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

Table 3 Metabolic pathway abnormalities in type 2 diabetes mellitus and their impact on mental health

Metabolic pathway	Abnormalities in T2DM	Neuropsychiatric effects	Biomarkers/evidence
Insulin signaling	Peripheral and central insulin resistance; insulin receptor dysfunction; PI3K/Akt signaling alterations	Decreased serotonin transporter function; reduced dopaminergic activity; impaired reward processing; cognitive decline	Insulin resistance associated with depression; impaired insulin signaling in CNS; mendelian randomization studies
Adipokine regulation	Decreased adiponectin; leptin resistance; increased pro-inflammatory adipokines	Associated with depression; altered brain appetite regulation; energy metabolism dysregulation	Adipokine levels correlated with depression; cortisol promotes visceral fat accumulation; components of metabolic syndrome
Amino acid metabolism	Increased branched-chain amino acids (leucine); increased aromatic amino acids (tyrosine, tryptophan); BBB transport alterations	Reduced serotonin synthesis; competition for neurotransmitter precursors; altered BDNF levels	Changes in amino acid profile; competitive transport at blood-brain barrier; metabolomics studies
Gene regulation	Elevated miR-29a-3p; targeting IGF-1 signaling pathway; epigenetic changes	IGF-1 has neurotrophic effects; IGF-1 reduction associated with depression/cognition; neuroplasticity changes	Correlation with metabolic parameters; targeting key pathways; diagnostic potential
Microvascular function	Small vessel disease; endothelial dysfunction; insufficient tissue perfusion	White matter lesions; “vascular depression”; cognitive dysfunction; neuropathic pain	Related to retinopathy/nephropathy; cerebral small vessel disease; complication burden

T2DM: Type 2 diabetes mellitus; CNS: Central nervous system; BBB: Blood-brain barrier; BDNF: Brain-derived neurotrophic factor; IGF-1: Insulin-like growth factor-1; PI3K/Akt: Phosphoinositide 3-kinase/protein kinase B.