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.

Table 2 Role of the gut-brain axis in type 2 diabetes mellitus and depression comorbidity

Component	Changes in T2DM	Impact on mental health	Potential intervention measures
Gut microbiota composition	Dysbiosis (microbial imbalance); reduction in beneficial bacteria; increase in pathogenic bacteria	Changes in neurotransmitter production; immune activation; vagus nerve signal dysregulation	Probiotics; prebiotics; dietary fiber
Intestinal barrier	“Leaky gut” syndrome; increased intestinal permeability; bacterial translocation	LPS-mediated endotoxemia; systemic inflammation; brain TLR4 activation	Intestinal barrier enhancers; anti-inflammatory drugs; restoration of symbiotic state
Bacterial metabolites	Reduction in SCFAs; increase in toxic metabolites; amino acid imbalance	Decreased GABA/serotonin production; neuroinflammation; vagus nerve afferent signaling	Prebiotic fiber; SCFA supplementation; dietary adjustment
Neuroendocrine signaling	HPA axis hyperactivation; elevated cortisol levels; adrenal-gut-brain axis dysregulation	Worsening of depression symptoms; further gut microbiota dysbiosis; malignant inflammatory cycle	Stress reduction measures; mindfulness therapy; HPA regulators
Vagus nerve	Autonomic neuropathy; altered gut-brain communication; gastrointestinal symptom signaling	Anxiety induction; emotional regulation disorder; altered stress response	Vagus nerve stimulation; management of gastrointestinal symptoms; autonomic nervous system regulation

T2DM: Type 2 diabetes mellitus; LPS: Lipopolysaccharide; TLR4: Toll-like receptor 4; SCFAs: Short-chain fatty acids; GABA: Gamma-aminobutyric acid; HPA: Hypothalamic-pituitary-adrenal.

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.

Table 4 Treatment strategies for type 2 diabetes-depression comorbidity

Treatment category	Specific interventions	Mechanism of action	Evidence/considerations
Anti-inflammatory treatment	NLRP3 inflammasome inhibitors; TNF-α inhibitors (pentoxifylline); low-dose aspirin; minocycline	Reduces IL-1β and IL-18 levels; improves insulin resistance; reduces neuroinflammation	Early research phase; potential dual benefits; targets common mechanisms
Microbiome intervention	Probiotics (e.g., Lactobacillus, Bifidobacterium); prebiotics (e.g., inulin, FOS), dietary fiber; FMT	Restores microbial balance; enhances gut barrier integrity; reduces endotoxemia; modulates gut-brain neurotransmission (GABA, serotonin); regulates vagal nerve signaling	Clinical trials show improvements in glycemic control, inflammation, and depression scores in T2DM patients; FMT is a promising intervention under investigation; safety and long-term psychiatric efficacy remain to be confirmed
Microbiome intervention	Probiotics; prebiotics/dietary fiber; fecal microbiota transplantation	Restores microbial balance; strengthens intestinal barrier; reduces endotoxemia; increases SCFA production	Clinical trials show improvements in glycemic control and depression scores; low side effects; dietary integration
HPA axis regulation	Mindfulness-based stress reduction; cognitive behavioral therapy; mifepristone (glucocorticoid antagonist); agomelatine (melatonin receptor agonist)	Reduces perceived stress; lowers cortisol levels; regulates circadian rhythm; improves sleep	MBSR/CBT simultaneously improves diabetes management and depression; multi-target effects of agomelatine; HPA-targeted therapy for refractory cases
Metabolic treatment	Metformin; GLP-1 receptor agonists (liraglutide, semaglutide); SGLT2 inhibitors (empagliflozin)	Anti-inflammatory effects; promotes neurogenesis; penetrates blood-brain barrier; improves vascular function; neuroprotection	Metformin shows antidepressant effects in non-diabetic populations; GLP-1RAs improve mood/anxiety; SGLT2i reduces anxiety-like behavior; multi-system benefits
Integrated psychosocial interventions	Collaborative care model; diabetes self-management education + psychological support; regular exercise; nutritional guidance	Multidisciplinary approach; increases endorphins and myokines; anti-inflammatory diet; social support	Proven effective for chronic diseases; exercise as insulin sensitizer and antidepressant; omega-3, vitamins (D, folate); focus on “whole-patient” concept

NLRP3: NOD-like receptor pyrin domain-containing 3; TNF-α: Tumor necrosis factor-alpha; IL: Interleukin; FOS: Fructooligosaccharides; FMT: Fecal microbiota transplantation; GABA: Gamma-Aminobutyric Acid; T2DM: Type 2 Diabetes Mellitus; SCFA: Short-chain fatty acids; HPA: Hypothalamic-pituitary-adrenal; MBSR: Mindfulness-based stress reduction; CBT: Cognitive behavioral therapy; GLP-1RAs: Glucagon-like peptide-1 receptor agonists; SGLT2i: Sodium-glucose cotransporter-2 inhibitors.