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Type 2 diabetes mellitus (T2DM) and insomnia represent two of the most prevalent and interacting chronic conditions in global clinical medicine, sharing overlapping pathophysiological substrates involving dysregulated immune activation, impaired circadian rhythm, and systemic metabolic dysfunction. Despite epidemiological evidence documenting the high co-occurrence of insomnia in T2DM populations and converging mechanistic insights implicating shared inflammatory pathways, no prior study has integrated genome-wide genetic profiling, inflammatory immunophenotyping, and pathway-based analysis within a unified framework explicitly designed to characterize the infection susceptibility consequences of this comorbidity. This study fills that gap through a prospective case-control design enrolling 180 T2DM patients with comorbid insomnia, 180 T2DM patients without insomnia, and 120 healthy controls, recruited from three tertiary care centers. Peripheral blood samples were subjected to genome-wide SNP genotyping (Illumina MEGA array), a 40-analyte multiplex cytokine and chemokine panel, flow cytometric immunophenotyping of 12 peripheral blood mononuclear cell subsets, and polysomnographic sleep architecture assessment. Pathway-based analysis integrating Gene Ontology, KEGG, and STRING protein interaction networks identified 10 significantly enriched pathways, with the NF-kB signaling, NLRP3 inflammasome, and toll-like receptor pathways showing the strongest co-activation in the T2DM-insomnia group. The infection-free survival analysis demonstrated that T2DM-insomnia patients had a 52-week cumulative infection incidence 3.8-fold higher than healthy controls and 2.1-fold higher than T2DM-only patients. Mediation analysis identified IL-6, TNF-alpha, NF-kB pathway activation, and regulatory T-cell depletion as significant mediators of the insomnia-to-infection susceptibility pathway, collectively accounting for 64 % of the total indirect effect. Logistic regression models adjusted for age, sex, BMI, medication use, and glycaemic control documented significantly elevated odds of urinary tract infection, respiratory infection, skin and soft tissue infection, and sepsis in T2DM-insomnia patients compared with T2DM-only patients. These findings establish a convergent genetic-inflammatory signature unique to T2DM-insomnia comorbidity that mechanistically underlies heightened infection susceptibility and worse clinical outcomes.