Introduction
Malignant melanoma is a highly malignant tumor that typically arises on the skin surface, with a minority of lesions occurring in locations such as the intestines, nasal cavity and uveal tract (1). Both the incidence and mortality rates of malignant melanoma have shown a rising trend year by year between 2012 and 2020 (2). Although malignant melanoma accounts for <1% of all skin malignancies, its mortality rate accounts for 75% of all associated deaths from skin malignancies (2). The prognosis of patients with malignant melanoma is closely associated with the stage at diagnosis, with a 5-year survival rate of >90% for stage I patients, which is markedly superior to that of stage IV patients (35%) (2,3). Major risk factors for malignant melanoma include exposure to ultraviolet radiation, large congenital nevi and genetic mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A) and CDK4, among others (4–6). Given the generally poor prognosis of patients with melanoma, greater emphasis should be placed on this disease.
Insulin resistance (IR) is a response in which the body's insulin-mediated regulation of blood glucose diminishes due to energy surplus, and is closely linked with obesity, type 2 diabetes and fatty liver disease (7–9). In recent years, an increasing body of research has suggested that the impact of IR extends beyond endocrinology and cardiovascular fields, also promoting the progression of malignant tumors, including breast, colorectal, thyroid and lung cancer (10–13). However, studies on the association between IR and malignant melanoma are currently lacking. The hyperglycemic clamp technique serves as the gold standard for diagnosing IR, but its complexity and high cost mean that it is difficult to widely adopt in clinical practice (14). By contrast, the TyG index has been proven to be a simple and accurate marker of IR, more suitable for clinical application (15). Therefore, the present study aimed to explore the association between the TyG index, a marker of IR, and malignant melanoma.
Discussion
Malignant melanoma stands as one of the most malignant tumors, and despite advancements in immunotherapeutic and targeted approaches that have somewhat ameliorated the prognosis, the 5-year survival rate for late-stage malignant melanoma patients remains poor (35.1%) (2). Established high-risk factors for malignant melanoma include exposure to ultraviolet radiation, large congenital nevi and certain genetic mutations (4–6). However, despite measures taken to address these high-risk factors, the incidence of malignant melanoma continues to rise annually (2). This prompts the exploration of new high-risk factors for malignant melanoma occurrence. The present study suggested that the TyG index, indicative of IR, is an independent risk factor for malignant melanoma occurrence. IR is a potential mechanism underlying elevated TyG index values, and TyG index may serve as a surrogate marker for IR (15). Although the hyperinsulinemic-euglycemic clamp technique is considered the gold standard for diagnosing IR, its high cost and complexity limit its routine application (14). Therefore, the present study utilized the TyG index as a substitute for IR and elaborated on the underlying mechanisms. The study was retrospective in nature, and fasting insulin levels could not be obtained, limiting the ability to provide direct evidence of IR. These aspects will carefully be considered in future research. To the best of our knowledge, this is the first study to investigate the association between the TyG index and malignant melanoma incidence.
Independent t-tests, Mann-Whitney U tests and χ2 tests were used to analyze baseline variables. Other than TyG index, there was also a significant difference between the two groups in terms of drinking history (P=0.037). Multiple studies have long established that alcohol consumption is a high-risk factor for the development of malignant tumors (20). Recent studies have also shown a close association between alcohol consumption and MM. Alcohol intake may increase the severity of sunburn, which is a well-known high-risk factor for MM, and this could be a potential mechanism by which alcohol promotes MM (21). A Mendelian randomization analysis in 2023 suggested that alcohol consumption had a positive effect on the development of skin MM (OR, 2.23; 95% CI, 1.11–4.47; P=0.02) (22). A meta-analysis also indicated that alcohol consumption might be associated with an increased risk of melanoma, but residual confounding factors and bias could not be ruled out (23). This is contrary to the present findings, where an initial rank-sum test revealed that the control groups had a higher drinking rate (P=0.037). However, subsequent univariate and multivariate logistic regression analyses did not show an association between alcohol consumption and MM (P=0.081 and P=0.134, respectively). Therefore, the association between alcohol consumption and MM requires further exploration through large-scale prospective studies. However, it is important to note that this variable was not the primary focus of the present study, and its significance does not alter the central conclusions regarding the association between the TyG index and melanoma risk.
