Pregestational prediabetes induces maternal Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation and results in adverse foetal outcomes.

Abstract

Background Foetal programming refers to the concept that maternal insults have the ability to disrupt the normal pattern of foetal development, permanently changing the body's structure, physiology and metabolism, thereby predisposing it to chronic diseases in later life. During pregnancy, maternal HPA (hypothalamic-pituitary-adrenal) axis activity increases due to placental corticotropin-releasing hormone (CRH), leading to higher glucocorticoid (GCs) levels, though within normal ranges. The maternal glucocorticoid influences foetal system development, yet the foetal HPA axis is sensitive to excess glucocorticoids, especially in cases of maternal stress, synthetic glucocorticoids or pregestational diabetes pregnancies. Excess glucocorticoids can irreversibly reprogram the foetal HPA axis, causing persistent changes such as increased bioavailability of GC in basal levels observed from juvenile to adulthood. Alterations such as the programmed HPA axis have been associated with increasing risks of metabolic disorders like hypertension, T2DM, obesity, cardiovascular diseases, and mental health disorders. Prediabetes, often a precursor to T2DM, is marked by asymptomatic hyperglycaemia and is linked to high-caloric diets. Research using high saturated fat, high refined carbohydrate diet-induced prediabetic models indicates that T2DM complications, including myocardial injury, renal dysfunction, hormonal dysregulation and dysregulation in the function of the HPA axis, begin during prediabetic stages. However, there is a lack of research in the existing body of literature that clarifies the influence of maternal prediabetes on the HPA axis during pregnancy and its effects on foetal outcomes. Hence, the present study aimed to investigate the effects of pregestational prediabetes on maternal HPA axis function and postnatal offspring development. Methods Female Sprague Dawley rats (n=12) were randomly assigned to one of the two groups (n=6, per group): pre-diabetic (PD) and non-pre-diabetic (NPD). Prediabetes was confirmed through fasting blood glucose and glucose tolerance tests. After PD induction, mating occurred, and pregnancy was confirmed. Post-gestation, 36 male pups from PD and NPD groups were collected. Blood from dams was collected on the weaning day to measure insulin, glycated haemoglobin (HbA1c), and the homeostatic model assessment for insulin resistance, insulin sensitivity and beta cell function as well as the adrenocorticotropic hormone (ACTH) and corticosterone concentrations. In addition, the pups were divided into three independent experimental weeks, week 3, week 6 and week 16, with 6 pups in each group assigned to either the NPD or PD on the day of weaning. Pups were evaluated at weeks 3, 6, and 16, with body weight, fasting glucose, and glucose tolerance tests conducted. Terminal investigations on each experimental week included measuring plasma ACTH, corticosterone, insulin via ELISA and gene expressions for glucocorticoid and mineralocorticoid receptors, in pups' hippocampus via polymerase chain reaction (PCR). Results and Discussion The high-fat, high-carbohydrate diet caused moderate hyperglycaemia, elevated plasma insulin, HbA1c, and insulin resistance in the PD group. Pregnant PD rats showed higher ACTH and corticosterone levels, indicating HPA axis dysregulation when compared to the NPD group. Pups from the PD group had elevated ACTH and corticosterone, altered GR and MR gene expressions, and increased adrenal gland weights compared to the NPD group. These findings suggest constant HPA axis activation without external stress, indicating alterations at the hypothalamus, pituitary, or adrenal gland levels, which may have been due to exposure to excess maternal corticosterone in utero. PD pups also had lower body weight, glucose intolerance, and insulin resistance, suggesting that maternal corticosterone affected foetal growth and glucose metabolism pathways when compared to the NPD group. Conclusion The findings suggest that pregestational prediabetes is associated with dysregulated HPA axis function, and it is positively associated with pregestational diabetes and maternal stress pregnancy complications. The foetal adverse outcomes such as HPA axis hyperactivity, reduced growth development and glucose handling disturbances relative to foetal programming might also begin in prediabetic pregnancy.