To the best of our knowledge, this is the first study to describe a U-shaped association between the TyG index and the risk of incident T2DM. Moreover, we revealed a turning point (TyG = 7.27 in women vs. TyG = 7.97 in men) using threshold effect analysis (Table 3 and Fig. 2). Besides, as far as we know, in Japan area, the is the first study conducted to investigate the association between TyG and incident diabetes.
The association between the TyG index and the development of diabetes has been examined in previous studies in other areas [17, 18, 20, 32–34]. Ming Zhang et al. found that the risk of incident T2DM was increased with elevated TyG quartiles among 8003 Chinese participants[33]. Similarly, the Chungju Metabolic Disease Cohort (CMC) study revealed an increased risk of incident diabetes in participants with TyG index in Quartiles 2, 3 and 4, compared to those in Quarter 1[32]. Consistently, different studies on a white European population, middle-aged Koreans, residents of the northern region of Singapore reported a significantly higher risk of incident diabetes among participants in the highest TyG quartile relative to the lowest quartile[17, 18, 20]. However, all of these studies did not exclude the individuals with prediabetes (impaired glucose tolerance or 5.7 ≤ HbA1c levels < 6.5% [35]).
In the present study, all the participants with impaired fasting glucose tolerance or HbA1c ≥ 5.7 were excluded, and some new insights were demonstrated. Overall, there was a U-shaped association between the TyG index and the risk of developing T2DM. Besides, the thresholds (TyG = 7.27 in women vs. TyG = 7.97 in men) were identified on which the risk of incident diabetes was the lowest in this population (Table 3 and Fig. 2). Well in line with certain previous studies [17, 18, 20, 32–34], the risk of developing T2DM significantly increased with the elevated TyG index in men with TyG > 7.97 and women with TyG > 7.29 (Table 3 and Fig. 2). However, a lower level of TyG index (< 7.27 in women and < 7.97 in men) substantially changed the association between the TyG index and incident diabetes. In participants with TyG levels lower than the thresholds, the risk of incident diabetes among women and men decreased nearly by 90% and 80%, respectively, with each increment in the TyG index after fully adjusting for confounders (Table 3 and Fig. 2). This has not been reported in the existing literatures.
Actually, consistent with our study findings, previous cohort studies showed that after adjusting for confounders, the risk of incident diabetes increased significantly only in the third and fourth TyG quartiles[17, 18, 20, 34],but not in the second quartile, when compared with that in the first quartile[17, 18, 20]. This indicates a nonlinear association between the TyG index and incident diabetes. Furthermore, in the Vascular-Metabolic CUN cohort, the nonlinear relation became more obvious in the subgroup with the normal fasting glucose level in the stratified analyses[17]. Interestingly, some previous studies suggested that the risk of incident Type 2 diabetes was elevated across all TyG quartiles [32, 33]. However, most of these studies performed the analyses in all participants with fasting glucose level < 7 mmol/L and did not exclude those with impaired fasting glucose or with 5.7 ≤ HbA1c levels < 6.5% (prediabetes)[12, 21, 24]. Besides, the previous studies had a relatively small population scale. Hence, the nonlinear association between the TyG index and the risk of incident diabetes might have been neglected.
Although the U shape association between TyG and incident diabetes in apparent healthy individuals was firstly revealed in this study, there were several limitations that must be noted. Firstly, the current study was carried out only in a Japanese population, making the generalizability of its findings to non-Japanese populations uncertain. This implies the need to verify our results by conducting future studies on other ethnicities. Secondly, the oral glucose tolerance test was not performed in this study, and the prevalence of incident diabetes might have been underestimated. Lastly, the effects of the TyG index on the risk of incident diabetes require further investigation.
Despite the limitations mentioned above, this study had several strengths. Firstly, the data set extracted from the NAGALA database was relatively large and complete, covering wide range of TyG levels. Secondly, this study was performed in an apparently healthy population because we excluded all individuals with HbA1c levels ≥ 5.7% or impaired fasting glucose. These two strengths allowed us to evaluate the association across an extensive TyG range in healthy individuals and establish the U-shaped association between the TyG index and incident diabetes. Thirdly, our analysis of the relationship between the TyG index and incident diabetes was adjusted for more potential confounding factors, when compared to previous studies, probably making the result more robust and reliable.