Offspring Of Diabetic Pregnancy Research Articles

Diabetic pregnancy as a novel risk factor for cardiac dysfunction in the offspring\u2014the heart as a target for fetal programming in rats

Aims/hypothesisThe impact of diabetic pregnancy has been investigated extensively regarding offspring metabolism; however, little is known about the influence on the heart. We aimed to characterise the effects of a diabetic pregnancy on male adult offspring cardiac health after feeding a high-fat diet in an established transgenic rat model.MethodsWe applied our rat model for maternal type 2 diabetes characterised by maternal insulin resistance with hyperglycaemia and hyperinsulinaemia. Diabetes was induced preconceptionally via doxycycline-induced knock down of the insulin receptor in transgenic rats. Male wild-type offspring of diabetic and normoglycaemic pregnancies were raised by foster mothers, followed up into adulthood and subgroups were challenged by a high-fat diet. Cardiac phenotype was assessed by innovative speckle tracking echocardiography, circulating factors, immunohistochemistry and gene expression in the heart.ResultsWhen feeding normal chow, we did not observe differences in cardiac function, gene expression and plasma brain natriuretic peptide between adult diabetic or normoglycaemic offspring. Interestingly, when being fed a high-fat diet, adult offspring of diabetic pregnancy demonstrated decreased global longitudinal (−14.82 ± 0.59 vs −16.60 ± 0.48%) and circumferential strain (−23.40 ± 0.57 vs −26.74 ± 0.34%), increased relative wall thickness (0.53 ± 0.06 vs 0.37 ± 0.02), altered cardiac gene expression, enlarged cardiomyocytes (106.60 ± 4.14 vs 87.94 ± 1.67 μm), an accumulation of immune cells in the heart (10.27 ± 0.30 vs 6.48 ± 0.48 per fov) and higher plasma brain natriuretic peptide levels (0.50 ± 0.12 vs 0.12 ± 0.03 ng/ml) compared with normoglycaemic offspring on a high-fat diet. Blood pressure, urinary albumin, blood glucose and body weight were unaltered between groups on a high-fat diet.Conclusions/interpretationDiabetic pregnancy in rats induces cardiac dysfunction, left ventricular hypertrophy and altered proinflammatory status in adult offspring only after a high-fat diet. A diabetic pregnancy itself was not sufficient to impair myocardial function and gene expression in male offspring later in life. This suggests that a postnatal high-fat diet is important for the development of cardiac dysfunction in rat offspring after diabetic pregnancy. Our data provide evidence that a diabetic pregnancy is a novel cardiac risk factor that becomes relevant when other challenges, such as a high-fat diet, are present.Graphical abstract

High glucose alters the DNA methylation pattern of neurodevelopment associated genes in human neural progenitor cells in vitro

Maternal diabetes alters the global epigenetic mechanisms and expression of genes involved in neural tube development in mouse embryos. Since DNA methylation is a critical epigenetic mechanism that regulates gene functions, gene-specific DNA methylation alterations were estimated in human neural progenitor cells (hNPCs) exposed to high glucose (HG) in the present study. The DNA methylation pattern of genes involved in several signalling pathways including axon guidance (SLIT1-ROBO2 pathway), and Hippo pathway (YAP and TAZ) was altered in hNPCs exposed to HG. The expression levels of SLIT1-ROBO2 pathways genes (including its effectors, SRGAP1 and CDC42) which mediates diverse cellular processes such as proliferation, neurogenesis and axon guidance, and Hippo pathway genes (YAP and TAZ) which regulates proliferation, stemness, differentiation and organ size were downregulated in hNPCs exposed to HG. A recent report suggests a possible cross-talk between SLIT1-ROBO2 and TAZ via CDC42, a mediator of actin dynamics. Consistent with this, SLIT1 knockdown downregulated the expression of its effectors and TAZ in hNPCs, suggesting that HG perturbs the cross-talk between SLIT1-ROBO2 and TAZ in hNPCs. Overall, this study demonstrates that HG epigenetically alters the SLIT1-ROBO2 and Hippo signalling pathways in hNPCs, forming the basis for neurodevelopmental disorders in offspring of diabetic pregnancy.

