The following are the study's three key findings. First, the ratio of TG/HDL-C cut-off value for T2D development within 10 years was 2.1. Second, the ratio of TG/HDL-C outperformed LDL-C, HDL-C, and TG levels in predicting the development of diabetes within 10 years. Third, females and those with a BMI of < 25 kg/m2 may be more sensitive to lipid profile levels in terms of the risk of developing T2D.

Though the precise mechanism through which a high ratio of TG/HDL-C causes insulin resistance is unknown, several reports suggest a theory. In cellular experiments, LDL-C was shown to decrease the expression of cyclin B1 in pancreatic β-cells, resulting in increased insulin resistance, and HDL-C is thought to improve insulin resistance by suppressing the effects of LDL-C [20,21]. HDL has also been shown to possibly regulate glucose homeostasis through mechanisms such as insulin secretion, direct glucose uptake by muscle, and increased insulin sensitivity [22]. In contrast, hypertriglyceridemia increases free fatty acids, which accumulate in skeletal muscle and cause insulin resistance, while accumulation in pancreatic islets has been reported to cause β-cell dysfunction and apoptosis [23]. Moreover, hypertriglyceridemia increases the activity of cholesteryl ester transfer protein (CETP) [24,25]. While CETP enhances TG enrichment of HDL and LDL by causing cholesteryl ester to be converted to TG, it leads to lower HDL-C concentrations [24,25]. These findings may be related to the fact that the ratio of TG/HDL-C was more beneficial than LDL-C, HDL-C, and TG levels in predicting diabetes development. In addition, insulin resistance increases TG levels and reduces HDL-C through compensatory hyperinsulinemia and activation of fatty acid degradation [26], and in this regard, the ratio of TG/HDL-C is an important finding in conducting diabetes care.

Subgroup analysis revealed that an elevated lipid profile is more likely to affect diabetes development in females than in males and in those with a BMI of < 25 kg/m2 than in those with a BMI of ≥ 25 kg/m2. Generally, females have lower LDL-C and higher HDL-C levels than males. Due to the effect of female hormones, females have lower LDL-C levels and higher HDL-C levels than males of the same age [27]. Even though estrogen is known to increase TG levels [28], females still have lower TG levels than males. Females have been reported to have greater TG uptake by muscle cells and higher TG clearance than males [29]. Given that estrogen deficiency causes dysregulation of lipid metabolism and accumulation of visceral adipose tissue [30], it is possible that estrogen suppresses TG elevation indirectly by inhibiting the accumulation of visceral adipose tissue. In addition, females are known to be more sensitive to TG levels with respect to cardiovascular disease risk than males [31], suggesting that these results might be consistent with our findings. Furthermore, BMI is strongly connected to the risk of acquiring T2D [32], and several studies have linked increased visceral fat to insulin resistance [33]. Compared to participants with low BMI, the effect of BMI on insulin resistance may have been greater than the effect of lipid profiles in participants with high BMI. Females and individuals with a BMI < 25 kg/m2 may be more sensitive to levels of lipid profiles based on these findings.

Previous studies have evaluated the association between categorical or continuous TG/HDL-C ratio values and the incidence of T2D [13,14,15,16,17,18]. Kim et al. [13] and Lim et al. [14] conducted a study in a Korean population, Liu et al. [15] conducted a study in Chinese individuals (aged 75 years and older), Tohidi et al. [16] have studied the relationship in Iranians, and Wang et al. [17] investigated the relationship in Japanese people. While these studies have discovered a significant association between higher ratios of TG/HDL-C and an increased risk of new-onset diabetes, cut-off values and comparisons among lipid profiles were not presented [13,14,15,16,17], unlike in our study, which estimated cut-off values and compared ratio of TG/HDL-C, LDL-C, HDL-C, and TG parameters. Additionally, the sample size of some studies was not large enough [14,15,16]. Although Hadaegh et al. [18] reported the cut-off values of the ratio of TG/HDL-C, their sample size was small and they did not compare the performance among lipid profiles for predicting T2D incidence. Furthermore, the cut-off values of the TG/HDL-C ratio reported in their study were higher than the values reported by us [18]. This may be because their study was conducted in a Middle Eastern population, in which the pathophysiology of diabetes may be different from that in Japanese people.

It is also noteworthy that our study's sample size was large, and the follow-up period was lengthy, due to the use of a large corporate health checkup database. Furthermore, several dyslipidemia medications, such as statins, are known to increase the likelihood of developing diabetes [34,35], and by excluding participants taking these drugs, we avoided this confounding effect on our risk assessment.

This study had several limitations. First, only reasonably young Japanese were included. It is unknown whether our findings apply to other age and ethnic groups. Most of the participants in our study were males. Therefore, further research will be needed on sex differences in the relationship between lipid profiles and the development of T2D. Additionally, our study did not take into account other factors, such as genetic predisposition, diet, and medication other than antidiabetic drugs, that might influence diabetes risk. Furthermore, neither HbA1c nor a 75-g oral glucose tolerance test was employed in the diagnosis of T2D. The data of a self-reported history of diabetes or usage of antidiabetic medicines were collected using the self-administered questionnaire. Therefore, some participants with T2D might not have been identified. Finally, the lipid data was only available at baseline and was not tracked over time.