male diabetic placental explant activated AMPK and stimulated PGC-1α expression, concomitant with increased H3K27 acetylation and decreased PGC-1α promoter methylation. In vivo, we show that maternal metformin treatment along with maternal high fat diet significantly increased mouse placental abundance of PGC-1α expression and downstream mitochondrial transcription factor A (TFAM) and inhibited maternal high fat diet-impaired placental efficiency and glucose tolerance in offspring. Together, these findings suggest the capability of metformin to stimulate placental mitochondrial biogenesis and inhibit the aberrant epigenetic alterations occurring in maternal diabetes during pregnancy, conferring protective effects on offspring.

Maternal and paternal exercise regulate offspring metabolic health and beta cell phenotype

ObjectivePoor maternal and paternal environments increase the risk for obesity and diabetes in offspring, whereas maternal and paternal exercise in mice can improve offspring metabolic health. We determined the effects...

722-P: Maternal Exercise Improves Metabolic Health of Grand-Offspring

Maternal environments are critical factors in determining risk for obesity and diabetes in both first generation (F1) and second generation (F2) offspring. Maternal exercise in mice has been shown to improve metabolic health in F1, including prevention of the detrimental effects of maternal high-fat feeding on F1 offspring. Whether the beneficial effects of maternal exercise can be transmitted to the F2 generation (grand-offspring) is not known. To test this, C57BL/6 females were fed a chow or high fat diet (60% fat) and grouped by housing in cages with (Exercise Trained) or without (Sedentary) running wheels for 2 weeks before breeding (7.04±0.5 km/day) and during gestation (2.2±0.3 km/day). Females were bred with chow-fed, sedentary males. F1 offspring were sedentary and chow-fed. At 8 weeks of age, two male mice (F1) from each litter (selected based on average body weight of the litter), were bred with age-matched female mice from untreated parents. Thus, four groups of F2 offspring resulted based on grand-maternal treatment: sedentary and chow-fed; sedentary and high fat-fed; trained and chow-fed; trained and high fat-fed (n=5-10 litters/group). F2 offspring were sedentary and chow-fed post-weaning. Unexpectedly, there was no effect of grand-maternal high fat diet on F2 glucose tolerance at any age. There was also no effect of grand-maternal exercise on glucose tolerance in offspring at 16 or 24 weeks of age. However, grand-maternal exercise resulted in a tendency for improvement in glucose tolerance in 36-week-old offspring (P=0.07), and a significant improvement at 52 weeks (males: P=0.03; females: P=0.0001). Male and female body weights were not different among F2 groups. F2 offspring from exercise-trained grand-mothers had decreased % fat mass (males: P=0.04; females: P=0.05) and increased % lean mass in males (P=0.04), with a tendency to increase in females (P=0.06) at 52 weeks of age. In conclusion, grand-maternal exercise training has beneficial effects in the metabolic health of adult male and female F2 offspring. Disclosure A.B.A. Wagner: None. J. Kusuyama: None. P. Nigro: None. M.F. Hirshman: Stock/Shareholder; Self; Abbott Laboratories, AbbVie Inc., Amgen Inc., Colgate-Palmolive Company, Medtronic. L.J. Goodyear: None. Funding American Diabetes Association (1-17-PMF-009 to A.B.A.W.); National Institutes of Health (R01DK101043)

A Novel Micronutrient Supplement to Mitigate the Transgenerational Effects of Paternal Obesity on Body Composition of Male Offspring (P11-138-19)