Abstract P151: Cardiac Outcome in Offspring of Diabetic Pregnancy

Introduction: Obesity and associated pathologies like insulin resistance and diabetes reach epidemic proportions worldwide. Parental diabetes has been acknowledged as a risk factor for cardiovascular disease in offspring. Objective: We investigated the influence of a diabetic pregnancy on the heart in offspring using a transgenic rat model of diabetes. Methods: We elicited pre-gestational hyperglycemia and hyperinsulinemia in transgenic Tet29 rats by application of doxycycline, which induces a knock down of the insulin receptor via RNA interference. Wild-type Sprague-Dawley (SD) rats served as controls receiving doxycycline as well. Heart analysis was performed in fetuses and adult groups at the age of 8 months challenged by a high fat diet lasting over 12 weeks. Cardiac function was evaluated by speckle tracking echocardiography and gene expression levels were measured by qRT-PCR. Results: Tet29 mothers had higher blood glucose levels throughout and at the end of pregnancy (blood glucose 153.9±22.2 vs. 93.3±4.2 mg/dl). The quantity of pups was unaffected. Fetuses from diabetic mothers were growth restricted (brain-liver-ratio 0.554±0.011 vs. 0.515±0.009) and they had lower blood glucose levels at birth (63.3±3.0 vs. 91.2±3.2 mg/dl). Fetal heart-body-ratio remained unchanged. After 8 months of normal chow, no difference in cardiac performance was detectable. However, after feeding a high fat diet, the male offspring of diabetic mothers showed a reduced cardiac function revealed by echocardiography (ejection fraction 50.4±2.7 vs. 57.0±1.9 %, global longitudinal strain -16.2±0.5 vs. -18.0±0.5 %, left ventricular mass 1242.3±32.9 vs. 989.4±65.1 mg) and gene expression analysis (Myh-6/Myh-7 1.1±0.1 vs. 1.7±0.2). Discussion: We hypothesize that a diabetic pregnancy per se, has no acute effect on cardiovascular health in offspring in our model. However, challenges like a high fat diet, may unravel an increased susceptibility of these rats.

Regulation and Role of Human Resistin in Diabetes during Pregnancy

Diabetes during pregnancy affects placental function, which impacts fetal development and the long-term health of offspring. Resistin is a peptide hormone originally discovered in mice as an adipocyte-derived factor that induced insulin resistance. Unlike rodent, human resistin is primarily secreted by monocytes or macrophages. Resistin may act differently in humans, which remains unclear. The present study examined the effects of maternal diabetes on fetal resistin levels and the actions of human resistin in placenta mitochondrial biogenesis pathway. Concentrations of human resistin in cord sera were higher in diabetic pregnancies (67 ng/ml, n=42) compared to healthy controls (50 ng/ml, n=81, P< 0.05), and correlated (r=0.4, P=0.002) with a measure of maternal glycemia (glucose concentration 2 h post challenge). Resistin mRNA was abundant in cord blood mononuclear cells (CBMCs). Secretion of resistin from cultured CBMCs was increased in response to high glucose (25 mM) treatment. Exposing placental trophoblastic cells (BeWo cells) or human placental explant to resistin decreased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as the abundance of mitochondria transcription factor A (TFAM). In human term placentae, the levels of PGC-1α promotor methylation were positively correlated with cord blood resistin concentrations (r= 0.45, p=0.04, n=16). In summary, we have shown that resistin is increased in the fetal circulation during diabetic pregnancy and that this potentially reflects the response of monocytes/macrophages to hyperglycemia and metabolic stresses associated with diabetic pregnancy. In addition, human resistin has the capacity to decrease mitochondrial biogenesis by affecting the epigenetic regulation of PGC-1α expression. Thus, increased exposure to resistin may contribute to mitochondrial dysfunction and long-term aberrant energy metabolism characteristic of the offspring of diabetic pregnancies. Disclosure S. Jiang: None. A.M. Teague: None. J.B. Tryggestad: None. T. Lyons: None. S. Chernausek: Advisory Panel; Self; Novo Nordisk Inc..

