Pathophysiology of Immune Dysfunction Caused by Diabetes leading to the Development of Rheumatoid Arthritis and Periodontitis

Diabetes is linked to several comorbidities, including a heightened susceptibility to infections. The current review examined the impact of diabetes mellitus (DM) on the immune system, highlighting how it disrupts immune cell proliferation and induces cellular senescence. The researchers also investigated the similarities between diabetes-related immune dysfunction and "inflammaging," a chronic low-grade inflammation often seen in older adults, which may lead to conditions like rheumatoid arthritis (RA) and periodontitis at younger ages. 

Aging is marked by chronic low-grade inflammation known as "inflammaging," which increases disability and mortality. T2DM contributes to this process, linking it to complications like beta-cell dysfunction and rheumatoid arthritis. 

T2DM is characterized by insulin resistance and high blood sugar, leading to elevated reactive oxygen species (ROS) that promote inflammation. Excess ROS cause oxidative stress and cellular damage, with T2DM patients showing higher inflammatory markers than non-diabetics. This inflammation is driven by transcription factors like AP-1 and NF-kB, leading to pro-inflammatory cytokine production. Studies showed that poor glycemic control in T2DM patients correlates with increased inflammation. 

T2DM-Derived Inflammaging causes Beta-Cell Death

Pancreatic β-cells produce insulin, crucial for glucose regulation, but can be damaged in the context of inflammaging from T2DM. The tumour necrosis factor-α (TNF-α) pathway was found to be a modulator of beta-cell apoptosis in studies conducted on experimental animals with non-obese diabetes (NOD).

To address this, therapies like vitamin D3 and chromium picolinate have shown promise in reducing TNF-α levels, preventing beta-cell damage and improving insulin sensitivity in T2DM patients. Additionally, caspase inhibitors have been found to protect beta-cells from TNF-α induced apoptosis in NOD experimental animal.

T2DM-Derived Inflammaging causes the Development of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that increases in risk among individuals with T2DM. RA can cause major consequences, such as cardiovascular disease, and is typified by joint inflammation, bone degradation, and damage to several organs. Although the precise relationship between T2DM and RA is unknown, there is evidence that T2DM-induced inflammation may contribute to the development of RA.

Research, including a study by Ming-Chi and colleagues, indicated that T2DM patients have a higher risk of developing RA due to chronic inflammation. One potential treatment being explored is anti-interleukin-1 (IL-1) therapy. Moreover, anakinra, an IL-1 receptor antagonist, reduced glycated haemoglobin (HbA1c%) in individuals with both T2DM and RA, according to a study by Piero and colleagues. This is significant because a 1% drop in HbA1c% can reduce the risk of cardiovascular disease in RA patients by 15%.

T2DM-Derived Inflammaging causes the Development of Periodontitis

Periodontitis is a serious gum disease that worsens with age and can destroy the bone supporting teeth. T2DM is a known risk factor, with patients sometimes developing gingivitis even without plaque. The severity of hyperglycemia impacts gum health.

According to recent research, inflammation links hyperglycemia in T2DM to a higher risk of developing periodontitis. Studies on diabetic experimental animal demonstrated inflammatory bone loss linked to GLUT-1-driven macrophage inflammaging, with older experimental animal showing more severe damage. In addition to glycaemic control, metformin treatment has been demonstrated to reduce markers of periodontal damage, suggesting possible advantages against inflammation.

Source: Alexander M, Cho E, Gliozheni E, Salem Y, Cheung J, Ichii H. Pathology of Diabetes-Induced Immune Dysfunction. Int J Mol Sci. 2024 Jun 28;25(13):7105. doi: 10.3390/ijms25137105. PMID: 39000211; PMCID: PMC11241249.