European Journal of Cardiovascular Medicine

Diabetes mellitus (DM), a chronic endocrine disease characterised by increased blood glucose levels due to abnormalities in insulin secretion, action or insulin resistance (IR). The prevalence of diabetes mellitus is increasing rapidly. According to estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, diabetes was reported to be the eighth leading cause of death and disability in the world. [1]

In India, according to the ICMR–INDIAB Study individuals with diabetes mellitus was 74 million in 2021 and it is now 101 million. The situation got even more alarming when a more recent report from the NCD Risk Factor Collaboration (NCD-RisC) survey reported the number of people with diabetes in India to be 212 million. Increased prevalence of T2DM is mainly due to consumption of unhealthy diets and sedentary lifestyles, resulting in increased body mass index (BMI) and fasting plasma glucose. [3]

In the recent years, there has been a growing recognition of the role of the inflammatory response in the pathophysiology of diabetes and its vascular complications. Recently, systemic immune-inflammation (SII) index and the systemic inflammation response index (SIRI), are considered as a novel biomarkers and are capable of providing a more comprehensive reflection of the inflammatory state and immune response of the body by integrating neutrophils, lymphocytes, monocytes, and platelets. [4]. It has been demonstrated that SII index and SIRI are significantly associated with the prognosis of a range of tumors, cardiovascular diseases, and infectious diseases [5,6].

The SII index, a novel inflammatory biomarker and can help in identify patients at risk of poor outcomes for whom the predictive capability of traditional clinicopathologic signs is inefficient, a higher score is usually indicative of poorer prognoses. Perhaps, because SII index incorporates more features of the inflammatory response, using three individual parameters [7],

Now, SII index is thought to better and more objectively reflect the state of inflammation and immune balance in the body compared with white blood cells and its subtypes (neutrophil and lymphocyte) as well as the neutrophil-to- lymphocyte ratio (NLR) and platelet-to lymphocyte (PLR), and predict the prognosis of certain autoimmune disorders. [8] Recently, growing evidence suggests that SII index may be associated with metabolic disorder and its components, such as central obesity, non-alcoholic fatty liver disease, metabolic syndrome, dyslipidemia, and hypertension, which are components of type 2 diabetes mellitus. [9,10]

In a study conducted by Amani Y. Alhalwani et al., reported that elevated SII index values were linked to elevated HbA1c in type 2 diabetes mellitus (T2DM) ‐ dry eye disease (DED) patients. The potential of SII index and HbA1c as early diagnostic indicators for ocular problems associated with DM is highlighted by their favorable connection in diagnosing T2DM‐DED. [11]

Another study by Yan P et al., reported that higher SII index is independently associated with an increased risk of the presence and severity of Diabetic Kidney Disease (DKD), and SII index may serve as a promising biomarker for DKD. [12]

Similarly, a study by Aljuraiban GS et al., reported that SII was associated with the markers of DM. The utility of SII index for predicting diabetes can be confirmed with prospective cohort studies. [13] A study conducted by Lin et al., in 2023 reported that elevated SIRI has been independently associated with the risk of diabetic cardiovascular diseases (CVDs). [14] A study by Fan Zhang et al., reported that SII index and SIRI can be utilized as biomarkers for forecasting the likelihood of all-cause and cardiovascular mortality in patients with diabetic nephropathy (DN). [15] 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. [16]

However, a very few studies were reported about SII index and SIRI levels in T2DM. Therefore, the present study aimed to associate Systemic Immune Inflammation (SII) index, Systemic Inflammation Response Index (SIRI) with blood sugar and HbA1c in T2DM patients.

A prospective case-control study was conducted in the Department of Biochemistry, Lt Shri BRKM Govt. Medical College, Dimrapal, Jagdalpur, Chattisgarh - 494 001, India. After obtaining the Institutional Ethics Committee, a total of 220 subjects were involved in this study. Among them, 110 T2DM patients as cases and 110 non-diabetic subjects as controls.

Inclusion Criteria:

Subjects willing to participate in the study, male and female subjects with age of ≥18 years, T2DM subjects diagnosed as per ADA criteria.

Exclusion criteria:

Subjects not willing to participate in the study, patients with autoimmune diseases, immunosuppressive therapy, type 1 diabetes, patients with history of renal and liver diseases, thyroid disorders, malignancy conditions, and pregnant women were excluded.

Sample collection:

Under aseptic conditions, fasting blood samples were collected; 3 ml in plain vacutainer and 2 ml in EDTA tubes. 2 ml post-prandial sample were collected from all the study subjects. The blood samples were allowed to stand for 1 hour and centrifuged at 3000 rpm for 10 minutes to obtain serum sample. The obtained 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 and HbA1c. SII index and SIRI were calculated from CBC values by using the following formulas:

• SII index: Platelet x Neutrophil to lymphocyte ratio
• SIR index: Monocyte x Neutrophil to lymphocyte ratio

In addition to this, demographic details such as age, BMI and blood pressure were recorded.

