A review on linking stress, depression, and insulin resistance via low-grade chronic inflammation

Abstract

Stress is a disturbance in homeostasis caused by psychological, physiological, or environmental factors. Prolonged reactions to chronic stress can be detrimental, resulting in various metabolic abnormalities, referred to as metabolic syndrome (MS). There is a reciprocal increased risk between MS and major depressive disorder. Recent studies established an association between inflammation and insulin signaling in type 2 diabetes mellitus with depression. In the present review, we discuss chronic low-grade inflammation, pathways of insulin resistance, and brain glucose metabolism in the context of neuroinflammation and depression. Specific attention is given to psychotropic drugs such as bupropion, mirtazapine, and nefazodone, anti-inflammatory drugs like Celecoxib (COX-2 inhibitor), Etanercept, adalimumab, IL-4Ra antagonist, Anti-IL- 17A antibody (Ixekizumab) and lifestyle modifications including exercise, dietary changes, and sleep hygiene. These therapeutic solutions offer potential in treating depression by targeting metabolic conditions like insulin resistance and inflammatory pathways. The article further explains the significance of a nutrition and antioxidants-rich diet, emphasizing the role of omega-3 fatty acids, vitamin D, zinc, and polyphenols, to improve immunity and activate anti-inflammatory signaling pathways.

Keywords: Chronic stress; Insulin resistance; Low-grade chronic inflammation; Major depressive disorder; Metabolic syndrome; Neurodegeneration; Pharmacological intervention.

Fig. 1

The underlying mechanism of depression. Brain insulin resistance develops due to the failure of brain cells to respond to insulin activity. The hippocampus, hypothalamus, and cortex regions of the central nervous system regulate insulin levels in the brain. The factors that relate to brain insulin resistance and severe depression include the HPA stress axis, reduced volume of the Anterior Cingulate Cortex (ACC), hippocampal gray matter, and the brain's reward system-Created with BioRender.com.

Fig. 2

Obesity, diabetes, and metabolic syndrome are metabolic diseases that coexist with depression-Created with BioRender.com.

Fig. 3

A schematic representation of various factors leading to metabolic syndrome and depression and their subsequent impact-Created with BioRender.com. CVD: Cardiovascular Disorder; HPA: Hippocampal Pituitary Axis; MS: Metabolic Syndrome; HR: Heart Rate; HRV: Heart Rate Variability; PUFA: Polyunsaturated Fatty acids.

Fig. 4

The tryptophan-kynurenine pathway and how depression affects the HPA axis and inflammation. The main source of nicotinamide adenine dinucleotide (NAD+), a vital co-factor for Kreb's cycle that supports metabolic function, is shown in this diagram. Reproduced with permission from Ref. [62] which was published under the Creative Commons CC BY license.

Fig. 5

Treatment option for major depressive disorders-Created with BioRender.com.

Fig. 6

A schematic representation of the factors affecting metabolic syndrome and the corresponding dietary and lifestyle changes for the alleviating the same.