Type 2 diabetes mellitus (T2DM) is a disease caused by a complex interplay of genetic, epigenetic, and environmental factors and is characterized by insulin resistance and insufficient insulin secretion. Research has shown that T2DM clusters in families, and specific causative genes and susceptibility genes associated with the disease have been identified (1). The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is an important intracellular signaling pathway discovered in recent years. Numerous studies have shown that there is dysregulation of the JAK/STAT signaling pathway in T2DM and autoimmune diseases. The combination of T2DM with autoimmune diseases is rarely reported, particularly in the case of T2DM in an immediate family member with multiple autoimmune diseases. These cases suggest that genetic factors may regulate the co-occurrence of T2DM and autoimmune diseases. Detection of the JAK/STAT signaling pathway genes is a direction worthy of further research.

The final diagnoses of case 1 were T2DM, HT, and connective tissue disease (SSc and antiphospholipid syndrome). The final diagnoses of case 2 were T2DM, HT, and autoimmune liver disease (PBC). Although both patients had preserved β-cell function and negative diabetes-associated autoantibodies, they do not meet the diagnostic criteria for latent autoimmune diabetes in adults (LADA) (2). It is necessary to be vigilant of the possibility of LADA. Therefore, ruling out LADA requires longitudinal monitoring. During follow-up, long-term monitoring of C-peptide and diabetes-associated autoantibodies in these patients is required.

The conditions of the two patients in this report might be related to the JAK/STAT signaling pathway. This pathway has three main components: cytokine receptors, Janus kinases (JAKs), and signal transducers and activators of transcription (STATs) (3). JAKs are non-receptor tyrosine kinases composed of four members: JAK1, JAK2, JAK3, and TYK2. Dimerized kinases bind cytokine receptors, phosphorylating the intracellular tyrosine residues to propagate activation signals. Of these, JAK1, JAK2, and TYK2 are ubiquitously expressed, whereas the expression of JAK3 is restricted to the bone marrow and the lymphatic system (4). The human STAT family consists of seven members: STAT1, STAT2, STAT3, STAT4, STAT5a/b, and STAT6 (5).

Gene mutations in the JAK/STAT signaling pathway can drive the release of interferons (IFNs) and other cytokines. These IFNs and other cytokines can further enhance the activation of the JAK/STAT signaling pathway, establishing a pathogenic positive feedback loop that promotes multi-organ damage. IFNs are cytokines that can be classified into three groups: type I (IFN-α, IFN-β, IFN-δ, IFN-ϵ, IFN-κ, IFN-τ, IFN-ω, and IFN-ζ), type II (IFN-λ), and type III ( IFN-λ) (6). After transcriptional activation and mRNA translation, type I IFNs (IFN-I) are secreted by immune cells to adjacent cells and bind to two receptor subunits: IFN-α receptor 1 (IFNAR1) and IFNAR2. These two receptors are respectively associated with TYK2 and JAK1 (7). The dimerization of the receptor initiates the autophosphorylation of JAK1. JAK1 subsequently phosphorylates and activates the STAT1 and STAT2 proteins. These proteins form a complex with interferon regulatory factor 9 (IRF9), eventually forming a well-characterized complex, IFN-stimulated gene factor 3 (ISGF3). ISGF3 translocates into the nucleus and binds to the IFN-stimulated response elements (ISREs) in the promoters of genes, thereby promoting the transcription of IFN-stimulated genes (ISGs) (8). JAKs also mediate the signaling pathways of various other cytokines, including interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15, and IL-21 (9).

Numerous studies have shown that mutations in the STAT-related genes can lead to the occurrence of autoimmune diseases. For instance, gain-of-function (GOF) mutations in STAT1 amplify IFN-α/β signaling, predisposing to disorders ranging from autoimmune thyroiditis to systemic lupus erythematosus (10, 11). In thyroiditis, infiltrating pro-inflammatory cytokines (e.g., TNF-α and IFN-γ) induce inflammasome activation and thyrocyte apoptosis (12). Similarly, the STAT3 P471R variant hyperactivates the T helper 17 (Th17) pathway, increasing IL-17 production and triggering autoimmunity (13). Conversely, STAT5B deficiency impairs regulatory T-cell function, facilitating multi-organ autoimmune manifestations such as eczema, juvenile idiopathic arthritis, and immune thrombocytopenia (14). A meta-analysis further implicates the STAT4 rs7574865 T-allele in the increased risk of SSc and antiphospholipid syndrome (15).

The onset of SSc is associated with the abnormal increase of cytokines. An elevated IL-4 is a key mediator. It synergizes with IL-13 and transforming growth factor beta (TGF-β) to amplify the inflammatory and pro-fibrotic responses, facilitating the pathogenic T cell-fibroblast crosstalk (16, 17). Phosphorylated STAT1/3 levels increase in peripheral blood T cells and monocytes, and cells with STAT3 phosphorylation are also found in skin sections of patients with SSc (18). Such IL-4-driven signaling promotes fibrosis via JAK/STAT transcriptional programs. The level of IFN-I are also associated with severe cutaneous, pulmonary, and musculoskeletal involvement in patients with SSc (19). Critically, the anti-IFNAR monoclonal antibody anifrolumab suppresses disease activity (20), confirming the central role of IFN-I in SSc.

IFN-γ plays a central role in the pathogenesis of vitiligo. IFN-γ acts on keratinocytes to induce the secretion of the serum chemokines CXC ligand 9 (CXCL9) and CXCL10. These chemokines recruit the CXC receptor 3 (CXCR3) CD8⁺ T cells. The activated CXCR3 CD8⁺ T cells can induce melanocyte apoptosis and IFN-γ secretion (21).

IFN-I promote liver injury in both metabolic and cholestatic contexts. In fatty liver diseases, they amplify Toll-like receptor 4 signaling in macrophages and recruit CD8⁺ T cells (22, 23). In PBC, portal tract immune cells overexpress IFN-I (24), indicating a common effector mechanism.

The involvement of the JAK/STAT signaling pathway in the pathogenesis of T2DM is increasingly recognized. Genetic variants in JAK2 exemplify this link: the allele/genotype frequencies of rs10974914 and rs10815157 differ significantly between diabetic and control cohorts, with the rs10974914-AA genotype increasing the T2DM risk while the rs10815157-C allele conferring protection (25). Mechanistically, JAK2 overexpression amplifies the insulin promoter activity (26), whereas phosphorylated STAT3 impairs the insulin signaling and glucose uptake in skeletal muscle, driving insulin resistance (27). Complementary evidence implicates STAT4 polymorphisms (e.g., rs7574865) in T2DM susceptibility among Chinese Han populations (28).

These cases underscore that, in clinical diagnosis and treatment, it is important to closely observe the symptoms and signs of patients with familial T2DM and to pay attention to the autoimmune manifestations for early diagnosis and treatment. The association of T2DM and autoimmune diseases with the JAK/STAT signaling pathway has been well studied, and patients with T2DM combined with autoimmune diseases may have specific JAK/STAT variants. The characteristics of these cases suggest a possible genetic predisposition, and genetic testing of these patients could help identify potential genetic risks. Neither patient underwent genetic testing. Future research could investigate the association of specific JAK/STAT variants with T2DM complicated with autoimmune diseases through targeted genetic screening.