In the present study, we found a significant positive correlation between VSR and all indicators of multi-organ IR, while all indicators of IR were significantly higher in the high-VSR group, compared to the low-VSR group. Similarly, the risk of multi-organ IR increased progressively with increasing VSR, and the results still held after calibration for confounding factors. Neither of these results differed by gender. In addition to that, we performed a ROC analysis and found that VSR had a strong predictive effect on IR.
The swift progression of China's economy and the adoption of westernized lifestyles have resulted in a rise in overweight and obesity prevalence over time. This phenomenon presents a significant obstacle to public health in both developing and developed nations, as it is linked to a multitude of illnesses and heightened all-cause mortality[4]. Numerous epidemiological studies have established that obesity constitutes a primary risk factor for cardiometabolic diseases[20]. Nevertheless, not all individuals who are obese are vulnerable to these conditions, as some "metabolically healthy obese" individuals exhibit normal insulin sensitivity despite being overweight, but unhealthy patients with obesity are mainly characterized by excessive visceral fat content. Therefore, people with the same BMI who have different body composition are quite different risk in the progression of cardiometabolic diseases[21].
In nearly a decade of research, we have observed that VFA is a more reflective indicator of physical health and cardiometabolic diseases as opposed to BMI, or waist-to-hip ratio[22, 23]. Meanwhile, the accumulation of visceral fat was the major contributor to IR[24]. Increased visceral adipose tissue promoted the release of numerous inflammatory cytokines, such as interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β), leading to a state of systemic hypo-inflammation[25]. The inflammatory state of adipose tissue reduced the production and secretion of adiponectin, which led to a reduction in insulin sensitivity. IR hampered the uptake and utilization of glucose, and excess insulin can be secreted, enhancing the catabolism of peripheral adipose tissue and releasing excess FFA into the blood, promoting the synthesis of adipose tissue in the liver, leading to visceral fat accumulation. Visceral fat accumulation can further block insulin signaling pathways, thereby increasing IR. IR was the underlying cause of the metabolic syndrome (MS) in patients with obesity and an influential pathogenic mechanism for cardiometabolic diseases[26]. Skeletal muscle is an important endocrine organ, which involved in the key sites of insulin-induced glucose metabolism, maintaining normal glucose homeostasis environment. The decrease of SMM can lead to the disruption of glucose metabolism in internal environment, resulting in IR[27, 28]. At the same time, IR contribute to reduced muscle protein synthesis and accelerated muscle protein catabolism, which promotes skeletal muscle loss and may eventually lead to type 2 diabetic sarcopenia[29]. Skeletal muscle is the target of obesity-induced inflammation, while the obesity-induced inflammation and IR can also cause the release of specific skeletal muscle cytokines, such as IL-6, irisin, myostatin and muscle growth inhibitor[30, 31], etc. The release of these cytokines can increase or decrease the risk of obesity, inflammation, and IR[32, 33]. Overall, skeletal muscle loss is strongly associated with IR.
The distinctive feature of IR is its tissue specificity, which can involve the liver, muscle and adipose tissue, IR in different tissues cause varying degrees effects on the body. The liver is the first organ where insulin reaches after being secreted from the pancreas and it regulates both storage and disposal of glucose in response to the requirements of the body for insulin. As the most sensitive organ to IR, hepatic IR is also the main cause of IR in other peripheral organs and tissues. Skeletal muscle and adipose tissue are two primary target organs for glucose disposal. The infiltration of lipids into myocytes produces massive amounts of reactive oxygen species, which in turn induces the release of calcium ions, cytochrome C and apoptosis-inducing factors. Intramuscular lipids also trigger mitochondrial dysfunction, as evidenced by impaired β-oxidation capacity, the numerous damaged mitochondria are removes by autophagy in the body, resulting in a decline both in mitochondrial density and function, impairing the oxidative capacity of skeletal muscle cells, and further lead to lipid infiltration, ectopic lipid deposition and the progression IR[34]. Hypertrophic adipose tissue have the capacity to release excess FFA and proinflammatory cytokines, once excess FFA and dietary lipids enter the cells of non-adipose tissue such as liver, muscle, and pancreas as ectopic fat deposits, there will be stepwise development of lipotoxicity[35]. The development of lipotoxicity sets the stage for IR and chronic low-grade systemic inflammation [36].
HOMA-IR is a reliable alternate predictor of insulin resistance in addition to hyperinsulinemic euglycemic clamp technique. We demonstrated that VSR is an independent risk factor for insulin resistance and also has a high predictive ability for IR, which clearly indicates a strong relationship between VSR and IR.Insulin has different functions in organ system, in the liver it reduces hepatic glucose production and in adipose tissue it inhibits lipolysis. While hepatic IR is considered an early event in peripheral IR and usually precedes the onset of obesity and other metabolism-related diseases, hepatic IR has the potential to contribute to cardiovascular disease (CVD) and lead to patient morbidity and mortality through a vicious circle[37]. ADIPO-IR, as a unique predictor of IR in adipose tissue, may reflect the anti-lipolytic effect of insulin in adipose tissue[14], as well as suggesting progression of aortic valve calcification and adverse cardiovascular features[38]. Findings suggest that HOMA-AD is more accurate at assessing insulin resistance than HOMA-IR in individuals with overweight non-diabetes[39]. Increased VSR in the highest quartile exacerbated the risk of 1/HISI, ADIPO-IR, and HOMA-AD, compared to the lowest quartile group. The results reveal a close relationship between them. Based on our previous study, we demonstrated the validity of the New Model while the model is based on easily available and inexpensive parameters. It is well known that visceral adiposity plays a key role in the development of IR. Therefore, using surrogate indicators that include visceral fat may have a higher predictive value than indicators that use only biochemical measures and this conjecture has been confirmed in previous study[19]. Then we conducted an analysis using the New Model with the VSR, resulting in similar results as HOMA-IR, with the VSR being an independent risk factor for the New Model, while also having the same strength of predictive power for the new model resistance.
IR is widely acknowledged as a significant risk factor for vascular stiffness and the development of adverse cardiometabolic diseases[40, 41]. In a state of normal physiological functioning, insulin stimulates the production of nitric oxide by vascular endothelial cells, thereby promoting vasodilation and increasing blood flow[42]. However, in a state of insulin resistance, the sensitivity of insulin to vascular action is diminished, and may even exacerbate vessel constriction by upregulating the production of vasoconstrictive factors such as endothelin, leading to pathological vascular sclerosis[42, 43].An abnormal increase in vascular stiffness have been demonstrated to be an independent predictor of cardiometabolic diseases. In the inflammatory state of the body, the increased plasma concentrations of pro-inflammatory cytokines, IL-1β, IL-6 and TNF-α, and C-reactive protein (CRP) reflected a stronger propensity for cardiometabolic diseases [44, 45]. Consequently, IR is a risk factor for cardiometabolic diseases and increases the prevalence of cardiometabolic diseases [46].
As a new indicator, VSR could provide new ideas for weight loss in individuals with obesity. we consider that VSR as a key target to help promote health in large populations, through accessible and scalable dietary-exercise modality interventions to improve body composition, reduce visceral fat, increase SMM, mitigate or even reverse the progression of cardiometabolic diseases, and in the long run, the benefits are also enormous for the minimization of CVD events mortality. This is also a direction that our team will continue to work on in the future. The drawbacks of the research are that it is only a cross-sectional study, which cannot judge the causal relationship between VSR and IR, as well as the small sample size of the present study. With the hope that future experiments based on the present study can explore how improvements in VSR can improve IR in population with obesity.