Investigating the effect of diet-induced prediabetes on the HPA-axis, sympathetic nervous system and endogenous opioids in male Sprague-Dawley rats

Abstract

Prediabetes is associated with metabolic dysfunction that may disrupt neuroendocrine regulation before the onset of overt type 2 diabetes mellitus. Although previous studies have independently examined alterations in the hypothalamic–pituitary–adrenal (HPA) axis, sympathetic nervous system (SNS), and endogenous opioid system during prediabetes, the temporal interactions among these systems during disease progression remain poorly understood. This study aimed to investigate changes in these interconnected neuroendocrine pathways in a diet-induced prediabetic rats. Male Sprague-Dawley rats (n = 48) were exposed to a standard diet (non-prediabetic, n =24) or an HFHC diet (prediabetic, n =24) for 20 weeks. Prediabetes was confirmed using FBG, OGTT and HbA 1c . Body weight, FBG, and OGTT were measured at weeks 20 to 32, prior to sacrifice. At each point, animals were sacrificed to assess plasma adrenocorticotropic hormone (ACTH), corticosterone, catecholamines (noradrenaline, adrenaline, and dopamine), and β-endorphin using ELISA. Hippocampal GR, MR, β 1 AR, β 2 -AR, MOR, DOR, and KOR mRNA expression were quantified by qRT-PCR. At week 20, the PD group exhibited marked reductions in circulating ACTH (30.70 ± 2.10 vs. 42.79 ± 2.91 pg/mL), corticosterone (16.89 ± 0.26 vs. 19.94 ± 0.24 pg/mL), noradrenaline (3.46 ± 0.15 vs. 4.36 ± 0.14 ng/mL), dopamine (1224.61 ± 24.83 vs. 1664.00 ± 19.43 pg/mL), and β-endorphin (376.72 ± 18.04 vs. 529.35 ± 9.70 ng/ml) compared with NPD group. These changes were accompanied by significant expressions of glucocorticoid and opioid receptors. By week 24, CORT, dopamine, and β-endorphin concentrations increased in the PD group compared with the NPD group, receptor transcripts were significantly downregulated, except for MOR, which was upregulated. At week 28, receptor expression remained downregulated. By week 32, plasma hormones and hippocampal receptor mRNA expression increased in the PD group. KOR was strongly inversely associated with β-endorphin in the NPD group at week 32. Diet-induced prediabetes is associated with progressive changes in hormones and hippocampal receptors of the HPA axis, SNS, and endogenous opioid system that become more pronounced with disease progression. Functional studies are required to determine whether these transcriptional and hormonal alterations translate into impaired neuroendocrine feedback regulation and are similar in other brain areas.