ObjectivesEmerging evidence suggests that paternal obesity plays a significant role on offspring health. Our previous work in rodents showed that high fat diet (HFD) induced paternal obesity reduced offspring glucose tolerance. It has also been reported that paternal obesity can initiate metabolic disturbance in subsequent generations. Therefore, we designed a novel micronutrient supplement to ameliorate the transgenerational effects of paternal obesity. MethodsFounder (F0) male Sprague Dawley rats (3 weeks, 12 per group) were weaned on control (CD) or HFD or diets containing micronutrient supplement (CS; HS), after which they were mated with CD fed females at 19 weeks of age. Twelve F1 offspring from each litter across the four diet groups were weaned on day 21 onto CD, generating four F1 groups. After 14 weeks on CD, they were mated with CD fed females. Male F2 siblings were fed CD or HFD from day 21. After 6 weeks on diet, they underwent EchoMRI (See attached study design). ResultsHFD increased adiposity (CD: 12.3%, HFD: 18.6%) in F0 which was normalized by supplementation (HS: 11.7%). Though no paternal effect on adiposity was found in F1 males across the four groups, supplementing F0 had significant impact on F2 body composition (fat mass, fat and lean percentage) without influencing body weight and lean mass after 6 weeks on diet.In F2, post weaning HFD significantly increased fat mass in rats from CD and HFD fed founders (CH vs CC P = 0.0001; HH vs HC P = 0.009) but this effect was significantly reduced by F0 supplementation irrespective of F0 diets (CSH vs CH P = 0.017; and HSH vs HH P = 0.04) [3-way ANOVA][See attached table].Moreover, lean percentage was decreased by post weaning HFD in rats from both non-supplemented F0 diet groups but interestingly this effect was significantly reduced only in rats sired by supplemented CD fed F0 (CSH > CH; P = 0.04). ConclusionsSupplementing CD fed grandfathers ameliorated the deleterious effect of HFD, decreasing fat deposition and increasing lean percentage whereas supplementing HFD fed F0 reduced only fat deposition without affecting lean mass of male grand offspring. Therefore, our designed supplement could eventually reduce the transgenerational effect of paternal obesity. Funding SourcesSupported by Australian NHMRC grant to MJM and CAM; MMB is supported by Scientia PhD Scholarship, UNSW. Supporting Tables, Images and/or Graphs▪▪

Maternal Western-style diet affects offspring islet composition and function in a non-human primate model of maternal over-nutrition

ObjectiveIn humans, offspring of women who are overweight or obese are more likely to develop metabolic disease later in life. Studies in lower animal species reveal that a calorically-dense maternal diet is associated with alterations in islet cell mass and function. The long-term effects of maternal diet on the structure and function of offspring islets with characteristics similar to humans are unknown. We used a well-established non-human primate (NHP) model to determine the consequences of exposure to Western-Style Diet (WSD) in utero and during lactation on islet cell mass and function in the offspring. MethodsFemale Japanese Macaques (Macaca fuscata) were fed either control (CTR) or WSD before and throughout pregnancy and lactation. Offspring were weaned onto CTR or WSD to generate four different groups based on maternal/offspring diets: CTR/CTR, WSD/CTR, CTR/WSD, and WSD/WSD. Offspring were analyzed at three years of age. Pancreatic tissue sections were immunolabelled to measure α- and β-cell mass and proliferation as well as islet vascularization. Live islets were also isolated to test the effects of WSD-exposure on islet function ex vivo. Offspring glucose tolerance was correlated with various maternal characteristics. Resultsα-cell mass was reduced as a result of maternal WSD exposure. α-cell proliferation was reduced in response to offspring WSD. Islet vasculature did not differ among the diet groups. Islets from WSD/CTR offspring secreted a greater amount of insulin in response to glucose ex vivo. We also found that maternal glucose tolerance and parity correlated with offspring glucose tolerance. ConclusionsMaternal WSD exposure results in persistently decreased α-cell mass in the three-year old offspring. WSD/CTR islets secreted greater amounts of insulin ex vivo, suggesting that these islets are primed to hyper-secrete insulin under certain metabolic stressors. Although WSD did not induce overt impaired glucose tolerance in dams or offspring, offspring born to mothers with higher glucose excursions during a glucose tolerance test were more likely to also show higher glucose excursions.

Obesity and abnormal glucose tolerance in the offspring of mothers with diabetes.

