In the aggregate of 86,659 participants (57% male), the average age of the them was 42.23 ± 12.82 years. 1826 participants occurred incident diabetes during the following up with the mean following-up time of 3.14 ± 0.92 years. The average value of ALT/AST was 0.92± 0.36, and the average value of BMI, FPG, SBP, DBP, cholesterol, triglyceride and SCR were 23.22 ± 3.30 kg/m2, 4.93 ± 0.62 mmol/L, 119.24 ± 16.52 mmHg, 74.10 ± 10.85 mmHg, 4.69 ± 0.90 mmol/L, 1.32 ± 1.01 mmol/L and 71.21 ± 15.69 mmol/L, separately. The quantity of missing data of SBP, DBP, cholesterol, triglyceride, SCR, HDL, LDL, smoking and drinking status were 12, 13, 1080, 1080, 3475, 37600, 36761, 64967and 64967, respectively.
Quartiles of the ALT/AST and the total population’s baseline characteristics were shown in Table 1. We distributed the total population into subgroup according to ALT/AST quartiles (≤0.64, 0.64-0.83, 0.83-1.10, >1.10), and the different indexes were
compared between quartiles. When P for trend was <0.05, in higher ALT/AST quartiles, participants were observed mostly have higher BMI, fasting plasma glucose, SBP, DBP, cholesterol, SCR and more current smoking and drinking status. On the contrary, none of family history status was considered statistically significant difference amongst Quartiles of the ALT/AST.
Incidence rate of incident diabetes
Table 2 showed that 1,826 (2.11%), 205 (0.99%), 320 (1.43%), 517 (2.40%), 784 (3.56%) participants developed incident diabetes during the following up in total participants, ALT/AST quartile 1, 2, 3, and 4, respectively. The incidence rate of incident diabetes was 671.79, 318.73, 452.34, 761.29, 1138.85 per 100,000 person-years the aggregate of participants, ALT/AST quartile 1, 2, 3, and 4, respectively. And the cumulative incidence (95% CI) was 2.112 (2.016-2.208), 0.992 (.0.857-1.127), 1.430 (1.274-1.586), 2.396 (2.192-2.600) and 3.559 (3.314-3.803), respectively. These results indicated that individual with higher ALT/AST ratio had a higher cumulative incidence.
The consequence of univariate analyses was demonstrated in Table 3 that age, BMI, FPG, SBP, DBP, cholesterol, triglyceride, SCR, LDL were undeniably related to incident diabetes. Besides, the outcome also manifested that men had a higher risk of incident diabetes than women, the participants with family history of diabetes have a higher risk of incident diabetes than without family history, and the participants with current drinking or smoking status have a higher risk of incident diabetes than the participants with never or ever drinking or smoking status.
The Kaplan-Meier curves of the cumulative hazards of incident diabetes risk was depicted in figure1 when stratified by quartiles of ALT/AST. Incident diabetes risk between each quartile of ALT/AST was evidentially various (log-rank test, p < 0.0001). When ALT/AST increased, the cumulative incident diabetes risk raised by degrees, and the Q4 ALT/AST (top of the quartiles) was notarized having maximum risk of incident diabetes.
Association of ALT/AST and incident diabetes
General reference to previous research, we used different adjusted models (crude model, minimally adjusted model and fully adjusted model) to detect whether the conclusion is stable under different adjusted models(14-16). The association of ALT/AST and incident diabetes was judged by Cox proportional hazard regression model in which Table 4 demonstrated the non-adjusted and adjusted models. Shown in Figure3, ALT/AST was observed positively associate with incident diabetes (HR= 3.176, 95% confidence interval (CI): 2.847 to 3.542, P < 0.00001) in crude model. Similar outcome was not only demonstrated in minimally adjusted model (adjusted age, gender, BMI, DBP, SBP, family history of diabetes, smoking status, drinking status) with (HR:3.434, 95%CI:2.980 to 3.958, P<0.00001), but also in full adjusted model (adjusted age, gender, BMI, DBP, SBP, family history of diabetes, smoking status, drinking status, FPG, HDL, LDL, cholesterol, triglyceride, SCR) with (HR=2.535, 95%CI: 2.190 to 2.934, P < 0.00001). In addition, when ALT/AST was conducted as a categorical variable by quartiles, the Q4 was detected 2.04 times of the risk of incident diabetes than Q1 in full adjusted model with (P for trend=0.00007).
Analysis of generalized additive models (GAM)
As ALT/AST ratio was a continuous variable, the non-linear relationship of ALT/AST and incident diabetes was identified through generalized additive models (GAM). In Table 5 and Figure2, we figured out the inflection point of ALT/AST was 0.68 (Log-likelihood ratio test P=0.176) through a two-piecewise linear regression model (after adjusting age, gender, BMI, FPG, SBP, DBP, cholesterol, triglyceride, SCR, HDL, LDL, family history of diabetes, smoking and drinking statuses). An undeniable relationship between ALT/AST and incident diabetes was detected on both the left side (HR:1.317, 95%CI: 0.514-3.375, P=0.5665) and right side (HR: 2.641, 95%CI: 2.257-3.091, P<0.0001) of the inflection point. As for the P value for Log-likelihood ratio test is above 0.05, so the relation between ALT/AST and incident diabetes is only linear. That means we used generalized linear models (Cox proportional hazard models) to analyze the relation between ALT/AST and incident diabetes is appropriate.
In Figure4a,b, subgroup analysis was used to examined if other variables (age, gender, BMI, FPG, SBP, DBP, HDL, LDL, family history of diabetes, smoking status, drinking status) would affect the relation between ALT/AST and incident diabetes. By treating them as stratified variables, we could study their impact on the association of ALT/AST and incident diabetes. As the output result depicted, age, BMI and SBP were detected interactional through the priori specification test (all P values for interaction <0.05). The population with age (30 to <40 years), BMI (<24kg/m2) and SBP (<140mmHg) was found to be the stronger association. On the contrary, the population with age (20 to <30 years, >50 years), BMI (≥24kg/m2) and SBP (≥140mmHg) was found to be the weaker association. (Detailed statistics were demonstrated in supplementary appendix TableS1.)