Statistical Analysis:

Results were expressed as Mean±SD. Categorical variables were represented in number and percentages. Mann-Whitney U test was used for continuous non-normally distributed variables. Spearman correlation was applied to correlate SII index and SIRI index with FBS and HbA1c. P value of <0.05 is considered as significant. Data analysis was done by using SPSS software, version 22.0.

In this study, out of 110 T2DM subjects, 65 (59.1%) were males and 45 (40.9%) were females. In non-diabetic subjects, 59 (53.6%) were males and 51 (46.3%) were females. In this study, mean age (57.1±11.5 years) and BMI (27.3±3.2 kg/m²) was significantly high in T2DM cases than non-diabetics. Significant increase in systolic blood pressure (SBP) (120.1±15.4 mmHg), diastolic blood pressure (DBP) (80.6±5.4 mmHg), fasting blood sugar (FBS) (149.6±45.6 mg/dl), post-prandial blood sugar (PPBS) (202.2±51.6 mg/dl), HbA1c (7.9±2.6%), urea (38.1±5.3 mg/dl), creatinine (1.1±0.3 mg/dl) and neutrophil count (71.5±12.3 %) was observed in T2DM cases compared with non-diabetic subjects. Significant decrease in lymphocytes (20.9±11.5 %) observed in T2DM.

Concerned with the inflammatory markers such as SII index (12.3±2.5) and SIRI (25.2±3.5) were significantly increased in T2DM cases as compared to controls (table 1).

Table: 1 Comparison of demographic details, biochemical, haematological parameters and inflammatory markers in T2DM cases and non-diabetic controls

* P < 0.05 significant.

In this study, FBS showed significant positive correlation with SII index (r=0.602) and SIRI (r=0.381). However, HbA1c also showed positive correlation, but not reached statistical significance (Table 2).

Table 2: Correlation of Inflammatory markers with FBS and HbA1c

** Correlation is significant at the 0.01 level (2-tailed)

* Correlation is significant at the 0.05 level (2-tailed).

Diabetes mellitus is a chronic metabolic disease and its prevalence is dramatically increasing. A number of chronic comorbidities and its vascular complications drastically shorten life expectancy. Therefore, reducing diabetic vascular complications and improving patient quality of life can be achieved by having a complete grasp of the underlying causes that influence the development of lesions. [17]

The present study observed that significant elevation of inflammatory markers such as SII index and SIRI in T2DM subjects and were positively correlated with FBS and HbA1c. SII index and SIRI are CBC derived inflammatory markers.  

There is substantial evidence that the chronic low-grade inflammation is also a contributing factor in the pathophysiology and the development of vascular complications of T2DM.   Inflammatory responses can induce insulin resistance (IR), which in turn contributes to the onset and progression of type 2 diabetes vascular complications. [18,19] The association of SII index, 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. The chronic low-grade inflammation contributes to organ dysfunction and tissue damage. [20,21] The insulin resistance is associated with immune system activation and persistent low-grade inflammation, and it is connected to both obesity and T2DM [22].

Various studies have reported increased levels of inflammatory markers such as cytokines, chemokines and circulating acute-phase proteins in patients with type 2 diabetes. Moreover, increased CRP, interleukin-1b (IL-1b) and IL-6 T2DM-predictive values are found. [23-25] However, recent studies have indicated that SII index can predict the prognosis and clinical outcomes of certain inflammatory diseases, various atherosclerotic cardio-cerebrovascular diseases (eg myocardial infarction, heart failure, stroke, peripheral arterial disease), and other diseases and may be associated with metabolic disorder and its components, such as diabetes mellitus, metabolic syndrome, dyslipidemia, central obesity, DR, DKD, diabetic foot infections, that are closely associated with low-grade inflammation. [26,27] 

In accordance with our study findings, few studies reported the similar findings. A study conducted by Marra A et al., reported significantly increased CBC-derived inflammatory markers in patients with metabolic syndrome. [29] Another study by Wang S et al., reported that the SII index and SIRI are independent risk factors for diabetic retinopathy (DR) and suggested that SII index combined with SIRI may serve as early biological indicators for DR diagnosis. [30] Another study by Liu W et al., reported an association between SII index, SIRI, and renal function in patients with T2DM. Significantly increased SIRI was an independent risk factor for diabetic kidney disease (DKD) and SII index was correlated with an increased risk of kidney disease progression in biopsy-confirmed DKD cases. They suggested that for monitoring DKD in primary care settings the SII index and SIRI serve as inflammatory indicators. [31] Similarly, a study by Wang S et al. suggested that SII index and SIRI as independent risk factors for diabetic retinopathy (DR). The high accuracy of SII index combined with SIRI in diagnosing DR underscores their potential as early biological indicators for DR diagnosis. [32].

This study results may conclude that increased levels of SII index, SIRI and their positive association with fasting blood sugar and HbA1c. Therefore, SII index and SIRI 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 the authorities of Lt Shri BRKM Govt. Medical College, Dimrapal, Jagdalpur, Chattisgarh - 494 001, India.

Conflict of interest: Nil

Funding: Nil

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