Offspring Of Diabetic Mothers Research Articles

Neuropathology of hypoglycaemic brain injury

It has long been recognised that the neurobiochemistry of hypoglycaemic brain injury differs markedly from that of hypoxic-ischaemic brain injury. The neuropathology of hypoglycaemic brain injury may also be distinctive. Such distinctive changes, aiding discrimination from hypoxic-ischaemic brain injury, are though commonly absent even in cases of biochemically proved profound hypoglycaemia. Neuronal depletion or necrosis may only be observed in 29% of cases. Autopsy findings in cases of suspected insulin overdose or overdose from oral hypoglycaemic agents may not uncommonly be non-specific. It should be appreciated that neuronal death due to hypoglycaemic brain injury may only intervene after a sustained period of blood glucose levels below 1 mmol/l and after EEG tracing has become silent. The neuropathology of hypoglycaemic brain injury may also be modified by concurrent hypoxia resulting from concomitant cardiorespiratory depression and by seizures. Atypical presentations also include strikingly asymmetric involvement of the cerebral hemispheres. It should further be appreciated that the postmortem findings in cases of hypoglycaemic brain injury may include neurogenic pulmonary oedema (seen in over half of cases). The majority of cases of suspected hypoglycaemic drug overdose represent suicides (66%) with the remainder representing accidental poisoning and homicide, with insulin the most commonly drug implicated (around 95%). In paediatric practice, hypoglycaemia frequently occurs in newborn infants who previously suffered asphyxia, offspring of diabetic mothers and with a low birth weight for gestational age. The immature brain is relatively resistant to the damaging effects of hypoglycaemia. Hypoglycaemia in this age group combined with hypoxic-ischaemic injury, in particular asphyxia, may though be more deleterious to the immature brain than either condition alone.

The role of folate in mitigating murine cardiac hypertrophy in offspring of diabetic dams

Maternal diabetes is associated with short- and long-term cardiac disease. Prenatal folate is often recommended for diabetic pregnant women to reduce the incidence of cardiac and neural tube defects in their offspring. However, no such recommendation exists for the progeny of offspring of diabetic mothers despite the epidemiologic observation that there is a two-fold increase in cardiovascular disease. Contrary to previous reports, our lab has shown that left ventricular hypertrophy re-emerges in early adulthood. This study aimed to determine the role of folate supplementation in mitigating cardiac hypertrophy in the offspring of diabetic mice. Maternal hyperglycemia was induced in CD-1 females (n=10) with streptozotocin (150mg/kg). Control mice (n=10) were given an equal volume of saline. After hyperglycemia was confirmed ( >250mg/dL), both groups were mated with CD-1 males. After weaning, the offspring of diabetic (ODM) and control (OCM) were fed a non-supplemented versus supplemented folate diet for five weeks. Cardiac hypertrophy was assessed with echocardiograms at eight weeks and stratified by sex. We used t-test to compare the left ventricular internal diameter and left posterior wall thickness. P-values < 0.05 were significant. At eight weeks, compared to OCM, ODM had a smaller left ventricle internal diameter and increased posterior wall thickness consistent with myocardial hypertrophy. However, after receiving folate supplementation, only male ODM had a resolution of cardiac hypertrophy at eight weeks. For females ODM fed with folate supplementation, cardiac hypertrophy persisted. Folate did not mitigate cardiac hypertrophy overall. However, it did for male offspring of diabetic dams specifically. Folate supplementation may have a role in attenuating hypertrophy in male offspring of diabetic dams. Future studies will assess cardiac hypertrophy in the offspring of mothers with diabetes and determine if there is a role in post-natal folate supplementation.

Dysregulation of Mir-193B and Mir-376A as a Biomarker of Prediabetes in Offspring of Gestational Diabetic Mice

