Comparative evaluation of salivary and serum Interleukin-38 levels in periodontitis subjects with and without type 2 diabetes mellitus following non-surgical periodontal therapy

IL-38 is a member of the IL-1 superfamily. It is an anti-inflammatory cytokine

with protective role.It is involved in the pathogenesis of several diseases including

cardiovascular diseases, cerebrovascular disease, pulmonary disease, infectious

diseases , autoimmune diseases, Diabetes mellitus etc. It was first identified in

2001 from organs associated with immune response and has a molecular weight of

17kDa.The gene is located in the chromosome 2q13-14.1 clustered with the IL-1

family. The interleukin was previously referred to as IL-1F10 and IL-1HY2 and is

secreted by epithelial cells, monocytes, macrophages and immune cells. It lacks a

signal peptide hence secreted from the cells by different unknown mechanisms.

IL‐1R1, IL‐36R, and IL‐1RAPL1 are the main receptors of IL‐38. The

structure has 37% similarity to IL-1Ra and 41% similarity to IL-36Ra, by binding

to IL-1R1 and IL-36R it inhibits NF-KB, ERK, JNK, P38.It exists in 2 forms , the

full (aa 1-152) and the truncated form (aa 20-152). Proteases that are currently

unknown cleave the pre-cursor form at the N terminal end allowing activation.

Despite its largely anti-inflammatory role Pan et al, Mora et al, and Van de

Veerdonk et al have reported that IL-38, upregulated IL-6 and IL-22 levels

depending on the concentration, form (full length or truncated form), and the

presence of external stimuli. However, information available on this particular

biomolecule is minimal, preliminary, not definitive, necessitating further research

to fully understand its characteristics.

In pulmonary diseases, IL-38 has anti-inflammatory and anti-fibrotic effect.

Likewise, it reduces neuroinflammation in neurodegenerative illnesses like

Alzheimer's. In 2023, Wei et al. showed that IL-38 suppressed macrophage-

mediated inflammation and decreased myocardial apoptosis by blocking the

activation of the NLRP3 inflammasome. In an attempt to combat obesity and

insulin resistance, it also suppresses preadipocyte differentiation by upregulating

GATA-3 expression, lowers triglyceride synthesis, and reduces adipocyte size.

Furthermore, it lowers the levels of Total Cholesterol, Triglycerides, and Low-

density lipoproteins as well as the production of IL-1β, IL-6, and Monocyte

chemotactic protein-1, which enhances lipid and glucose metabolism and lowers

the risk of cardiovascular diseases. According to de Graaf et al., overweight

people with a high risk of CVDs had considerably lower serum IL-38 levels than

healthy people. The above literature indicates the protective role of IL-38 in

cardiovascular system.

Huard et al,2023, Lauritano et al, 2023, reported that IL-38 plays an important

role in the pathogenesis of autoimmune diseases by inactivating immune cells and

inflammatory responses. It further, inhibits the release of inflammatory cytokines

and chemotaxis. Additionally, it promotes the activity of regulatory T cells to

suppress autoimmune responses. IL-38 also regulates the release of cytokines

secreted by Th1 and Th17 cells. Further, Yan Li et al in their study demonstrated

that IL-38 reduced the levels of GATA3, GLUT4, inflammatory cytokines like

IL-1b, IL-6, MCP-1, reduced the number of lipid droplets indicating its protective

role in inhibiting adipogenesis. Therefore, it can be inferred that IL-38 has a

predominantly anti-inflammatory role in the pathogenesis of multiple diseases.

The role of IL-38 in the pathogenesis of type 2 diabetes mellitus has been

investigated and discussed by few authors. Felicia Gurau et al, 2021 observed

considerably higher plasma concentrations of IL-38 in T2DM with and without

diabetic nephropathy patients. Likewise , shahad Nassurat et al in 2024, reported

upregulated serum levels of IL-38 in T2DM with and without diabetic neuropathy.

Similar trend in the IL-38 levels have been reported in gestational diabetes

mellitus and in children with T2DM. On the contrary, Tingqi Zhao et al, 2022,

observed reduced serum levels of IL-38 and negative correlation with IL-17 in

T2DM.The author suggested that IL-38 could be a marker for diagnosis of T2DM.

Furthermore, it has been suggested that IL-38 increases insulin sensitivity in

T2DM. However, the precise role and the pathways associated with this

biomolecule is unclear and needs to be explored in future studies.

Diabetes and Periodontitis share similar pathophysiology and diabetes is a risk

factor for periodontitis. The role of IL-38 in periodontitis has been investigated

only in two studies by Korkmaz et al, 2023 and Toraman & colleagues in 2024.

The former in their study demonstrated higher levels of salivary and serum IL-38

in the periodontitis group when compared with healthy and gingivitis group.

Salivary levels of IL-38 were higher in stage III, grade B and stage III, grade C

subjects when compared to periodontal health and gingivitis. Similarly, serum IL-

38 levels were higher in periodontitis group when compared to periodontal health

and gingivitis. Based on their results the authors concluded that IL-38 could be

used as a marker to identify periodontal disease activity. On the contrary,

Toraman & colleagues demonstrated reduced salivary levels of IL-38 in

periodontitis group when compared to periodontal health and gingivitis. The role

of IL-38 in periodontitis needs further clarity and the role of IL-38 in T2DM

associated periodontitis has never been studied till date and needs to be

investigated. Further the effect of non-surgical periodontal therapy (NSPT) on the

levels of IL-38 has never been studied. Hence, this study was carried out. We

hypothesis that the salivary and serum levels of IL-38 will be dysregulated in

T2DM associated periodontitis when compared with periodontal health. Further

treatment intervention by NSPT will alter IL-38 levels favorably towards

periodontal health.

The present study aims to evaluate the role of IL-38 in the pathogenesis of Type 2

Diabetes mellitus (T2DM) associated periodontitis, as well as to detect the

influence of NSPT on the serum and saliva levels of IL-38 to evaluate its utility as

a biomarker for T2DM associated periodontitis.