Type 2 diabetes and obesity during childhood, puberty, and adulthood have become more common. This trend presents a global problem in terms of public health and health economics. Associations between intrauterine exposure to hyperglycemia, obesity, and abnormal glucose tolerance (AGT) in offspring have been reported in populations at high risk of diabetes such as Pima Indians, but these associations have not been established in other groups. In this review, we summarize the evidence on obesity and AGT in the offspring of mothers with diabetes. Although there are many reports indicating that the incidence of obesity or overweight is higher in the offspring of mothers with gestational diabetes, there is no consensus on whether maternal prepregnancy obesity has a larger impact than intrauterine exposure to hyperglycemia. While the risk of AGT or type 2 diabetes in the offspring of mothers with gestational diabetes is thought to increase after puberty, the incidence of AGT is elevated by the age of 7 years in the offspring of mothers with untreated gestational diabetes. Maternal gestational diabetes is a risk factor for AGT or type 2 diabetes independent of maternal prepregnancy BMI. When the offspring of women who had gestational diabetes and received therapeutic intervention in two randomized controlled studies were followed, the prevalence of obesity and impaired fasting glucose was lower in some 7-year-old girls, but the effect of maternal intervention was limited. The risk of obesity or overweight is higher in the offspring of mothers with type 1 diabetes, even after adjustment for maternal prepregnancy BMI. The risk of type 2 diabetes in such offspring is also higher. Although the offspring of mothers with type 2 diabetes are likely to be at high risk for type 2 diabetes, there are only limited reports supporting this hypothesis. Intrauterine exposure to hyperglycemia is associated with obesity and AGT among offspring. The present review suggests that these associations might depend on the type of maternal diabetes, that is, the timing and degree of exposure to hyperglycemia. There are only a small number of studies on the effect of therapeutic interventions for maternal diabetes on metabolism in the offspring.

Four weeks of exercise early in life reprograms adult skeletal muscle insulin resistance caused by a paternal high-fat diet.

A paternal high-fat diet/obesity before mating can negatively influence the metabolism of offspring. Exercise only early in life has a remarkable effect with respect to reprogramming adult rat offspring exposed to detrimental insults before conception. Exercise only early in life normalized adult whole body and muscle insulin resistance as a result of having a high-fat fed/obese father. Unlike the effects on the muscle, early exercise did not normalize the reduced adult pancreatic beta cell mass as a result of having a high-fat fed/obese father. Early-life exercise training may be able to reprogram an individual whose father was obese, inducing long-lasting beneficial effects on health. A paternal high-fat diet (HFD) impairs female rat offspring glucose tolerance, pancreatic morphology and insulin secretion. We examined whether only 4weeks of exercise early in life could reprogram these negative effects. Male Sprague-Dawley rats consumed a HFD for 10weeks before mating with chow-fed dams. Female offspring remained sedentary or performed moderate intensity treadmill exercise (5daysweek-1 , 60minday-1 , 20mmin-1 ) from 5 to 9weeks of age. Paternal HFD impaired (P< 0.05) adult offspring whole body insulin sensitivity (i.p. insulin sensitivity test), as well as skeletal muscle ex vivo insulin sensitivity and TBC1D4 phosphorylation. It also lowered β-cell mass and reduced in vivo insulin secretion in response to an i.p. glucose tolerance test. Early-life exercise in offspring reprogrammed the negative effects of a paternal HFD on whole body insulin sensitivity, skeletal muscle ex vivo insulin-stimulated glucose uptake and TBC1D4 phosphorylation and also increased glucose transporter 4 protein. However, early exercise did not normalize the reduced pancreatic β-cell mass or insulin secretion. In conclusion, only 4weeks of exercise early in life in female rat offspring reprograms reductions in insulin sensitivity in adulthood caused by a paternal HFD without affecting pancreatic β-cell mass or insulin secretion.