Gestational diabetes mellitus (GDM) is a type of diabetes initiated during pregnancy and is characterized by maternal hyperglycemia that induces complications in mothers and children. In the current study, we used a GDM mouse model (through i.p. injection of a single dose of streptozocin, STZ, 60 mg/kg/bw) to investigate the biochemical and immunological changes in the blood and brain of diabetic mothers and their offspring relative to their appropriate controls. In addition, we estimated the expression levels of a set of microRNAs (miRNAs) to link between the dysregulation in the levels of miRNAs and the exposure to oxidative stress during embryonic development, as well as metabolic changes that occur after birth and during puberty in offspring (5-weeks-old). At the biochemical level, newborn pups appeared mostly to suffer from the same oxidative stress conditions of their mothers as shown by the significant increase in nitric oxide (NO) and malondialdehyde (MDA) in blood and brain of diabetic mothers and their pups. However, the 5-week-old offspring showed a significant increase in proinflammatory cytokines, IL-1β, IL-6, and TNF-α, and based on their blood glucose levels, could be considered as prediabetic (with glucose mean value of 165 mg/dl). In the meantime, the tested miRNAs, especially miR-15b, miR-146a, and miR-138 showed mostly similar expression levels in diabetic mothers and newborn pups. In this regard, miR-15a and -15b, miR-146a, and miR-138 are downregulated in diabetic mothers and their newborn pups relative to their appropriate controls. However, in offspring of diabetic mothers at puberty age, these miRNAs displayed different expression levels relative to mothers and control offspring. Interestingly, miR-193 and miR-763 expression levels were significantly lower in diabetic mothers but upregulated in their 5-week-old offspring, suggesting that miR-193 and miR-763 could be used as biomarkers to differentiate between prediabetes and diabetes.

How Do the Different Types of Maternal Diabetes during Pregnancy Influence Offspring Outcomes?

Background/Aim of the study: Exposure to maternal diabetes is considered one of the most common in utero insults that can result in an increased risk of complications later in life with a permanent effect on offspring health. In this study, we aim to assess the level of risk associated with each type of maternal diabetes on obesity, glucose intolerance, cardiovascular diseases (CVD), and neurodevelopmental disorders in offspring. Methods: We conducted a systematic review of the literature utilizing PubMed for studies published between January 2007 and March 2022. Our search included human cohorts and case control studies following offspring exposed at least to two different types of maternal diabetes clearly identified during pregnancy. Collected outcomes included prevalence, incidence, odds ratio, hazard ratio and risk ratio. Results: Among 3579 published studies, 19 cohorts were eligible for inclusion in our review. The risks for overweight, obesity, type 2 diabetes (T2D), glucose intolerance, metabolic syndrome, and CVD were increased for all types of maternal diabetes during pregnancy. The risk of overweight or obesity in infancy and in young adults was similar between gestational diabetes mellitus (GDM) and type 1 diabetes (T1D). The risk for T2D or abnormal glucose tolerance was double for offspring from GDM mothers compared to offspring from T1D mothers. In contrast, the risk for T1D in offspring at any age until young adulthood was increased when mothers had T1D compared to GDM and T2D. The risk for CVD was similar for all types of maternal diabetes, but more significant results were seen in the occurrence of heart failure and hypertension among offspring from T2D mothers. The risk of autism spectrum disorders and attention deficit/hyperactivity disorders was mainly increased after in utero exposure to preexisting T1D, followed by T2D. Conclusions: Offspring of diabetic mothers are at increased risk for multiple adverse outcomes with the highest risk detected among offspring from T2D mothers. Future work warrants large multiethnic prospective cohort studies that aim to identify the risks associated with each type of maternal diabetes separately.

Maternal alloxan exposure induces damage in rat offspring lumbar vertebrae and protective role of arachidonic acid.

Vertebral abnormalities in offspring of diabetic mothers make major challenges worldwide and were not sufficiently studied before. To investigate the effects of alloxan-induced diabetes on rats' lumbar vertebrae, and to assess the potential beneficial impact of arachidonic acid. Pregnant rats were randomly equally divided into four groups: control, alloxan-induced diabetes received alloxan injection 150 mg∕kg, alloxan + arachidonic acid group received arachidonic acid 10 μg∕animal then given alloxan injection, and arachidonic acid group received it, until offspring age of three weeks. Six male offspring from each group were included in this study at ages of newborn, three-week-old, two-month-old, and their body measurements were recorded. Lumbar vertebrae and pancreas specimens were examined by light microscopy, morphometry, transmission electron microscopy (TEM), and immunohistochemistry for insulin expression. In alloxan-induced diabetes newborn, three-week-old, and two-month-old rats, body measurements were significantly declined, histomorphometry of 6th lumbar vertebrae revealed disorganized chondrocytes, with vacuolated cytoplasm, empty lacunae, diminished matrix staining, with areas devoid of cells. TEM showed shrunken reserve and proliferative cells, with irregular nuclei, and damaged mitochondria. In contrast, alloxan + arachidonic acid group had cytoarchitecture of lumbar vertebrae that were like control group. Histomorphometry of pancreas in alloxan-induced diabetes group showed significant reduction in pancreatic islets number and surface area, damaged pancreatic islet cells appeared atrophied with apoptotic nuclei, and very weak insulin immunostaining. Whereas alloxan + arachidonic acid group displayed healthy features of pancreatic islets, which resembled control group, with strong insulin immunostaining. Arachidonic acid mitigated alloxan-induced diabetes by its antidiabetic activity.

