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

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.