Maternal and Paternal Exercise Regulates Offspring Metabolic Health and Beta-Cell Phenotype

Maternal and paternal environment are critical factors in determining risk for obesity and diabetes in offspring. Maternal exercise in mice can prevent the detrimental effects of maternal high-fat feeding on offspring metabolic health, whereas the effects of paternal exercise on offspring are less clear. Little is also known about the effects of maternal or paternal exercise on offspring beta cells, a major factor in glucose homeostasis. We determined the effects of maternal, paternal and maternal+paternal exercise on offspring glucose tolerance and beta cell morphology. Male sires were housed ± running wheels for 3 weeks before breeding (4.4±0.8 km/day) and dams were housed ± running wheels for 2 weeks before breeding (8.4±0.5 km/day) and during gestation (4.7±0.5 km/day). All male and female breeders were fed a high-fat diet. Four groups of male offspring were studied: both parents sedentary (Sed); maternal exercise only (Mat Ex); paternal exercise only (Pat Ex); maternal+paternal exercise (Mat+Pat Ex) (n=5-8 litters/group). Offspring were sedentary and separate cohorts were studied at weaning, 52, and 80 weeks. Post-weaning, offspring were fed a chow diet. There was no effect of parental exercise on offspring glucose tolerance at weaning. At 52 weeks, offspring of exercised parents had ∼25% lower fasting blood glucose concentrations vs. Sed (all p&amp;lt;0.01), and glucose tolerance was improved in Mat Ex (33%), Pat Ex (35%), and Mat+Pat Ex (50%) vs. Sed (p&amp;lt;0.001). Mat Ex, Pat Ex and Mat+Pat Ex had decreased beta cell size (40%) and mass (40%), whereas islet size and density were only decreased in offspring from Mat+Pat Ex parents (28% and 40%, respectively). Older offspring (80 weeks) from all three parental exercise treatments displayed improved glucose tolerance (p&amp;lt;0.05). Maternal and paternal exercise in high-fat fed parents has profound positive effects on offspring glucose tolerance during adulthood and older age that may be linked to adaptations in the endocrine pancreas. Disclosure J. Zheng: None. A.B.A. Wagner: None. N.B. Prince: None. K. So: None. J. Mul: None. E. Dirice: None. M.F. Hirshman: None. K.I. Stanford: None. R. Kulkarni: None. L.J. Goodyear: None.

Paternal Bisphenol A Exposure Alters Offspring Glucose Tolerance in a Time, Dose, and Sex-Specific Manner

As it is becoming increasingly accepted that maternal exposure to the ubiquitous environmental pollutant bisphenol A (BPA) predisposes offspring to metabolic impairments, paternal contribution in this context remains unresolved. To investigate a relationship between paternal BPA exposure and offspring obesity and glucose tolerance, a mouse model was developed using dietary BPA exposure at doses comparable to human exposure levels (7% Corn Oil diet (Control), 10 μg/mg/day (Lower BPA), and 10 mg/kg/day (Upper BPA)). Two exposure windows were investigated: 1) direct exposure of male mice beginning at sexual maturation (5 weeks of age) and continuing for 12 weeks prior to mating, and 2) in utero exposure, in which dams were exposed beginning 2 weeks prior to mating and ending at weaning. F1 males were sired to unexposed females. At 16 weeks of age, offspring from both exposure windows underwent body composition analysis via NMR or DEXA scan as well as glucose tolerance testing. Paternal BPA exposure during adulthood did not affect body weight, adiposity or glucose tolerance in offspring. In utero-exposed sires produced offspring that also had no changes in body weight or adiposity. However, female offspring from the Lower BPA dose were glucose intolerant. Females with glucose intolerance were selected for islet perifusion, and interestingly, those females from Lower BPA dose exhibited enhanced glucose-stimulated insulin secretion compared to controls indicating insulin resistance. These data demonstrate that while paternal BPA exposure after sexual maturity may be metabolically innocuous, paternal BPA exposure during gestation and lactation precipitates sex-specific impairments in glucose tolerance. Further studies are required to describe precisely the glucose homeostatic impairment and elucidate epigenetic changes in sperm associated with phenotypic transmission. Disclosure C.S. Rashid: None. A. Bansal: None. R.A. Simmons: None.