Association of maternal diabetes during pregnancy with visual acuity development in offspring: a prospective cohort study.

We aimed to investigate the association between maternal diabetes before or during pregnancy and visual acuity development in offspring at 1 and 4years old. This prospective cohort study comprised 301 individuals born in 2015-2017.Those who had maternal diabetes during or before pregnancy (type 1 diabetes, type 2 diabetes and gestational diabetes) were investigated.Two visual examinations were routinely performed on children relatively at the age of 1 at physical examination and at the age of 4 at admission to school to assess the possible effects of gestational exposure to diabetes on the visual system of the offspring. Data were collected on children aged 1 and 4, which consisted of 173 children of mothers exposed to diabetes and 128 children of mothers without diabetes). We found no significant association between maternal diabetes during pregnancy and visual acuity development in 1-year-old offspring. At 4years old, the incidence of amblyopia and strabismus was similar in both groups. Prenatal exposure to maternal diabetes was associated with a 171% increased risk of high RE: OR 2.71 (95% CI 1.08, 6.81), p < 0.05. Astigmatism (13.3% vs 5.5%) was found to be significantly more prevalent in children born to mothers with GD than in the controls (p = 0.025 in both groups). Moreover, offspring exposed to PGDM had a higher overall risk of high RE than those exposed to GDM during pregnancy (25.0% vs 17.4%). We further found that in the offspring of diabetic mothers, the risk of high RE was significantly increased among children who were female or who spent more time using electronic devices daily. Our findings suggest that maternal diabetes during pregnancy is associated with an increased risk of high RE in offspring.Regular ophthalmological screening should be advised to offspring of mothers with diabetes diagnosed before or during pregnancy.

Role of heme oxygenase in the regulation of the renal hemodynamics in a model of sex-dependent programmed hypertension by maternal diabetes.

Intrauterine programming of cardiovascular and renal function occurs in diabetes because of the adverse maternal environment. Heme oxygenase 1 (HO-1) and -2 (HO-2) exert vasodilatory and antioxidant actions, particularly in conditions of elevated HO-1 expression or deficient nitric oxide levels. We evaluated whether the activity of the heme-HO system is differentially regulated by oxidative stress in the female offspring of diabetic mothers, contributing to the improved cardiovascular function in comparison with males. Diabetes was induced in pregnant rats by a single dose of streptozotocin (STZ, 50 mg/kg ip) in late gestation. Three-month-old male offspring from diabetic mothers (MODs) exhibited higher blood pressure (BP), higher renal vascular resistance (RVR), worse endothelium-dependent response to acetylcholine (ACH), and an increased constrictor response to phenylephrine (PHE) compared with those in age-matched female offspring of diabetic mothers (FODs), which were abolished by chronic tempol (1 mM) treatment. In anesthetized animals, stannous mesoporphyrin (SnMP; 40 µmol/kg iv) administration, to inhibit HO activity, increased RVR in FODs and reduced glomerular filtration rate (GFR) in MODs, without altering these parameters in control animals. When compared with MODs, FODs showed lower nitrotirosyne levels and higher HO-1 protein expression in renal homogenates. Indeed, chronic treatment with tempol in MODs prevented elevations in nitrotyrosine levels and the acute renal hemodynamics response to SnMP. Then, maternal diabetes results in sex-specific hypertension and renal alterations associated with oxidative stress mainly in adult male offspring, which are reduced in the female offspring by elevation in HO-1 expression and lower oxidative stress levels.

Maternal hyperglycemia and epigenetic regulation of Cacna1D in cardiac hypertrophy

The objectives for this study were: 1. To evaluate the short and long-term cardiac function in offspring of diabetic mothers in a murine model. 2. Determine how gene programming during embryonic heart development translates to adult heart gene expression. We hypothesized that abnormal post-natal heart function origins have their origins in gene programming during embryonic heart development.