The Cross-Link between Adipokines, Insulin Resistance and Obesity in Offspring of Diabetic Pregnancies

Background/Aims: Intrauterine exposure to hyperglycemia might impact the risk for future metabolic deteriorations. The aim was to characterize the association between different adipokines and neuropeptides and insulin resistance and BMI-SDS in children affected by diabetes during pregnancy. Methods: 76 children (mean age: 6 years, male:female = 36:40) born to mothers with gestational or pregestational diabetes and nondiabetic women were consecutively included for clinical assessments comprising anthropometrics and metabolic characterization [2-hour glucose tolerance test, leptin, peptide YY (PYY), neuropeptide Y (NPY), ghrelin, growth differentiation factor 15 (GDF-15), and adiponectin]. Results: The level of insulin resistance was associated with BMI-SDS (p < 0.001), leptin (p < 0.001), ghrelin (p = 0.002), age (p < 0.002) and negatively with GDF-15 (p = 0.005). BMI-SDS, leptin and GDF-15 were shown to have independent effects on insulin resistance by using a multiple regression model (additionally including age, and maternal diabetes status), whereas ghrelin lost significance (p = 0.345). No differences were present in adipokines and insulin resistance when children were evaluated by maternal glucometabolic status. However, we observed more strengthened associations between insulin resistance and covariates BMI-SDS and leptin in offspring of diabetic pregnancies. Conclusions: Young children with elevated BMI or leptin are affected by higher indices of insulin resistance, particularly those who were born to mothers with diabetes during pregnancy. The impact of this special risk constellation should be considered in future studies.

Maternal Hyperleptinemia Is Associated with Male Offspring’s Altered Vascular Function and Structure in Mice

Children of mothers with gestational diabetes have greater risk of developing hypertension but little is known about the mechanisms by which this occurs. The objective of this study was to test the hypothesis that high maternal concentrations of leptin during pregnancy, which are present in mothers with gestational diabetes and/or obesity, alter blood pressure, vascular structure and vascular function in offspring. Wildtype (WT) offspring of hyperleptinemic, normoglycemic, Leprdb/+ dams were compared to genotype matched offspring of WT-control dams. Vascular function was assessed in male offspring at 6, and at 31 weeks of age after half the offspring had been fed a high fat, high sucrose diet (HFD) for 6 weeks. Blood pressure was increased by HFD but not affected by maternal hyperleptinemia. On a standard diet, offspring of hyperleptinemic dams had outwardly remodeled mesenteric arteries and an enhanced vasodilatory response to insulin. In offspring of WT but not Leprdb/+ dams, HFD induced vessel hypertrophy and enhanced vasodilatory responses to acetylcholine, while HFD reduced insulin responsiveness in offspring of hyperleptinemic dams. Offspring of hyperleptinemic dams had stiffer arteries regardless of diet. Therefore, while maternal hyperleptinemia was largely beneficial to offspring vascular health under a standard diet, it had detrimental effects in offspring fed HFD. These results suggest that circulating maternal leptin concentrations may interact with other factors in the pre- and post -natal environments to contribute to altered vascular function in offspring of diabetic pregnancies.

Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction.

Offspring of diabetic pregnancies are at risk of cardiovascular disease at birth and throughout life, purportedly through fuel-mediated influences on the developing heart. Preventative measures focus on glycemic control, but the contribution of additional offenders, including lipids, is not understood. Cellular bioenergetics can be influenced by both diabetes and hyperlipidemia and play a pivotal role in the pathophysiology of adult cardiovascular disease. This study investigated whether a maternal high-fat diet, independently or additively with diabetes, could impair fuel metabolism, mitochondrial function, and cardiac physiology in the developing offspring's heart. Sprague-Dawley rats fed a control or high-fat diet were administered placebo or streptozotocin to induce diabetes during pregnancy and then delivered offspring from four groups: control, diabetes exposed, diet exposed, and combination exposed. Cardiac function, cellular bioenergetics (mitochondrial stress test, glycolytic stress test, and palmitate oxidation assay), lipid peroxidation, mitochondrial histology, and copy number were determined. Diabetes-exposed offspring had impaired glycolytic and respiratory capacity and a reduced proton leak. High-fat diet-exposed offspring had increased mitochondrial copy number, increased lipid peroxidation, and evidence of mitochondrial dysfunction. Combination-exposed pups were most severely affected and demonstrated cardiac lipid droplet accumulation and diastolic/systolic cardiac dysfunction that mimics that of adult diabetic cardiomyopathy. This study is the first to demonstrate that a maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancies through metabolic stress and serves as a critical step in understanding the role of cellular bioenergetics in developmentally programmed cardiac disease.

