Diabetes Impairs Hypothalamo-Pituitary-Adrenal (HPA) Responses to Hypoglycemia, and Insulin Treatment Normalizes HPA but not Epinephrine Responses

Abstract

We recently established that in addition to plasma adrenocorticotrophic hormone (ACTH) and corticosterone, hypothalamic corticotrophin-releasing hormone (CRH) mRNA and hippocampal type 1 glucocorticoid receptor (GR1) mRNA were also upregulated in uncontrolled streptozotocin-induced diabetes. In the current study, control, diabetic, and insulin-treated diabetic rats underwent a hyperinsulinemic-hypoglycemic glucose clamp to evaluate central mechanisms of hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulininduced hypoglycemia. Increases in plasma ACTH, corticosterone, and epinephrine were significantly lower in diabetic rats versus controls. Insulin treatment restored ACTH and corticosterone but not epinephrine responses to hypoglycemia in diabetic rats. Glucagon and norepinephrine responses to hypoglycemia were not affected by diabetes or insulin treatment. In response to hypoglycemia, hypothalamic CRH mRNA and pituitary proopiomelanocortin mRNA expression increased in control and insulin-treated but not in untreated diabetic rats. Arginine vasopressin mRNA was unaltered by hypoglycemia in all groups. Interestingly, hypoglycemia decreased hippocampal GR1 mRNA expression in control and insulintreated diabetic rats but not in diabetic rats. In contrast, type 2 glucocortoid receptor (GR2) mRNA was not altered by hypoglycemia. In conclusion, despite increased basal HPA activity, HPA responses to hypoglycemia were markedly reduced in uncontrolled diabetes. We speculate that the defect in CRH response could be related to the defective GR1 response. It is intriguing that insulin treatment restored the HPA response to hypoglycemia but, surprisingly, not the deficient epinephrine response. This is important because during severe hypoglycemia, epinephrine is an important counterregulatory hormone. Diabetes

Voluntary physical activity and leucine correct impairments in muscle protein synthesis in partially pancreatectomised rats

“…3b). This level of basal insulin is similar to other rodent models of type 1 diabetes such as the Akita mouse [8,38] or the streptozotocininduced diabetic rodent [8,39,40]. Considering that these diabetic animals ran considerably less than what is typically observed in healthy animals of the same age/strain (~2.2 vs 9 km per night) [31], these findings provide strong evidence for the anabolic effect of aerobic type exercise on leucine stimulated protein synthesis in the skeletal muscle of diabetic rat models.…”

A new test for autonomic cardiovascular and neuroendocrine responses in diabetes mellitus: evidence for early vagal dysfunction

“…This suggests that the HPA axis response to this challenge remains intact in diabetic subjects and is independent of peripheral autonomic dysfunction. However, it should be noted that subjects in the present study were matched in terms of glycaemic control and all had relatively normal glucose levels at the time of testing, and previous studies have reported that uncontrolled diabetes and acute hyperglycaemia or hypoglycaemia may be associated with altered HPA axis activity [12,23]. Cortisol responses to graded exercise have been shown to be impaired in diabetic subjects with autonomic neuropathy, albeit only at maximum workload [14,24], and it has been suggested that this is due to an impairment in sympathetic afferent impulses [24].…”

“…Several studies have therefore examined the integrity of the stress response in people with diabetic autonomic neuropathy. Most of these studies have concentrated on the response to hypoglycaemia, and reduced counter-regulatory hormone responses with impaired sympatho-adrenomedullary (SAM) function are well described [11,12]. Responses to other challenges are more variable [2,13,14].…”

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

“…Patients and animals with poorly controlled or uncontrolled diabetes commonly show diurnal hypersecretion of GCs and altered regulation of the HPA axis, with enhanced responses to stressors (Chan et al 2002a,b, Sharma et al 2014. In type 1 diabetes mellitus (DM1) patients, stressrelated adaptation of the HPA axis is impaired, with weaker adrenal overnight responsiveness to endogenous adrenocorticotropic hormone (ACTH) and lower free cortisol concentrations (Sharma et al 2014).…”