Breaking the diabetes-depression cycle: Exploring shared mechanisms, neuroinflammation, and emerging interventions for metabolic-mood comorbidities

Table 1 Common immune-inflammatory mechanisms of type 2 diabetes and depression

Mechanism	Manifestation in T2DM	Manifestation in depression	Shared pathways/outcomes
Cytokine dysregulation	Elevated TNF-α, IL-1β, IL-6; activation of NF-κB pathway; reduction in anti-inflammatory cytokines	Depression “cytokine hypothesis”; elevated pro-inflammatory factors; neuroinflammation	Systemic inflammation; HPA axis hyperactivation; neurotransmitter imbalance
TLR4 signaling pathway	Activated by gut-derived LPS; promotes β-cell damage; exacerbates insulin resistance	Hippocampal TLR4 overexpression; aggravates depressive behavior; microglial activation	Neuroinflammation; synaptic dysfunction; oxidative stress
AGEs	Produced by chronic hyperglycemia; binding to RAGE receptors; promotes vascular damage	Acts as danger signals in the brain; exacerbates neuroinflammation; induces “diabetic encephalopathy”	Blood-brain barrier disruption; amplification of inflammation; endothelial dysfunction
Comorbidity burden	Multiple complications (CIRS assessment); chronic inflammatory load; multi-organ impact	Independently increases depression severity; chronic inflammatory state; treatment resistance	Cumulative inflammatory burden; systemic effects; dysregulation of multiple systems

T2DM: Type 2 diabetes mellitus; TNF-α: Tumor necrosis factor-alpha; IL: Interleukin; NF-κB: Nuclear factor kappa B; HPA: Hypothalamic-pituitary-adrenal; LPS: Lipopolysaccharide; TLR4: Toll-like receptor 4; RAGE: Receptor for advanced glycation end products; CIRS: Cumulative Illness Rating Scale.