European Journal of Cardiovascular Medicine

Diabetes mellitus (DM) is epidemic in India and showing sharp increase. It was reported that in 2021, 72 million people are living with DM. This is further projected to increase 125 million by the year 2045. 1 This increasing burden imposes a substantial economic impact on patients, healthcare systems, and society. DM patients have twice the risk of mortality as compared with non-DM patients, due to micro-and macro vascular complications of diabetes. Micro-vascular complications include retinopathy, nephropathy, and neuropathy and Macro-vascular complications such as cardiovascular disease, cerebro-vascular disease, and stroke. 2

Systemic inflammation and immune response plays significant role in pathophysiology and progression of diabetes including vascular complications. Especially, chronic low-grade inflammation contributes to dysfunction of body organs and damage to tissues, which can promote insulin resistance and its impaired insulin secretion. 3,4 Studies have reported many inflammatory markers associated with T2DM including interleukin [(IL1), IL-6, IL-18], TGF-β1, and TNF-α. Despite of their established role in inflammation, these markers are not done routinely and are costly. 5,6

Recently, systemic immune-inflammatory index (SII) and systemic inflammatory response index (SIRI) are proposed as novel inflammatory markers in various disease conditions. SII and SIRI are derived from complete blood count (CBC) values. The SII = platelet count × neutrophil count/lymphocyte count, while SIRI = monocyte count × neutrophil count/ lymphocyte count. SII and SIRI indices sensitivity to the inflammatory status across a diverse range of diseases.7 A few studies have documented role of SII and SIRI in diabetic complications, coronary artery disease (CAD) and malignancies. 7-10

A study conducted by Yan P et al., in 2024 reported that increased SII is independently associated with an increased risk of and severity of diabetic kidney disease (DKD), and suggested that SII might be useful as a promising biomarker for DKD and its distinct phenotypes among Chinese population. 11 In a study conducted by Wang S et al, in 2023 reported that SII and SIRI are independent risk factors for diabetic retinopathy (DR) and also indicated that also serve as biological indicators for DR diagnosis. 12

A study conducted by Lin et al., in 2023 reported that elevated SIRI has been independently associated with the risk of diabetic CVDs. 13 In 2023 a study conducted by Zhao S et al., reported that increased SIRI level is associated with increased all-cause and CVD mortality among hypertensive patients and suggested that SIRI is considered as a potential biomarker of inflammation in the clinical practice. 14 In addition to SII and SIRI, NLR and PLR are also considered as markers of inflammation in various disease conditions. 15,16

However, despite their established roles inflammatory markers, there is limited studies were on SII and SIRI in T2DM patients, especially in Karnataka. Therefore, this study aimed to assess the Systemic Immune Inflammation index (SII), Systemic Inflammation Response Index (SIRI) in T2DM patients.

A cross-sectional study design was conducted at Department of Biochemistry and Department of General Medicine, Akash Institute of Medical Sciences and Research Centre, Devanahalli, Bengaluru, Karnataka, India. After obtaining the Institutional Ethics Committee approval and informed consent from all the study subjects, a total 200 subjects were recruited into the study. Among them, 100 were type 2 diabetes mellitus patients and 100 were non-diabetic subjects (healthy individuals). The sample size was calculated by using the formula: (Z_1-α/2)² (SD)²/d². ¹⁷

Inclusion Criteria:

Subjects willing to participate in the study, age ≥18 years, both male and females were included in the study.

Exclusion criteria:

Patients refused to participate in the study, patients with autoimmune diseases, immunosuppressive therapy, anti-inflammatory drugs, infections, diabetic complications, diabetes other than type 2, thyroid diseases, gestational diabetics, hypertensive encephalopathy, malignancy conditions and pregnant women were excluded from the study.

Sample collection:

Under aseptic conditions, fasting venous blood samples 5 ml and post-prandial sample 2 ml were collected from study subjects, visiting to General Medicine Department. The collected blood samples were allowed to stand for 1 hour and centrifuged at 3000 rpm for 10 minutes to obtain serum sample. The serum sample was used for the estimation of fasting and post-prandial glucose by (GOD-POD method), urea (urease), creatinine (Jaffe’s) by using commercially available auto analyzer kits. EDTA samples were used for complete blood count (CBC) analysis. SII, SIRI, NLR and PLR were calculated from CBC values by using the following formulas.

SII: Platelet x Neutrophil to lymphocyte ratio

SIRI: Monocyte x Neutrophil to lymphocyte ratio

NLR: Neutrophil to lymphocyte ratio

PLR: Platelet to lymphocyte ratio

Blood pressure and BMI will be recorded, in addition to family history and lifestyle parameters.

Statistical Analysis

The results were expressed in mean and standard deviation. Categorical variables were expressed in percentages. Mann-Whitney U test was used for continuous non-normally distributed variables. P value <0.05 was considered as significant. Data analysis was performed by using SPSS software, version 22.0.