IR arises from diminished responsiveness to insulin in the body. Initial research predominantly focused on the association of IR with cerebrovascular and cardiovascular diseases, diabetes and other endocrine disorders (such as Cushing's syndrome and hyperuricemia) (7,9,24). However, subsequent studies have revealed significant implications of IR in the onset and progression of tumors. A comparative study by Panigoro et al (11) involving 212 patients with breast cancer and 212 healthy individuals demonstrated a non-linear correlation between the TyG index and breast cancer risk, with individuals having a TyG index >8.87 facing a three-fold increase in breast cancer risk. This finding aligns with results from a large-scale study indicating a correlation between IR and breast cancer incidence in postmenopausal women (25). Furthermore, research by Li et al (13) on patients with colorectal cancer suggested an association between elevated TyG index and an increased risk of colorectal cancer. Similarly, Yan et al (10) demonstrated that a higher TyG index elevated the risk of NSCLC. The value of the TyG index is also reflected in renal cell carcinoma. A retrospective study by Qin et al (26) showed that individuals with a higher TyG index had a higher incidence of renal cell carcinoma, and that patients with renal cell carcinoma had a poor prognosis. This is consistent with the present study showing the predictive value of IR (TyG index) for cancer. To the best of our knowledge, this is the first study to explore the association between TyG index and melanoma incidence. These studies corroborate our conclusion that IR, or a higher TyG index, represents a significant risk factor for malignant melanoma incidence.
IR leads to hyperinsulinemia, which is one of the mechanisms through which IR promotes tumor onset and progression (27). Insulin binding to the insulin receptor (INSR) activates the PI3K/Akt/mTOR pathway, thereby exerting its effects on promoting angiogenesis, cell proliferation and differentiation (28). Additionally, INSR-A has been shown to be upregulated in various tumors (such as breast and lung cancer) (29). Therefore, the interaction between elevated insulin levels and upregulated INSR-A plays a crucial role in promoting tumor onset and development. For instance, in an animal model study by Zhang et al (30), a decrease in insulin levels significantly reduced the incidence of pancreatic cancer precursor lesions. Similarly, a 16-year observational study found that individuals with higher blood insulin concentrations had a significantly higher risk of pancreatic cancer compared with those with lower blood insulin concentrations (31). By contrast, the indirect reduction of blood insulin levels by metformin demonstrated anticancer effects (32). The anticancer properties of metformin stem from its ability to activate adenosine 5′-monophosphate-activated protein kinase, thereby inhibiting mTOR signaling and protein synthesis, ultimately suppressing cell proliferation (33). Several studies have indicated that metformin can inhibit the proliferation of various tumors, including lung and breast cancer (34,35). This highlights the importance of not only recognizing the role of IR in promoting tumor growth, but also considering the improvement of IR as a potential target for cancer therapy.
In addition, under the state of IR, there is a decrease in insulin-like growth factor (IGF) binding protein production, leading to an increase in circulating IGF-1, which is another mechanism through which IR promotes tumor onset and development (36). On the one hand, IGF-1 binds to the IGF-1 receptor (IGF-1R) and exerts its effects on promoting cell proliferation and inhibiting apoptosis through the PI3K/Akt/mTOR pathway (37). Use of a hybrid mouse model in the study by Wang et al (38) suggested that elevated IGF-1 levels led to increased incidence and invasiveness of prostate cancer. Additionally, Yakar et al (39) observed that implantation of colon cancer tissue into IGF-1 gene-deleted (LID) mice and normal mice showed significantly higher tumor incidence in the control mice compared with that in the LID mice, with lower circulating IGF-1 levels in the LID mice. However, after administration of IGF-1 to the LID mice, there was no difference in tumor growth between the two groups (39). IGF-1 can also bind to INSR-1 and, through the aforementioned mechanism, promote tumor onset (40).