Risks of specific congenital anomalies in offspring of diabetic mothers: a systematic review and meta-analysis of population-based studies of more than 80 million births

Risks of specific congenital anomalies in offspring of diabetic mothers: a systematic review and meta-analysis of population-based studies of more than 80 million births

Metabolic changes in female rats exposed to intrauterine hyperglycemia and postweaning consumption of high-fat diet†.

We evaluated the influence of the hyperglycemic intrauterine environment and postweaning consumption of a high-fat diet (HFD) on the glycemia, insulin, lipid, and immunological profile of rat offspring in adulthood. Female rats received citrate buffer (Control-C) or Streptozotocin (a beta cell-cytotoxic drug to induce diabetes-D) on postnatal day 5. In adulthood, these rats were mated to obtain female offspring, who were fed a standard diet (SD) or HFD from weaning to adulthood (n= 10 rats/group). OC/SD and OC/HFD represent female offspring of control mothers and received SD or HFD, respectively; OD/SD and OD/HFD represent female offspring of diabetic mothers and received SD or HFD, respectively. At adulthood, the oral glucose tolerance test (OGTT) was performed and, next, the rats were anesthetized and euthanized. Pancreas was collected and analyzed, and adipose tissue was weighted. Blood samples were collected to determine biochemical and immunological profiles. The food intake was lower in HFD-fed rats and visceral fat weight was increased in the OD/HFD group. OC/HFD, OD/SD, and OD/HFD groups presented glucose intolerance and lower insulin secretion during OGTT. An impaired pancreatic beta-cell function was shown in the adult offspring of diabetic rats, regardless of diet. Interleukin (IL)-6 and IL-10 concentrations were lower in the OD/HFD group and associated to a low-grade inflammatory condition. The fetal programming was responsible for impaired beta cell function in experimental animals. The association of maternal diabetes and postweaning HFD are responsible for greater glucose intolerance, impaired insulin secretion and immunological change.

Down-regulation of AMPK/PPARδ signalling promotes endoplasmic reticulum stress-induced endothelial dysfunction in adult rat offspring exposed to maternal diabetes.

Exposure to maternal diabetes is associated with increased prevalence of hypertension in the offspring. The mechanisms underlying the prenatal programming of hypertension remain unclear. Because endoplasmic reticulum (ER) stress plays a key role in vascular endothelial dysfunction in hypertension, we investigated whether aberrant ER stress causes endothelial dysfunction and high blood pressure in the offspring of dams with diabetes. Pregnant Sprague-Dawley rats were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at Day 0 of gestation. Compared with control mother offspring (CMO), the diabetic mother offspring (DMO) had higher blood pressure and impaired endothelium-dependent relaxation in mesenteric arteries, accompanied by decreased AMPK phosphorylation and PPARδ expression, increased ER stress markers, and reactive oxygen species (ROS) levels. The inhibition of ER stress reversed these aberrant changes in DMO. Ex vivo treatment of mesenteric arteries with an AMPK agonist (A769662) or a PPARδ agonist (GW1516) improved the impaired EDR in DMO and reversed the tunicamycin-induced ER stress, ROS production, and EDR impairment in mesenteric arteries from CMO. The effects of A769662 were abolished by co-treatment with GSK0660 (PPARδ antagonist), whereas the effects of GW1516 were unaffected by Compound C (AMPK inhibitor). These results suggest an abnormal foetal programming of vascular endothelial function in offspring of rats with maternal diabetes that is associated with increased ER stress, which can be ascribed to down-regulation of AMPK/PPARδ signalling cascade.

Risks of Specific Congenital Anomalies in Offspring of Diabetic Mothers: A Systematic Review and Meta-Analysis of Population-Based Studies of More than 76 Million Births