Melatonin prevents neural tube defects in the offspring of diabetic pregnancy.

Melatonin, an endogenous neurohormone secreted by the pineal gland, has a variety of physiological functions and neuroprotective effects. However, its protective role on the neural tube defects (NTDs) was not very clear. The aim of this study was to investigate the effects of melatonin on the incidence of NTDs (including anencephaly, encephalocele, and spina bifida) of offspring from diabetic pregnant mice as well as its underlying mechanisms. Pregnant mice were given 10 mg/kg melatonin by daily i.p. injection from embryonic day (E) 0.5 until being killed on E11.5. Here, we showed that melatonin decreased the NTDs (especially exencephaly) rate of embryos exposed to maternal diabetes. Melatonin stimulated proliferation of neural stem cells (NSCs) under hyperglycemic condition through the extracellular regulated protein kinases (ERK) pathway. Furthermore, as a direct free radical scavenger, melatonin decreased apoptosis of NSCs exposed to hyperglycemia. In the light of these findings, it suggests that melatonin supplementation may play an important role in the prevention of neural malformations in diabetic pregnancy.

TGFβ and Wnt in cardiac outflow tract defects in offspring of diabetic pregnancies.

Diabetes mellitus in pregnancy causes defects in infant heart, including the outflow tracts (OFTs). Development of the aorta and pulmonary artery, which are derived from the common OFT in the embryo, is regulated by the transforming growth factor β (TGFβ) and Wnt families, and can be perturbed by hyperglycemia-generated intracellular stress conditions. However, the underlying cellular and molecular mechanisms remain to be delineated. Female mice were induced diabetic with streptozotocin. Embryonic and fetal OFTs were examined morphologically and histologically. Cell proliferation was assessed using 5'-bromo-2'-deoxyuridine incorporation assay. Oxidative and endoplasmic reticulum (ER) stress markers and TGFβ factors were detected using immunohistochemistry. The expression of genes in the Wnt-signaling system was assessed using real-time reverse transcription polymerase chain reaction array. The role of activin-A in cell proliferation was addressed by treating embryos cultured in high glucose with activin-A. Maternal diabetes caused complex abnormalities in the OFTs, including aortic and pulmonary stenosis and persistent truncus arteriosus. The development of the endocardial cushions was suppressed, manifested with insufficient cellularization of the tissues. Cell proliferation was significantly decreased under oxidative and ER stress conditions. The expression of genes in the Wnt signaling was significantly altered. Activin-A and Smad3 were found to be expressed in the OFT. Treatment with activin-A rescued cell proliferation in the endocardial cushions. Maternal diabetes generates oxidative and ER stress conditions, suppresses TGFβ and Wnt signaling, inhibits cell proliferation and cellularization of the endocardial cushions, leading to OFT septal defects. Activin-A plays a role in hyperglycemia-suppressed proliferation of the endocardial cells.

The impact of neonatal breast-feeding on growth trajectories of youth exposed and unexposed to diabetes in utero: the EPOCH Study