IR can also inhibit PTEN function. As a negative regulator of the PI3K/Akt signaling pathway, PTEN plays a critical role in tumor suppression. PTEN induces oxidative phosphorylation and reduces glycolysis, thereby decreasing energy metabolism in cancer cells, which may be a key mechanism underlying its tumor-suppressive effects (41). Inactivation of PTEN leads to increased PIP3 recruitment and excessive activation of Akt and downstream signaling cascades, promoting cell survival and tumorigenesis (42). Enhanced Akt activity may increase immune evasion by downregulating the expression of programmed death ligand 1 on the tumor cell surface, thereby promoting cancer development and progression (43). Additionally, excessive activation of the PI3K/Akt pathway can further impair insulin sensitivity and contribute to the development of IR, establishing a vicious cycle of IR and PTEN inactivation that ultimately leads to tumorigenesis (44). In hepatic malignancies, IR and hyperinsulinemia lead to upregulation of the IGF axis (including IGF-1, IGF-2, IGF-1R, IGF-2R, and IGF binding proteins IGFBP1-6 and INRS-1), subsequently promoting activation and phosphorylation of the PI3K/PTEN/Akt signaling pathway, inducing cell proliferation and inhibiting apoptosis, which together drive tumorigenesis (45). Given that PTEN mutations are a significant susceptibility factor for malignant melanoma, greater attention should be paid to the risks associated with IR (46).
The tumor-promoting effects of IR are also related to inflammation. IR causes adipocyte dysfunction, increasing the infiltration of M1-type pro-inflammatory macrophages in adipose tissue, thereby enhancing the secretion of pro-inflammatory cytokines from adipocytes, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β (47–49). These cytokines further inhibit insulin signaling, exacerbating IR. IL-6, as an inflammatory cytokine, can induce cancer cell proliferation through STAT signaling and simultaneously block host antitumor immune responses (50). Elevated levels of IL-6 have been observed in overweight and obese women with IR and early stage breast cancer (51). Additionally, circulating IL-6 levels are higher in men with prostate cancer compared with those in men with benign conditions (52). TNF-α, a key pro-inflammatory factor, is involved in maintaining immune system homeostasis, inflammation and host defense. TNF-α promotes and amplifies IR by inhibiting INSR signaling, and plays a crucial role in the formation and progression of various tumors (53). For instance, serum TNF-α levels are significantly associated with tumor stage in patients with prostate cancer (54). TNF-α also promotes tumor progression and metastasis in breast cancer by facilitating epithelial-mesenchymal transition (55). Furthermore, elevated circulating TNF-α levels can activate the NF-κB pathway, exerting anti-apoptotic effects that promote tumorigenesis in overweight patients with IR (56). As melanoma is an immunogenic tumor, it is not unexpected that this phenomenon is also observed in malignant melanoma (57). A study by Molinelli et al (58) indicated that TNF-α expression was significantly elevated in the peritumoral tissue of melanoma samples compared with that in controls, suggesting that the upregulation of TNF-α may contribute to the growth and local invasiveness of cutaneous melanoma. Therefore, the interaction between IR and inflammation should be evaluated as a risk factor in tumor diagnostics.
The present study also had several limitations: Firstly, it was a retrospective study with a limited number of participants, and due to excessive missing data and as it was not a primary focus of this study, high-density lipoprotein (HDL) was removed. Secondly, an association was not found between the TyG index and BMI, which may be due to the limited sample size. Thirdly, there was no direct evidence of IR or hyperinsulinemia due to the limitations of a retrospective study. Finally, the dynamic changes in the TyG index were not observed. Furthermore, we also acknowledge the potential influence of insulin deficiency on the TyG index (15). However, the present study was retrospective, and diabetic patients were excluded to minimize the confounding effect. Fasting insulin is not routinely measured due to its limited clinical applicability and cost in patients without specific diseases (59), so we did not have access to fasting insulin data in the analysis. In future prospective studies, greater emphasis will be placed on assessing fasting insulin levels to better elucidate the underlying mechanisms of TyG index variations. Therefore, further basic research and large-scale observational studies are needed to further substantiate the association between IR and the incidence of malignant melanoma.
In conclusion, the present study provides the first evidence that the TyG index, representing IR, is a significant risk factor for the incidence of malignant melanoma. This finding has significant clinical implications, including the following: i) Early risk assessment: The TyG index can help identify individuals at higher risk for melanoma, enabling early detection and more frequent skin monitoring. ii) Comprehensive risk evaluation: The TyG index provides a tool for assessing the risk of melanoma. iii) Guiding interventions: High TyG index can prompt lifestyle and therapeutic interventions to improve insulin sensitivity, potentially reducing melanoma risk. iv) Prognostic value: The index may serve as a marker for monitoring metabolic health and treatment outcomes in patients with melanoma. Overall, the TyG index offers a simple, cost-effective approach to melanoma risk assessment and metabolic health management.