Background: Pregestational diabetes (PGDM) has been known to be a risk factor for congenital heart defects (CHD) for decades. However, the associations between maternal PGDM and gestational diabetes (GDM) and risk of specific types of CHD and other systems congenital anomalies (CAs) remains under debate. We investigated type-specific CAs in offspring of diabetic mothers and examined the extent to which different types of maternal diabetes increase CAs risks in offspring. Methods: For this systematic review and meta-analysis, we searched PubMed and Embase from inception to December 27, 2020, for population-based studies reporting on type-specific CAs in offspring of diabetic mothers. We assessed methodological quality using the Cochrane Risk of Bias Tool for Non-randomised Studies of Interventions. We calculated summary estimates for meta-analysis using random effects models. The primary outcomes were overall CAs and specific types of CHD. Findings: 56 studies (76,860,298 participants) were included. The meta-analyses showed increased risks of overall CAs/CHD, in offspring born to mothers with PGDM (for overall CAs, relative risks [RR] 1.99, 95% CI 1.82 to 2.17 and for CHD, 3.42, 95% CI 2.73 to 4.28) or GDM (for overall CAs, 1.18, 95% CI 1.13 to 1.23 and for CHD, 1.50, 95% CI 1.38 to 1.64). Results of meta-regression analyses showed significant differences in RRs of CAs/CHD in PGDM versus GDM (all P ˂ 0.001). Of 23 type-specific CAs of other systems in offspring, maternal PGDM was associated with a significantly increased risk of CAs in 21 categories, while maternal GDM had a small but significant increase in risk of CAs in 9 categories. Interpretation: The findings suggest that timely screening for diabetes in women who are pregnant or planning to be pregnant provides a window of opportunity to prevent congenital anomalies in offspring. Registration Information: This systematic review is registered with PROSPERO, number CRD42021229217. Funding Information: None. Declaration of Interests: We declare no competing interests.

Diminished substrate-mediated cardiac mitochondrial respiration and elevated autophagy in adult male offspring of gestational diabetic rats.

Heart diseases are common in the offspring of diabetic mother (ODM). Defects in mitochondrial metabolism and autophagy may, in part, be responsible for the adverse structural and functional alterations in the heart. The principal objective of this study was to investigate cardiac mitochondrial respiration and autophagy in male and female offspring of diabetic pregnancy at two different developmental stages of life, weaning and adult. Male and female offspring of rats with streptozotocin-induced gestational diabetes were used for the study and compared with offspring of control (non-diabetic) mother (OCM) rats. High-resolution respirometry was used to measure substrate-mediated respiration in mitochondria isolated from ventricular tissues of ODM and OCM. Expression of proteins associated with autophagy and oxidative stress was examined by western blot analysis. Mitochondrial complex I and complex II respiration was significantly reduced in adult male ODM while it was unaltered or less affected in weaning male, adult and weaning female ODM. Elevated autophagy was observed in adult male but not in adult female ODM. Expression of oxidative stress markers was observed to be similar in all the groups. Altered cardiac mitochondrial respiration and autophagy were observed in adult male ODM compared to OCM, while the male and female offspring at weaning stage were less affected. The results of the study show that maternal hyperglycemia affects mitochondrial respiration and autophagy in the ODM heart, which may potentially be responsible for the cardiovascular complications observed in adult life.

1004 Male mouse offspring of diabetic mothers have worsening heart function with age

The objective of this study is to characterize the post-natal heart function in offspring of diabetic mothers stratified by sex and age. We hypothesize that maternal diabetes will lead to abnormal heart function in her progeny postnatally and will differ in respect to sex and aging. 8-week old CD1 female mice were given with a one-time dose of 150 mg/kg of Streptozotocin or normal saline, respectively. Hyperglycemic and control females were mated with normal CD1 males. A Kaplan-Meier survival curve was used to track survival of offspring in both cohorts. Transthoracic left ventricular (LV) echocardiograms were performed on the (n=7) offspring of diabetic mothers (ODM) and (n=15) offspring of control mothers (OCM) mothers at 4, 8, and 24-28 weeks. High frequency oscillation echocardiograms were performed by a single blinded examiner. Non-parametric data was analyzed through Mann-Whitney tests, Kruskal-Wallis tests, and two-way ANOVA with post-Hoc Tukey test where appropriate. P-values < 0.05 were considered significant. All graphs and analysis performed via GraphPad Prism 8 software. All experiments were approved and performed in accordance with the Institute of Animal Care and Use Committee at Vanderbilt University Medical Center (Protocol #: M1700155-00). ODM have a lower post-natal survival rate than relative controls (77% vs 95% , p < 0.0001). Compared with OCM at 24-28 weeks, male ODM have a lower cardiac output (31.26 +/- 4.45 ml/min vs 21.65 +/- 4.74 ml/min, p<0.001), smaller internal ventricle diameter (1.8 +/- 0.33 mm vs. 1.3 +/- 0.14, p<0.001) and thicker posterior wall (1.77+/-0.19 mm vs. 1.98 +/- 0.11, p<0.001). Male offspring of diabetic mothers demonstrated significant changes in cardiac function and heart size from the male offspring of control mothers at 24-28 weeks old. Female offspring of diabetic mother did not have a significant difference in similar cardiac indices from female offspring of control mothers at 24-28 weeks. Male ODM have an increased vulnerability to abnormal cardiac function parameters that persist overtime than female ODM.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Diminished substrate-mediated cardiac mitochondrial respiration and elevated autophagy in adult male offspring of gestational diabetic rats.

