In this cross-sectional study, 10,321 participants were involved. We found that subjects with a higher SII were more likely to develop T2DM independently of the multiple confounding variables. These findings have been seen in the ln-SII and categorical analyses. Subgroup analysis and interaction tests indicated that the relationship between the two groups was similar. Our findings indicate that increased SII is an independent risk factor for increased T2DM.
As we know, this is the first study assessing the relationship between SII and an increased risk of T2DM. The relationship between SII and metabolic disorders has been identified in earlier studies[8] with different epidemiologic techniques and target populations. A cross-sectional study found that ln-SII at baseline was associated with all causes of death from any cause in the United States ASCVD population in the NHANES group[22]. Increased SII in ASCVD individuals is related to poor survival[23].In addition, higher levels of SII are related to an increased risk of hepatic steatosis[8], peripheral arterial disease[9], isolated coronary artery ectasia[10], urinary albuminuria excretion[5], diabetic kidney disease[11], and diabetic depression[12]. Likewise, T2DM patients were more likely to have elevated SII in our subgroup analysis compared with those who did not have T2DM, Indicating that inflammation may be significantly involved in developing T2DM.
In addition, our findings suggest that SII may serve as a simple and non-invasive marker for identifying high-risk T2DM patients. However, there are a variety of classic inflammation markers, including WBC and C-reactive proteins, which have been widely used in the clinic. Ki-Chul et al. demonstrated a positive correlation between inflammatory markers and insulin resistance, which may be independent predictors of T2DM[24]. Furthermore, Klisic et al. demonstrated that novel, modified NLR (neutrophil to lymphocyte ratio) was independently associated with HbA1c. Also, platelets to the neutrophil ratio (PNR) showed superiority over platelets (PLT) in relation to HbA1c[25]. These new indicators may contribute significantly to the early detection of disorders of glucose homeostasis in pre-diabetics and diabetes. In addition, inflammatory markers, like SII, can also be used in the treatment of complications of T2DM. Guo et al found that T2DM patients had an increased SII in association with diabetic kidney disease[11].
In general, M1-like macrophages are capable of producing a variety of chemokines and cytokines, including IL-1β, TNF-α, and Galectin-3, which can interfere with insulin signaling and decrease insulin sensitivity. Indeed, preventing the accumulation of M1-like macrophages or pro-inflammatory macrophage signaling can prevent obesity in obese mice and IR[26]. Furthermore, there is a wealth of data indicating that such activated inflammatory macrophages may interfere with the function of beta cells of the pancreas[16], resulting in impaired insulin formation. As with the majority of previous studies, we have shown that elevated SII is independently related to an increase in the risk of T2DM, indicating that SII may have a separate and major adverse effect on T2DM.
To diabetic patients, the clinical presentation, the underlying pathophysiology, and development of the disease differ significantly from person to person, and in some cases, atypical T2DM may be difficult to classify clearly. Many T2DM patients are asymptomatic at the time of diagnosis, while other patients present with severe hyperglycemia or even diabetic ketoacidosis[27], which brings a great challenge to clinical diagnosis. Our results suggest that SII may be a direct and non-invasive marker for identifying high-risk T2DM patients. Besides, there are several inflammatory markers associated with the incidence of T2DM, which could be widely used in clinical practice. Previous research has demonstrated that increased white blood cells and elevated hsCRP have been linked to the deterioration of glycemia levels before the diagnosis of type 2 diabetes[28]. In addition, studies have shown that a higher risk of developing T2DM is associated with high levels of pro-inflammatory cytokines like C-reactive protein, interleukin 6, and tumor necrosis factor[29], while high adiponectin concentrations with anti-inflammatory properties are associated with lower risk[30]. In this way, new inflammatory markers may be found that can be used in subsequent research for diabetes screening.
While there is a wide range of antidiabetic medicinal products available for the treatment of T2DM, the majority of patients are unable to reach optimum glucose concentrations. In addition, glucose control may not always be enough to protect patients from chronic diabetic complications. In this way, a better understanding of the underlying mechanism of T2DM may be helpful for the subsequent development of new drugs[13]. Multiple human studies of T2DM have shown that targeting islet inflammation has the potential to be an effective therapeutic strategy. Recently, a study in obese non-diabetic subjects showed reduced fasting blood glucose after 6 weeks of TNF inhibition[31]. Studies have demonstrated that IL 1β acts as a mediator for the harmful effects of hyperglycemia on human beta cells[32] In a proof-of-concept study of T2DM, the inhibition of IL-1 by the antagonist IL-1Ra receptor led to improved levels of glucose and beta cell secretion and reduced CRP[33]. Two multicentre, placebo-controlled trials showed clear evidence that sulfasalazine reduces systemic inflammation and improves glucose metabolism in T2DM patients[34, 35]. In addition, anti-inflammatory-related therapies can also protect the organs that are normally affected by diabetes, including the kidney, the eye, and the cardiovascular system[36]. In the current Canakinumab Anti-inflammatory Thrombosis Outcomes Study[37], 10,000 patients at risk for CAD(cardiovascular disease) and DM were enrolled to explore the possibility of IL 1β blocking for protection from CAD and the prevention or improvement of type 2 diabetes.
Our research has its merits. Firstly, the sample size is sufficient. Secondly, to achieve more reliable results, we corrected confounding variables. However, the deficiencies of the study require a careful interpretation of the results. First of all, the design of the cross-sectional study made it impossible for us to create a causal relationship. Second, although we have adjusted for several important confounding variables, we have not been able to completely exclude the effect of other possible confounding variables. Third, although SII is easy to quantify in clinical practice, it is common to lose neutrophils, lymphocytes, and platelets, which can cause selective bias. In conclusion, although we have corrected for many possible confounders, there might be other confounding variables, e.g. T2DM duration, type of insulin, dose of the medicine, and medicinal products, which might influence this conclusion. Therefore, further studies with more participants and more precise measurements are needed to determine the causality.