ObjectiveTo evaluate the influence of breastfeeding on the body mass index (BMI) growth trajectory from birth through 13 years of age among offspring of diabetic pregnancies (ODP) and offspring of non-diabetic pregnancies (ONDP) participating in the EPOCH study.SubjectsThere were 94 ODP and 399 ONDP who had multiple BMI measures obtained from birth throughout childhood. A measure of breast milk-months was derived from maternal self-report to categorize breastfeeding status as adequate (≥6 breast milk-months) or low (<6 breast milk-months). Mixed linear effects models were constructed to assess the impact of breastfeeding on the BMI growth curves during infancy (birth to 27 months) and childhood (27 months to 13 years).ResultsODP who were adequately breastfed had a slower BMI growth trajectory during childhood (p=0.047) and slower period-specific growth velocity with significant differences between 4 to 6 years of age (p=0.03) and 6 to 9 years of age (p=0.01) compared to ODP with low breastfeeding. A similar pattern was seen in the ONDP, with adequate breastfeeding associated with lower average BMI in infancy (p=0.03) and childhood (p=0.0002) and a slower growth trajectory in childhood (p=0.0002). Slower period-specific growth velocity was seen among the ONDP associated with adequate breastfeeding with significant differences between 12–26 months (p=0.02), 4–6 years (p=0.03), 6–9 years (p=0.0001) and 9–13 years of age (p<.0001).ConclusionOur study provides novel evidence that breastfeeding is associated with long-term effects on childhood BMI growth that extend beyond infancy into early and late childhood. Importantly, these effects are also present in the high-risk offspring, exposed to overnutrition during pregnancy. Breastfeeding in the early postnatal period may represent a critical opportunity to reduce the risk of childhood obesity.

Cardiovascular risk factors in children exposed to maternal diabetes in utero.

Recent studies have provided evidence that intrauterine exposure to maternal diabetes has lifelong effects on adult offspring, including increased risks of obesity, type 2 diabetes and cardiovascular disease. The aim of this study was to assess the relationship between exposure to maternal diabetes in utero and cardiovascular risk factors in healthy children and to investigate whether these associations are independent of maternal prepregnancy BMI and offspring attained BMI. Data were from a retrospective cohort of children aged 6-13years born during 1994-2002. Multiple linear regression was used to examine the associations between exposure and cardiovascular risk factors with adjustment for demographic factors and pubertal stage and additionally for maternal prepregnancy BMI and offspring attained BMI. Ninety-nine offspring of diabetic pregnancies had significantly increased E-selectin, vascular adhesion molecule 1 (VCAM1), leptin, waist circumference, BMI and systolic blood pressure and decreased adiponectin levels compared with 422 offspring of non-diabetic pregnancies after adjustment for age, sex and race/ethnicity (p < 0.05 for each risk factor). Additional adjustment for maternal prepregnancy BMI substantially attenuated group differences in the risk factors except for E-selectin, VCAM1 and waist circumference, which remained significantly higher in exposed children. Compared with unexposed children, healthy offspring exposed to maternal diabetes in utero have a worse cardiovascular risk profile. In particular, offspring have substantially increased levels of circulating cellular adhesion molecules, which are biomarkers of adverse endothelium perturbation and may be related to the earliest preclinical stages of atherosclerosis and diabetes.

Retinal Thickness in the Offspring of Diabetic Pregnancies

To compare macular and peripapillary retinal nerve fiber layer (RNFL) thickness in children from diabetic compared with nondiabetic pregnancy. Cross-sectional study. As part of the Sydney Myopia Study, 2367 children from grade 7 (age range 11.1 to 14.4 years) completed detailed ocular examinations during 2004-2005. Examination included determination of best-corrected visual acuity (logarithm of minimal angle of resolution) and autorefraction after cycloplegia. Axial length was measured using noncontact interferometry. Optical coherence tomography (OCT) was performed using Stratus OCT through dilated pupils. Participants and parents completed comprehensive questionnaires including questions on birth parameters and medical history. There were 1741 and 1687 children with adequate-quality RNFL and macular scans respectively, who had complete examination and questionnaire data. There were 57 children from diabetic pregnancies who had both RNFL and macular scans. Children from diabetic pregnancies had significantly thinner inner (264.9 μm vs 270.2 μm, P = .007) and outer (231.9 μm vs 238.6 μm, P = .0001) macular thickness and macular volume (6.75 mm(3) vs 6.92 mm(3), P = .0003) compared with children from nondiabetic pregnancies. However, central macular thickness, foveal minimum thickness, and RNFL parameters were not significantly different between the 2 groups. Diabetes during pregnancy is associated with changes in retinal morphology in the offspring. Thinning of the pericentral macular parameters was evident in Stratus OCT scans of children from diabetic pregnancies. These findings suggest the possibility that maternal diabetes impacts on the development of the retina.