Heart diseases are common in offspring of gestational diabetic mother (ODM). Defects in mitochondrial metabolism and autophagy may be one of the basic reasons behind the abnormal structural and functional behaviour of offspring's heart. So the main objective of the present study was to explore the cardiac mitochondrial respiration and autophagy in male and female offspring of diabetic pregnancy at two different developmental stages of life. High-resolution respirometry was used to measure substrate-mediated mitochondrial respiration in isolated mitochondria from ventricular tissues of offspring of streptozotocin-induced diabetic mother rats. To find the expression of proteins involved in autophagic process and oxidative stress, western blotting and densitometric analysis were done. Mitochondrial complex I and complex II respiration was found to be decreased in adult male offspring while it was unaltered or less affected in weaning male and female offspring. Elevated autophagy was shown by adult male, while there was no change observed in adult female. Also absence of elevated expression of oxidative stress markers was observed in all groups. The present study reports altered cardiac mitochondrial respiration and autophagy in male offspring of diabetic mothers than the control ones. The study also analysed the expression of various candidates of cardiac autophagic process in male and female offspring of diabetic pregnancy at two time points of development.

Maternal diabetes and risk of multiple sclerosis in the offspring: A Danish nationwide register-based cohort study

Background: Previous studies suggest a 3- to-10-fold increased risk of multiple sclerosis (MS) in offspring of mothers with diabetes mellitus (DM). Objectives: To examine MS risk in offspring of diabetic mothers, overall and according to type of maternal DM, that is, pregestational DM or gestational DM, as well as to examine MS risk among offspring of diabetic fathers. Methods: The study cohort included all 1,633,436 singletons born in Denmark between 1978 and 2008. MS diagnoses were identified in the Danish Multiple Sclerosis Registry, and parental DM diagnoses in the National Patient Register. We used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of parental DM with MS risk in the offspring. Results: MS risk among individuals whose mothers had pregestational DM was 2.3-fold increased compared with that among individuals with nondiabetic mothers (HR = 2.25; 95% CI: 1.35–3.75, n = 15). MS risk was statistically non-significant among offspring of mothers with gestational DM (HR = 1.03 (95% CI: 0.49–2.16), n = 7) and among offspring of diabetic fathers (HR = 1.40 (95% CI: 0.78–2.54), n = 11). Conclusion: Our nationwide cohort study utilizing high-quality register data in Denmark over several decades corroborates the view that offspring of diabetic mothers may be at an elevated risk of developing MS.

The effect of gestational diabetes on identification of key genes and pathways in human umbilical vein endothelial cell by integrated bioinformatics analysis

Maternal diabetes may lead to long-term risks for the offspring. The study aims at identifying the potential crucial genes and pathways associated with foetal metabolism and malformation of gestational diabetes mellitus (GDM). Gene Expression Series 49524 and 87295 were downloaded from Gene Expression Omnibus database, including eight from GDM and eight from non-GDM. A total of 35 differentially expressed genes were identified. Gene ontology functional annotation and signalling pathway analyses were performed. Four hub genes were identified by protein–protein interaction network: SHH, E2F1, STAT1, and HOXA9. The four hub genes were assessed by western blot and real-time quantitative PCR in clinical samples. The results of this data mining and integration help to reveal the pathophysiologic and molecular mechanism imprinted in primary umbilical cord-derived cells from GDM offspring. These genes and pathways identified are potential stratification biomarkers and provide further insight for developing therapeutic intervention for the offspring of diabetic mothers. Impact statement What is already known on this subject? Maternal diabetes may lead to long-term risks for the offspring. A high glucose environment might change the umbilical cord expression of genes implicated in foetal metabolism and development. However, underlying molecular mechanisms have not been investigated thoroughly. What do the results of this study add? GO functional annotation showed that the biological functions of differentially expressed genes mainly involved in metanephros development, salivary gland morphogenesis, fat cell differentiation, vasculogenesis, muscle cell proliferation, heart morphogenesis and Wnt signalling pathway. Signalling pathway analyses found that these differentially expressed genes mainly implicated in the apoptosis, cell cycle, Hedgehog, P53, and NOTCH signalling pathway. Four hub genes were identified by protein-protein interaction network: SHH, E2F1, STAT1 and HOXA9. What are the implications of these findings for clinical practice and/or further research? The genes and pathways identified in the present study are potential stratification biomarkers and provide further insight for developing therapeutic intervention for the offspring of diabetic mothers.