Association of serum ferritin with insulin resistance in offsprings of type 2 diabetics

ContextType 2 diabetes is prevalent worldwide, and insulin resistance (IR) is considered the main player in its pathogenesis. Previous studies suggested a link between iron and IR.AimThe aim was to study serum ferritin level in nondiabetic offsprings, with and without impaired glucose tolerance, of diabetic patients and its relation to IR.Settings and design This is a cross-sectional case–control study carried out in the Internal Medicine Department, Zagazig University Hospitals.Patients and methodsA total of 25 completely healthy individuals as a control group and 50 offsprings of patients with type 2 diabetes as a case group were included in the study. The case group was further divided into normal and impaired glucose tolerant offspring subgroups after glucose tolerance test. All of them underwent thorough clinical examination; routine laboratory investigation including complete blood count, liver and kidney function tests, fasting and postprandial blood glucose, serum ferritin, and fasting insulin by enzyme-linked immunosorbent assay; calculation of BMI; and homeostasis model assessment-estimated insulin resistance (HOMA-IR). Statistical package for the social sciences for windows (version 16) was used for statistical analysis.ResultsSignificant increase in mean±SD of serum ferritin, fasting insulin, HOMA-IR, and fasting and postprandial blood glucose levels in impaired glucose tolerant offspring subgroup was observed as compared with both control group and normal glucose tolerant offspring subgroup. Significant positive correlation was found between serum ferritin versus each of BMI, fasting insulin, fasting, postprandial blood glucose, and HOMA-IR in impaired glucose tolerant offspring subgroup.ConclusionElevated serum ferritin levels in nondiabetic offsprings with impaired glucose tolerance may play a role in the pathogenesis of IR state, which may progress to type 2 diabetes.

Antenatal antipsychotic exposure induces multigenerational and gender-specific programming of adiposity and glucose tolerance in adult mouse offspring

Second-generation antipsychotics (SGAs) are well known for their metabolic side effects in humans, including obesity and diabetes. These compounds are maintained during pregnancy to prevent the relapse of psychoses, but they readily diffuse across the placenta to the fetus, as documented with the widely-prescribed drug olanzapine (OLZ). However, observational studies have provided conflicting results on the potential impact of SGAs on fetal growth and body weight, and their effects on metabolic regulation in the offspring. For this reason, our study has tested whether antenatal exposure of CD1 mice to OLZ influenced metabolic outcomes in the offspring of the first (F1) and second (F2) generations. In F1 mice, OLZ antenatal treatment caused a decrease in neonatal body weight in both genders, an effect that persisted throughout life only in male animals. Interestingly, F1 female mice also displayed altered glucose homoeostasis. F2 mice, generated by mating normal males with F1 female mice exposed to OLZ during antenatal life, exhibited higher neonatal body weights which persisted only in F2 female animals. This was associated with expansion of fat mass and a concordant pattern of adipose tissue gene expression. Moreover, male and female F2 mice were glucose-intolerant. Thus, our study has demonstrated that antenatal OLZ exposure induces multigenerational and gender-specific programming of glucose tolerance in the offspring mice as adults, and points to the need for careful monitoring of children exposed to SGAs during pregnancy.

Maternal Macronutrient Consumption and the Developmental Origins of Metabolic Disease in the Offspring.

Recent research aimed at understanding the rise in obesity and cardiometabolic disease in children suggests that suboptimal maternal nutrition conditions organ systems and physiological responses in the offspring contributing to disease development. Understanding the mechanisms by which the macronutrient composition of the maternal diet during pregnancy or lactation affects health outcomes in the offspring may lead to new maternal nutrition recommendations, disease prevention strategies and therapies that reduce the increasing incidence of cardiometabolic disease in children. Recent mechanistic animal model research has identified how excess fats and sugars in the maternal diet alter offspring glucose tolerance, insulin signaling and metabolism. Maternal nutrition appears to influence epigenetic alterations in the offspring and the programming of gene expression in key metabolic pathways. This review is focused on experimental studies in animal models that have investigated mechanisms of how maternal consumption of macronutrients affects cardiometabolic disease development in the offspring. Future research using “-omic” technologies is essential to elucidate the mechanisms of how altered maternal macronutrient consumption influences the development of disease in the offspring.