Pregnancy in Women With Monogenic Diabetes due to Pathogenic Variants of the Glucokinase Gene: Lessons and Challenges

Heterozygous loss-of-function variants of the glucokinase (GCK) gene are responsible for a subtype of maturity-onset diabetes of the young (MODY). GCK-MODY is characterized by a mild hyperglycemia, mainly due to a higher blood glucose threshold for insulin secretion, and an up-regulated glucose counterregulation. GCK-MODY patients are asymptomatic, are not exposed to diabetes long-term complications, and do not require treatment. The diagnosis of GCK-MODY is made on the discovery of hyperglycemia by systematic screening, or by family screening. The situation is peculiar in GCK-MODY women during pregnancy for three reasons: 1. the degree of maternal hyperglycemia is sufficient to induce pregnancy adverse outcomes, as in pregestational or gestational diabetes; 2. the probability that a fetus inherits the maternal mutation is 50% and; 3. fetal insulin secretion is a major stimulus of fetal growth. Consequently, when the fetus has not inherited the maternal mutation, maternal hyperglycemia will trigger increased fetal insulin secretion and growth, with a high risk of macrosomia. By contrast, when the fetus has inherited the maternal mutation, its insulin secretion is set at the same threshold as the mother’s, and no fetal growth excess will occur. Thus, treatment of maternal hyperglycemia is necessary only in the former situation, and will lead to a risk of fetal growth restriction in the latter. It has been recommended that the management of diabetes in GCK-MODY pregnant women should be guided by assessment of fetal growth by serial ultrasounds, and institution of insulin therapy when the abdominal circumference is ≥ 75th percentile, considered as a surrogate for the fetal genotype. This strategy has not been validated in women with in GCK-MODY. Recently, the feasibility of non-invasive fetal genotyping has been demonstrated, that will improve the care of these women. Several challenges persist, including the identification of women with GCK-MODY before or early in pregnancy, and the modalities of insulin therapy. Yet, retrospective observational studies have shown that fetal genotype, not maternal treatment with insulin, is the main determinant of fetal growth and of the risk of macrosomia. Thus, further studies are needed to specify the management of GCK-MODY pregnant women during pregnancy.

Exposure to maternal hyperglycemia and high-fat diet consumption after weaning in rats: repercussions on periovarian adipose tissue

Clinical and epidemiological studies show that maternal hyperglycemia can change the programming of offspring leading to transgenerational effects. These changes may be related to environmental factors, such as high-fat diet (HFD) consumption, and contribute to the comorbidity onset at the adulthood of the offspring. The objective of this study was to evaluate the hyperglycemic intrauterine environment, associated or not with an HFD administered from weaning to adult life on the periovarian adipose tissue of rat offspring Maternal diabetes was chemically induced by Streptozotocin. Female offsprings were randomly distributed into four experimental groups (n = 5 animals/group): Female offspring from control or diabetic mothers and fed an HFD or standard diet. HFD was prepared with lard enrichment and given from weaning to adulthood. On day 120 of life, the rats were anesthetized and sacrificed to obtain adipose tissue samples. Then, the hyperglycemic intrauterine environment and HFD fed after weaning caused a higher body weight, total fat, and periovarian fat in adult offspring, which could compromise the future reproductive function of these females. These rats showed higher adiposity index and adipocyte area, contributing to hypertrophied adipose tissue. Therefore, maternal diabetes itself causes intergenerational changes and, in association with the HFD consumption after weaning, exacerbated the changes in the adipose tissue of adult female offspring.

Clinical, metabolic and neurological disorders in full-term newborns from mothers with gestational diabetes mellitus

Objective. To determine the clinical and metabolic changes in children born from mothers with gestational diabetes mellitus and to predict perinatal injury of the central nervous system (CNS), taking into account the level of maternal hyperglycemia.Material and methods. The period of early postnatal adaptation was analyzed in 258 full-term infants, who were divided into two groups, depending on the glucose level in the mother’s venous blood during pregnancy: Group 1: 5,1–5,6 mmol/L, Group 2: 5,7–7,0 mmol/L.Results. Based on clinical, functional and laboratory markers (electrolyte balance and carbohydrate metabolism in the blood of a newborn) there was established a correlation between the severity of maternal hyperglycemia and the severity of neonatal disorders. In Group II infants born from mothers with more severe hyperglycemia are more likely to have a respiratory distress syndrome and ischemic-hypoxic injury of the central nervous system in combination with excess birth weight which significantly complicates postnatal adaptation.Conclusion. The concentration of neuron-specific enolase of 4,9 ng/ml in the fetal amniotic fluid is an antenatal marker of perinatal damage to the central nervous system in a newborn.

Frequency of Neonatal Hypoglycemia Among Women Diagnosed with Maternal Hyperglycemia

Objective: To determine frequency of neonatal hypoglycemia, in maternal hyperglycemia Subject and Method: This cross-sectional study was conducted at department of Pathology with collaboration of gynae and OBS department of PNS SHIFA Karachi. Study duration was six months from March 2015 to August 2015. All pregnant women who reported at antenatal clinics of PNS SHIFA Hospital and diagnosed as the cases of hyperglycinemia were included in the study. Maternal blood glucose testing was done according to WHO guidelines i.e. fasting sample, ingestion of 75 g glucose, 01 h and 02 h sample for plasma glucose estimation. Neonatal blood glucose was checked immediately after birth by glucometer. All the data was collected via study proforma. Results: A total of 157 pregnant women were studied their average age was 28.20±4.67 years. Caesarean section was done in 62.4% cases and 58.6% babies were males. Neonatal hypoglycemia was observed among 24.8% of the cases. Neonatal hypoglycemia was statistically significant according to gestational age (p- 0.012), while statistically insignificant according to parity (p-0.184). Conclusion: As per study conclusion, the neonatal hypoglycemia was observed to be highly prevalent among neonates of diabetic mothers as 24.8%. It was found to be statistically significant according to gestational age. Keywords: Gestational diabetes mellitus, Neonates, Hypoglycemia

Maternal hyperglycemia impedes second heart field-derived cardiomyocyte differentiation to elevate the risk of congenital heart defects

Congenital heart disease (CHD) is the most frequently occurring structural malformations of the heart affecting ~1% of live births. Besides genetic predisposition, embryonic exposure to teratogens during pregnancy increases the risk of CHD. However, the dose and cell-type-specific responses to an adverse maternal environment remain poorly defined. Here, we report a dose-response relationship between maternal glucose levels and phenotypic severity of CHD in offspring, using a chemically-induced pregestational diabetes mellitus (PGDM) mouse model. Embryos from dams with low-level maternal hyperglycemia (matHG) displayed trabeculation defects, ventricular wall thinning, and ventricular septal defects (VSD). On the other hand, embryos from dams with high-level matHG display outflow tract malformations, ventricular wall thinning and an increased rate of VSD. Our findings show that increasing levels of matHG exacerbates CHD occurrence and severity in offspring compared to control embryos. We applied single-cell RNA- sequencing to define matHG-related transcriptional differences in E9.5 and E11.5 hearts as comparing to controls. Disease-dependent gene-expression changes were observed in Isl1+ second heart field (SHF) and Tnnt2+ cardiomyocyte subpopulations. Lineage tracing studies in Isl1-Cre; RosamTmG embryonic hearts showed Isl1+-SHF-derived cardiomyocyte differentiation was impaired with matHG. This study highlights the influence of matHG-dosage on cardiac morphogenesis and identifies perturbations in the Isl1-dependent gene-regulatory network that affect SHF-derived cardiomyocyte differentiation contributing to matPGDM-induced CHD.