Review of the direct and indirect effects of hyperglycemia on the HPA axis in T2DM and the co-occurrence of depression

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia which is further associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Several studies have shown that HPA axis hyperactivity is heightened in the chronic hyperglycemic state with severe hyperglycemic events more likely to result in a depressive disorder. The HPA axis is also regulated by the immune system. Upon stress, under homeostatic conditions, the immune system is activated via the sympatho-adrenal-medullary axis resulting in an immune response which secretes proinflammatory cytokines. These cytokines aid in the activation of the HPA axis during stress. However, in T2DM, where there is persistent hyperglycemia, the immune system is dysregulated resulting in the elevated concentrations of these cytokines. The HPA axis, already activated by the hyperglycemia, is further activated by the cytokines which all contribute to a diagnosis of depression in patients with T2DM. However, the onset of T2DM is often preceded by pre-diabetes, a reversible state of moderate hyperglycemia and insulin resistance. Complications often seen in T2DM have been reported to begin in the pre-diabetic state. While the current management strategies have been shown to ameliorate the moderate hyperglycemic state and decrease the risk of developing T2DM, research is necessary for clinical studies to profile these direct effects of moderate hyperglycemia in pre-diabetes on the HPA axis and the indirect effects moderate hyperglycemia may have on the HPA axis by investigating the components of the immune system that play a role in regulating this pathway.

Keywords: Depression; Glucocorticoids; Hyperglycemia; Prediabetic State.

Figure 1

A diagram depicting how the hypothalamic-pituitary-adrenal (HPA) axis and immune response interact during stress: stress activates the HPA resulting in the end product, glucocorticoids (GC). Simultaneously, the sympatho-adrenal-medullary (SAM) axis is activated by stress resulting in the release of norepinephrine (NE). NE activates the innate immune cells, which release cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). The cytokines activate all three levels of the HPA, resulting in further secretion of GCs. The increase in plasma GCs causes negative feedback regulation of the HPA axis and negative feedback of NE secretion and inhibits further activation of immune cells, decreasing cytokine production and secretion. ACTH, adrenocorticotropic hormone; CRH, corticotrophin-releasing hormone.

Figure 2

A diagram depicting the direct and indirect effects of hyperglycemia in type 2 diabetes mellitus (T2DM) on the hypothalamic-pituitary-adrenal (HPA) axis: hyperglycemia in T2DM dysregulates the HPA axis, which activates the sympatho-adrenal-medullary (SAM) axis resulting in an immune response. Hyperglycemia also dysregulates the immune system, which activates an immune response. Activation from the SAM axis and the dysregulated immune system cause an increase in immune cells secreting cytokines, especially interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-alpha (TNF-α). Increased levels of these cytokines contribute to the dysregulation of the HPA axis, which results in increased glucocorticoids. The elevated glucocorticoids and cytokines exacerbate the hyperglycemic state in T2DM by further causing insulin resistance, hyperinsulinemia, and hyperglycemia. All these further contribute to depressive symptoms such as anhedonia, altered sleep pattern and reduced appetite.