Evidence for a hyporesponsive limbic-hypothalamic-pituitary-adrenal axis following early-life repetitive hypoglycemia in adult male rats

Abstract

The developing limbic-hypothalamic-pituitary-adrenal (LHPA) axis is highly vulnerable to programming by early-life environmental factors, including exposure to synthetic glucocorticoids and nutrient deficiencies. Early-life repetitive hypoglycemia (RHG) is a common complication of insulin therapy for type-1 diabetes that may have long-term consequences in adulthood. Recent observations in a rat model of early RHG suggest persistent changes in LHPA axis function, including changes in relevant hormones and affective behaviors, which support a hyperresponsive LHPA axis. Thus, we hypothesized that early RHG would alter the expression of key genes regulating LHPA axis function in adulthood. The present study employed a rat model of insulin-induced RHG spanning postnatal days (P)24-28, a neurodevelopmental equivalent of early childhood in humans, to assess the long-term effects on mRNA levels for proteins relevant to the LHPA function and the corticosterone responses to ACTH stimulation of dispersed adrenocortical cells in vitro and restraint stress in vivo at adulthood. This early RHG model resulted in a hyporesponsive LHPA axis characterized by impaired corticosterone response, increased hippocampal glucocorticoid and mineralocorticoid receptor (GR and MR), decreased hypothalamic corticotropin-releasing hormone, increased adrenal steroidogenic-acute-regulatory protein and GR, and decreased adrenal MR, melanocortin-type-2 receptor and low-density lipoprotein receptor expression. Our findings highlight a complex environmental-gene interaction between RHG and LHPA axis during development that influences regulation of this axis in adulthood. The findings are consistent with the developmental origins of disease and underscore the influences of early-life events on the programming of a major regulatory system.

Assessment of body composition in Wistar rat offspring by DXA in relation to prenatal and postnatal nutritional manipulation

“…response to the postnatal environment (9)(10)(11)(12). Nutrition is one of the environmental variables with the widest range of effects on physical growth, metabolism, brain, adipose, and musculoskeletal development (13,14).…”

Deletion of novel protein TMEM35 alters stress-related functions and impairs long-term memory in mice

“…Serum corticosterone concentration was determined using a commercially available radioimmunoassay kit (Coat-A-Count; Diagnostic Products, Los Angeles, CA), as previously described (28).…”

Recurrent Moderate Hypoglycemia Suppresses Brain-Derived Neurotrophic Factor Expression in the Prefrontal Cortex and Impairs Sensorimotor Gating in the Posthypoglycemic Period in Young Rats

“…RH group was subjected to insulin-induced hypoglycemia from P24 to P28, once daily between 8 AM and 10 AM (total, 5 episodes). This model has been described previously [30]. Briefly, regular insulin (Novo Nordisk Inc., Clayton, NC) was injected in a dose of 10 IU/kg ip without prior fasting.…”

“…Briefly, regular insulin (Novo Nordisk Inc., Clayton, NC) was injected in a dose of 10 IU/kg ip without prior fasting. The target blood glucose concentration was 20–40 mg/dl, a value considered moderate hypoglycemia, as it is not associated with coma or seizures in rats of comparable age [9,30]. This severity and frequency of hypoglycemia is associated with cognitive and behavioral deficits in human infants and adults [31–33].…”

“…Littermates in the Control group were injected with an equivalent volume of 0.9% saline (Control group). Food was withheld (water available) in both groups and the ambient temperature was maintained at 34.0±1.0°C [30]. Blood glucose concentration was determined in tail vein samples every 15 min.…”