Dimorphism In The Association Between Diabetes And Depression: Unraveling Novel Biological Perspectives

Abstract

Background: Diabetes and depression are two disorders that are among the leading non-communicable diseases currently on the horizon worldwide. Recent epidemiological studies highlight the rising occurrence of depression among diabetic patients; however, this phenomenon has not been well understood. While both disorders have distinct pathological entities, they are multifactorial with shared genetic, biological, and environmental features that are to be elucidated. In this work, we aim to comprehend how the underlying mechanistic alterations driving diabetes exacerbate the severity of depression in male and female type 2 diabetic mice (T2DM). Aim: This study aims to investigate the mechanistic bidirectionality of both comorbidities in animals exhibiting a depressive, diabetic, and diabetic-depressive phenotype. We further assess whether the observed trends are reflected in a sexually dimorphic manner. Methods: Five groups of male and female mice were used throughout the work: Controls, Diabetic, Depressed, Diabetic-depressed, and Depressed-diabetic. The animal model for depression was induced in this study via the Chronic Mild Stress procedure in C57-BL6/J and High Fat Diet-induced T2DM mice. Depression was assessed via the Sucrose test, Tail Suspension test, and Forced Swim test. Sensory and motor function in addition to nociception were assessed via a series of behavioral tests: Raised beam walking test, Electronic Von-Frey Test, and Heat Hyperalgesia Test. Western blots were then performed to assess protein expression levels of signaling cascade markers, and neurotrophic factors: BDNF, IRS1, AMPK, and GLP1 in brain tissue lysates (Hippocampi and Prefrontal Frontal Cortices). Results: The results from behavioral testing reflect depressive-like symptoms in depressed animals in both male and female groups. However, the sexual dimorphism of depression was prominent in the female diabetic animals relative to the males. At the molecular levels, neurotrophic factor BDNF levels were significantly decreased in all groups relative to controls. These were further paralleled by alterations in metabolic homeostasis, reflected by reductions in protein expression of metabolic cascade markers AMPK, IRS1 and GLP1 in diabetic animals by contrast to controls. Interestingly, depressed, and diabetic-depressed animals exhibit signaling alterations that mimic the diabetic groups. Conclusion: The findings from this work highlight pivotal and shared molecular changes that underlie both depression and diabetes induced brain injury. We underline for the first time the involvement of insulin signaling alterations that may serve as a common ground in the pathogenesis of both comorbidities. We further show that the effects of depression and diabetes may be more pronounced in the nervous system of female subgroups than males.