Offspring of diabetic pregnancy: Short-term outcomes

In spite of clinicians apparently appreciating the risks of maternal diabetes to the baby, babies of mothers with diabetes are still at increased risk compared to those of non-diabetic women. The rate of prematurity in infants of diabetic mothers is five times that of the general population. Women with pre-gestational diabetes give birth to larger babies. In a recent study, half were above the 90th centile for weight. The postnatal management of these babies continues to give cause for concern. In a recent UK study, over half of all infants of diabetic mothers were admitted to a neonatal unit. One-third of these were at term. This admission rate is three times the UK average and examination of cases showed that two-thirds of admissions were unnecessary. It is likely that a high maternal blood glucose concentration is the most important factor causing this increased risk. Babies of women with type 1 and type 2 DM have similar complication rates. Tighter preconceptional glycaemic control as well as during the pregnancy is likely to be important in improving outcome for the babies of diabetic mothers.

Offspring of diabetic pregnancy: Long-term outcomes

Diabetes in pregnancy has been shown to induce long-term effects in offspring. While considerable attention is focused on the increased incidence of type 2 diabetes mellitus (T2DM) in adult offspring from diabetic mothers, cardiovascular alterations, including hypertension, are also part of lifelong consequences of in-utero exposure to increased glucose concentrations. This review examines the epidemiologic and mechanistic issues involved in the developmental programming of long-term consequences in offspring of diabetic mothers, with a particular emphasis on the renal and vascular mechanisms of hypertension. The factors of increased incidence of T2DM and of obesity in adults born after exposure to diabetes during pregnancy are also discussed, as evidence is accumulating that a vicious circle involving lifelong consequences of diabetes in pregnancy in offspring contributes to the current worldwide epidemic of T2DM.

Cardiovascular and metabolic abnormalities in the offspring of diabetic pregnancy.

Maternal fuel metabolism is known to exert long range effects on the later development of children of diabetic mothers. Recently cardiovascular disease in adult life has been linked retrospectively with foetal malnutrition. The aim of this study was to identify whether markers for fuel-related cardiovascular programming exist for the offspring of diabetic pregnancy. Sixty-one children aged 5 to 11 years, of mothers with Type I (insulin-dependent) diabetes mellitus were compared with 57 randomly selected control children of non-diabetic mothers similar in age, sex and social class. Fasting blood was taken for plasma glucose, insulin, lipids, IGF-1, plasminogen activating inhibitor 1 (PAI-1) and the adhesion molecules ICAM-1, VCAM-1 and E-Selectin. Fasting glucose and insulin were similar in the two groups. Differences existed between the offspring of diabetic and non-diabetic pregnancies (mean +/- SD) for total cholesterol (4.45+/-0.56 vs 4.18+/-0.66, p=0.03 ), LDL cholesterol (2.73+/-0.49 vs 2.39+/-0.54, p=0.001), Cholesterol-to-HDL ratio (3.41+/-0.76 vs 3.09+/-0.73, p=0.03), IGF-1 (22.5+/-7.3 vs 19.3+/-8, p=0.04), PAI-1 (20.1+/-6.2 vs 14.9+/-7.3, p=0.000), VCAM-1 (1852+/-444 vs 1509+/-385, p=0.000) and E-Selectin (geometric mean; 83.1 vs 63.9, p=0.001). These results indicate that important differences in cardiovascular risk factors exist between glucose-tolerant children of Type I diabetic and non-diabetic mothers, even in childhood. These data suggest that offspring of diabetic mothers might be at an increased risk for the development of vascular disease in later life.

Relationship between birth weight and body composition, energy metabolism, and sympathetic nervous system activity later in life.