Exposure to maternal diabetes induces endothelial dysfunction and hypertension in adult male rat offspring

The adverse environment in early life can modulate adult phenotype, including blood pressure. Our previous study shows, in a rat streptozotocin (STZ)-induced maternal diabetes model, fetal exposure to maternal diabetes is characterized by established hypertension in the offspring. However, the exact mechanisms are not known. Our present study found, as compared with male control mother offspring (CMO), male diabetic mother offspring (DMO) had higher blood pressure with arterial dysfunction, i.e., decreased acetylcholine (Ach)-induced vasodilation. But there is no difference in blood pressure between female CMO and DMO. The decreased Ach-induced vasodilation was related to decreased nitric oxide (NO) production in the endothelium, not NO sensitivity in vascular smooth muscle because sodium nitroprusside (SNP)-mediated vasodilation was preserved; there was decreased NO production and lower eNOS phosphorylation in male DMO. The reactive oxygen species (ROS) level was increased in male DMO than CMO; normalized ROS levels with tempol increased NO production, normalized Ach-mediated vasodilation, and lowered blood pressure in male DMO rats. It indicates that diabetic programming hypertension is related to arterial dysfunction; normalizing ROS might be a potential strategy for the prevention of hypertension in the offspring.

A combined in vivo and in silico model shows specific predictors of individual trans-generational diabetic programming.

Diabetic pregnancies are cleary associated with maternal type 2 diabetes and metabolic syndrome as well as atherosclerotic diseases in the offspring. The global prevalence of hyperglycemia in pregnancy was estimated as 15.8% of live births to women in 2019, with an upward trend. Numerous parental risk factors as well as trans-generational mechanisms targeting the utero-placental system, leading to diabetes, dysmetabolic and atherosclerotic conditions in the next generation, seem to be involved within this pathophysiological context. To focus on the predictable impact of trans-generational diabetic programming, we studied age- and gender-matched offspring of diabetic and nondiabetic mothers. The offspring generation consists of three groups: C57BL/6-J-Ins2Akita (positive control group), wild-type C57BL/6-J-Ins2Akita (experimental group), and C57BL/6-J mice (negative control group). We undertook intraperitoneal glucose tolerance tests at 3 and 11 weeks of age. Moreover, this in vivo model was complemented by a corresponding in silico model. Although at 3 weeks of age, no significant effects could be observed, we could demonstrate at 11 weeks of age characteristic and significant differences in relation to maternal diabetic imprinting based on the in silico model-based predictors. These predictors allow the generation of a concise classification tree assigning maternal diabetic imprinting correctly in 91% of study cases. Our data show that hyperglycemic in utero milieu contributes to trans-generational diabetic programming leading to impaired glucose tolerance in the offspring of diabetic mothers early on. These observations can be clearly and early distinguished from genetically determined diabetes, for example, type 1 diabetes, in which basal glucose values are significantly raised.

Could the E/A ratio be included in the cardiological evaluation of the offspring of diabetic mothers? A case-control study in South Sardinia

Introduction Diabetes mellitus (DM) is a chronic disease widespread in the world. Sardinia represents, together with Finland, the region with the highest incidence of type 1 DM (DM1), as well as a high prevalence of gestational DM (GDM). Despite the improvement in obstetric surveillance, perinatal and long-term adverse outcomes are still frequent in the offspring of diabetic mothers. During gestations complicated by DM, fetal heart is one of the most affected organ potentially undergoing structural heart defects or several degrees of fetal myocardium hypertrophy and impaired cardiac function. Aim The aim of our study was to evaluate, through echocardiographic examination, cardiac features and performance in a South Sardinian population of newborns of diabetic mothers comparing them to a group of control subjects. Conclusions In our sample, the E/A ratio resulted a significant marker of early diastolic dysfunction in asymptomatic neonates born by diabetic mothers, even if such result should be confirmed on larger samples.