In this study, out of 100 T2DM subjects, 58 were males and 42 were females. In non-diabetic subjects, 55 were males and 45 were females. In this study, mean age (55.1±11.5 years) and BMI (26.5±3.1 kg/m²) was significantly high in T2DM cases than non-diabetics. Significant increase in systolic blood pressure (SBP) (120.1±7.3 mmHg), diastolic blood pressure (DBP) (80.1±2.6 mmHg), fasting blood sugar (FBS) (155.2±50.2 mg/dl), post-prandial blood sugar (PPBS) (248.2±80.2 mg/dl), urea (30.6±6.2 mg/dl), creatinine (1.2±0.1 mg/dl) and neutrophil count (68.6±10.9 %) was observed in T2DM cases compared with non-diabetic subjects. Significant decrease in lymphocytes (25.1±9.7 %) observed in T2DM. The inflammatory markers such as SII (14.9±4.5), SIRI (27.5±6.1), NLR (5.1±1.5) and PLR (0.21±0.02) were significantly increased in T2DM cases as shown in table 1.

Table: 1 Comparison of demographic details, biochemical, and haematological parameters in T2DM patients and non-diabetic subjects

Diabetes mellitus, a complex, multi-factorial and group of common endocrine diseases associated with insulin resistance (IR), oxidative stress and inflammation. Chronic inflammation contributes significantly to the initiation and progression of T2DM and its associated micro and macro-vascular complications. Exaggerated inflammation and increased immune response can lead to up-regulation of pro-inflammatory cytokines and chemokines, like interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF), which can cause endothelial dysfunction and leukocyte infiltration. ¹⁸

This study observed that significant elevation of inflammatory markers such as SII, SIRI, NLR and PLR in T2DM subjects compared to non-diabetic controls. SII and SIRI are proposed as CBC derived markers of inflammation. A few studies have indicated the association of SII and SIRI with diabetic complications. ^{7, 8}

The association between SII, SIRI and diabetic vascular complications are unsurprising given some of the mechanisms underlying the development of diabetes and its complications. Inflammation and immune response play a significant role in pathophysiology and progression of diabetes. Especially, chronic low-grade inflammation contributes to organ dysfunction and tissue damage, which can promote insulin resistance and impaired insulin secretion. ^3,19

Immune cells, including monocytes, are considered as key players in inflammatory processes. When stimulated by hyperglycemia and advanced glycation end products (AGEs) and secrete Monocyte chemoattractant protein-1 (MCP-1) and colony-stimulating factor-1 (CSF-1). MCP-1 stimulates bone marrow to release monocytes into blood, leading to an increase in the number of peripheral blood monocytes. ²⁰

Neutrophils are important components of innate immune system. When activated, they release the anti-apoptotic proteins A1 and Bcl-xL, which delay neutrophil apoptosis and increase circulating neutrophil levels. Additionally, they produce reactive oxygen species (ROS), cytotoxic proteases, and inflammatory cytokines, causing endothelial dysfunction and inflammation. ^21-22

Activation of monocyte-macrophages is an important sign of chronic inflammation. These activated cells secrete various inflammatory factors such as IL-1, IL-6, TNF-α, and MCP-1, which inhibit the insulin signal transduction pathway, activate intracellular signals promoting insulin resistance and T2DM, and contribute to the occurrence and progression of T2DM. ^23,24

Platelets play an important role in hemostasis and thrombosis. Bioactive mediators expressed by activated platelets can induce platelet binding to other leukocyte subsets and up-regulate leukocyte pro-inflammatory function.  ²⁵

Research studies have revealed that SII and SIRI encompass platelets and various inflammatory cells found within while blood cells (WBCs). When compared to individual WBCs and platelets, these indices are less influenced by the body’s physiological and pathological states, enabling them to provide a more stable reflection of the body’s overall inflammatory condition. ^{9, 26}

Research studies have demonstrated an association between SII, SIRI and diabetes. ^{7, 8} Our study findings are in accordance with the studies conducted by Liu W. et al., Yang C et al. ^{27, 28} In addition, Elbeyli A et al., reported that increased SII was strongly associated with the development of diabetic macularedema. ²⁹

A recent study by Alhalwani AY et al., reported that increased SII levels were associated with increased HbA1c in T2DM- dry eye disease (DED) patients. ³⁰ Another study conducted by Tabakoglu NT et al, reported that elevated SII values predict early and late acute - chronic renal failure, peripheral arterial disease (PAD), and hospitalizations in T2DM patients with retinopathy and suggested that increased SII levels may predict vascular complications of T2DM. ³¹

This study results may concludes that increased levels of SII, SIRI, NLR and PLR in T2DM may indicate systemic inflammation and may be associated with pathogenesis of the T2DM. These markers are easily calculated from CBC values and are less expensive. Further studies with large sample size are recommended.

Acknowledgment

We would like to thank Ms Manjula, Statistician, Department of Community Medicine and the authorities of Akash Institute of Medical Sciences and Research Centre, Devanahalli, Bengaluru, Karnataka, India.  

Conflict of interest: Nil

Funding: Nil.

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