Epidemiological studies suggest that high birth weight might be associated with an increased risk of obesity later in life. Programming of metabolic, endocrine, and/or autonomic pathways during intrauterine development has been proposed to explain this association. To determine the relationship between birth weight and body composition and energy metabolism later in life, we measured fat mass and fat-free mass (hydrodensitometry or double-energy X-ray absorptiometry), 24-hour energy expenditure, sleeping metabolic rate, and 24-hour respiratory quotient (respiratory chamber) in 272 adult nondiabetic Pima Indians (161 males/ 111 females, age 25 +/- 5 years, mean +/- SD). In these subjects, birth weight varied over a wide range (2,000 to 5,000 g). Individuals known to be offspring of diabetic pregnancies were excluded. In 44 of the 272 subjects, muscle sympathetic nerve activity was assessed by microneurography. Birth weight was positively correlated with adult height (r = 0.20, p < 0.001) and fat-free mass (r = 0.21, p < 0.001), but not with fat mass (r = 0.01, not significant). Sleeping metabolic rate, adjusted for age, sex, fat-free mass, and fat mass, was negatively related to birth weight (r = -0.13, p < 0.05), whereas adjusted 24-hour energy expenditure (r = 0.07, not significant) and 24-hour respiratory quotient (r = -0.09, not significant) were not. There was no relationship between birth weight and muscle sympathetic nerve activity (r = 0.12, not significant, n = 44). In Pima Indians who are not offspring of diabetic pregnancies, high birth weight is associated with increased height and lean body mass, but not with increased adiposity later in life. Although high birth weight may be associated with relatively low resting energy expenditure, it is not associated with major abnormalities in 24-hour energy metabolism or with low muscle sympathetic nerve activity later in life.

Hyperglycemia-induced embryonic dysmorphogenesis correlates with genomic DNA mutation frequency in vitro and in vivo.

Congenital malformations affecting multiple organ systems are at least three times more common in infants of mothers with IDDM than in infants born to nondiabetic mothers. Numerous studies have confirmed the teratogenic effect of hyperglycemia on the developing embryo, although no direct mechanism has been determined. In this study, we aimed to correlate the frequency of lacI mutations with degree of hyperglycemic exposure and severity of malformations in mouse embryos from in vitro cultures. Day 8 transgenic mouse embryos cultured in 30 or 50 mmol/l glucose for 48 h exhibited a higher incidence of morphological abnormalities, as well as an increase in lacI mutation frequency, compared with embryos cultured in 10 mmol/l glucose with no abnormalities and a lower frequency of lacI mutations. We also used a transgenic lacI rat system to evaluate the relationship between abnormal embryonic development and DNA mutation frequency in day 11 embryos of severely diabetic rats (serum glucose >20 mmol/l). Compared with control embryos, the embryos from diabetic rats displayed significantly more malformations, shorter crown-rump lengths, fewer somites, and more than six times greater genomic DNA mutation frequency. Genetic analysis of the mutated lacI gene from both in vitro cultured mouse embryos and in vivo developed rat embryos revealed that the majority of mutations were due to base substitutions (transitions and transversions), but that the rate of large DNA mutations tended to increase in embryos exposed to a diabetic environment. Our results support the interrelationship between increased rates of congenital malformations and DNA mutations in the offspring of diabetic pregnancy.

What Happens to the Offspring of Diabetic Pregnancies?

What Happens to the Offspring of Diabetic Pregnancies?

The offspring of diabetic pregnancy

The offspring of diabetic pregnancy

1739 SURFACTANT CHOLESTEROL: A POSSIBLE INHIBITOR OF SURFACE ACTIVITY

We have previously shown that fetuses of diabetic rabbit does have diminished pulmonary surfactant function. To determine whether increased cholesterol may inhibit surfactant function in vitro, crystalline cholesterol in amounts 4-17 times higher than found naturally was added to lung lavage fluid of 30 day gestation fetal rabbits. Surfactant function was determined on a modified Wilhelmy surface balance. The minimum surface tension of lung lavage containing added cholesterol was 17.5 mN/m, compared to 7 mN/m for untreated samples (p <.001). None of six samples with added cholesterol reached a minimum surface tension of less than 12 mN/m, whereas all untreated samples reached this value. To determine whether naturally occurring cholesterol content of diabetic fetal lung lavage is increased above that of normal fetuses, lavage cholesterol from 27.5 day gestation rabbit fetuses was measured by gas chromatography. Lavage cholesterol content was found to be elevated in diabetic fetuses 50-100% above controls. We conclude that exogenous cholesterol can inhibit surfactant function in vitro, and may be responsible for the diminished surfactant function seen in vivo in offspring of diabetic pregnancies.(Supported in part by a grant from the Juvenile Diabetes Foundation)