Impact of Maternal Diabetes on Epigenetic Modifications Leading to Diseases in the Offspring

Abstract

Gestational diabetes, occurring during the hyperglycemic period of pregnancy in maternal life, is a pathologic state that increases the incidence of complications in both mother and fetus. Offspring thus exposed to an adverse fetal and early postnatal environment may manifest increased susceptibility to a number of chronic diseases later in life. Compelling evidence for the role of epigenetic transmission in these complications has come from comparison of siblings born before and after the development of maternal diabetes, exposure to this intrauterine diabetic environment being shown to cause alterations in fetal growth patterns which predispose these infants to developing overweight and obesity later in life. Diabetes of the offspring is also mainly the consequence of exposure to the diabetic intrauterine environment, in addition to genetic susceptibility. Since obesity and diabetes are known to increase the risk of cardiovascular disease, cardiovascular sequelae in the offspring of diabetic mothers are virtually inevitable. Research data also suggest that exposure to a diabetic intrauterine environment during pregnancy is associated with an increase in dyslipidemia, subclinical vascular inflammation, and endothelial dysfunction processes in the offspring, all of which are linked with development of cardiovascular disease later in life. The main underlying mechanisms involve persistent hyperglycemia hyperinsulinemia and leptin resistance.

GDM-associated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake

“…In pregnancies complicated by GDM, the signaling of insulin is impaired so that glucose uptake or production cannot be stimulated or suppressed. Like in other forms of hyperglycemia, GDM affected maternal pancreatic β-cells do not function sufficiently to provide the physiological insulin requirement resulting in decreased insulin sensitivity (increased insulin resistance) coupled with an inadequate insulin response via impairment in the insulin signaling mechanism (2)(3)(4)(5)(6)(7)(8)(9). GDM is associated with placental pathology and various maternal and fetal complications during pregnancy, birth and later in life (2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Endocrine Disruptors and Fetal Programming

“…Data suggest that exposure to a diabetogenic environment is associated with increased dyslipidemia (increased total LDL), subclinical vascular inflammation and endothelial dysfunction processes in the offspring, all of which are related to the development of cardiovascular diseases in the future [30]. Another fetal implication of exposure to GDM is the development of morphological abnormalities in Langerhans' islets in offspring, demonstrated through its abnormal form, as well as through hyperplasia and hypertrophy of the same [9].…”

“…These studies correlated the birth weight with the incidence of adult-onset diseases and proposed that the adverse fetal environment with nutritional deficiency followed by high nutritional intake during adulthood could be responsible for the development of chronic diseases in adulthood [30].…”

“…The mechanisms and pathophysiological that mediate this phenomenon, although still little understood, are probably multiple and complex. Most of the investigation of the intratuterine origins of arterial hypertension today has been directed to the kidneys, the neuroendocrine system and the vascular tree [30].…”

Diabetes-Induced Congenital Anomalies of the Kidney and Urinary Tract (CAKUT): Nurture and Nature at Work?

“…Thus, hyperglycemia during pregnancy could have a teratogenic effect by altering the embryonic epigenome, leading to defects like CAKUT in the fetus. 12,13 What are the implications of findings that link epigenetic changes to diabetic embryopathy? Other than CAKUT, neural tube defects in the fetus are associated with maternal diabetes, and recent studies have shown that the underlying mechanisms probably involve tissue-specific epigenetic changes and concomitant altered gene expression in neural stem cells.…”