<p>Abundant research indicates that type 2 diabetes mellitus (T2DM) and insulin resistance (IR) have a certain association with autoimmune-related diseases (ARDs). However, the conclusions remain elusive. Therefore, this study aimed to explore whether there are causal associations between T2DM and IR indicator, triglyceride-glucose (TyG) index with ARDs, and evaluate the impact of immune cells. Comprehensive Mendelian randomization (MR) analysis combined with Bayesian colocalization was employed to investigate the relationship between T2DM, TyG index, ARDs, and specific-marker immune cells by extracting summary-level data from various genome-wide association studies (GWASs). Further investigations utilizing single-cell RNA sequencing (scRNA-seq) analysis were performed to explore the potential molecular mechanisms underlying the MR analysis results. Causal associations of T2DM with multiple sclerosis (MS) and rheumatoid arthritis (RA) were detected. Additionally, the TyG index was genetically predicted to be associated with MS. Furthermore, immune cells were found to be related to T2DM and TyG index, of which CD3 on naive CD8 + T cell mediate the effect on the association between TyG index and multiple sclerosis (MS). Additionally, genetic variation of <i>TCF7L2</i> and <i>TNFSF13B</i> were assessed to play a crucial role in the aforementioned associations supported by colocalization analysis. This study identified T2DM and IR related to increased risk of MS and RA. The analysis of relevant immune cells and shared genetic loci provides a novel direction for exploring comorbidity mechanisms.</p>