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.
Baseline characteristics
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). In higher ALT/AST group, 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.
Table 1
Baseline Characteristics of participants
ALT/AST | Q1(≤0.64) | Q2(0.64 to ≤ 0.83) | Q3(0.83 to ≤ 1.10) | Q4(༞1.10) | P-value |
N | 20673 | 22378 | 21574 | 22034 | |
Age (years) | 42.15 ± 14.33 | 43.09 ± 13.47 | 43.15 ± 12.55 | 40.53 ± 10.51 | < 0.001 |
BMI (kg/m2) | 21.50 ± 2.74 | 22.42 ± 2.94 | 23.62 ± 3.07 | 25.24 ± 3.20 | < 0.001 |
FPG (mmol/L) | 4.85 ± 0.60 | 4.89 ± 0.61 | 4.96 ± 0.61 | 5.01 ± 0.63 | < 0.001 |
SBP (mmHg) | 115.44 ± 16.77 | 117.78 ± 16.55 | 120.38 ± 16.32 | 123.18 ± 15.42 | < 0.001 |
DBP (mmHg) | 71.38 ± 10.38 | 72.87 ± 10.54 | 74.86 ± 10.76 | 77.17 ± 10.82 | < 0.001 |
Cholesterol (mmol/L) | 4.58 ± 0.88 | 4.62 ± 0.89 | 4.71 ± 0.89 | 4.85 ± 0.91 | < 0.001 |
Triglyceride (mmol/L) | 0.82 (0.00-16.90) | 0.95 (0.00-18.35) | 4.65 (0.44–11.65) | 1.44 (0.00-27.20) | < 0.001 |
SCR (umol/L) | 66.36 ± 15.95 | 68.95 ± 15.33 | 72.93 ± 15.75 | 76.35 ± 13.83 | < 0.001 |
ALT/AST | 0.53 ± 0.08 | 0.74 ± 0.05 | 0.96 ± 0.08 | 1.42 ± 0.25 | < 0.001 |
Gender | | | | | < 0.001 |
male | 6101 (29.51%) | 10154 (45.37%) | 14067 (65.20%) | 18620 (84.51%) | |
female | 14572 (70.49%) | 12224 (54.63%) | 7507 (34.80%) | 3414 (15.49%) | |
HDL (mmol/L) | | | | | < 0.001 |
low(0 to ≤ 1.23) | 2649 (12.81%) | 3699 (16.53%) | 4416 (20.47%) | 5508 (25.00%) | |
middle(1.24 to ≤ 1.46) | 3748 (18.13%) | 4143 (18.51%) | 4094 (18.98%) | 3837 (17.41%) | |
high(1.47 to ≤ 10.40) | 5179 (25.05%) | 4814 (21.51%) | 3960 (18.36%) | 3012 (13.67%) | |
not recorded | 9097 (44.00%) | 9722 (43.44%) | 9104 (42.20%) | 9677 (43.92%) | |
LDL (mmol/L) | | | | | < 0.001 |
low(0 to ≤ 2.42) | 4577 (22.14%) | 4570 (20.42%) | 3891 (18.04%) | 3343 (15.17%) | |
middle(2.42 to ≤ 2.98) | 4116 (19.91%) | 4307 (19.25%) | 4272 (19.80%) | 4064 (18.44%) | |
high(2.99 to ≤ 10.07) | 3366 (16.28%) | 4011 (17.92%) | 4412 (20.45%) | 4969 (22.55%) | |
not recorded | 8614 (41.67%) | 9490 (42.41%) | 8999 (41.71%) | 9658 (43.83%) | |
Family history of diabetes | | | | | 0.028 |
no | 20255 (97.98%) | 21955 (98.11%) | 21165 (98.10%) | 21540 (97.76%) | |
yes | 418 (2.02%) | 423 (1.89%) | 409 (1.90%) | 494 (2.24%) | |
Smoking status | | | | | < 0.001 |
current | 526 (2.54%) | 795 (3.55%) | 1101 (5.10%) | 1663 (7.55%) | |
ever | 117 (0.57%) | 174 (0.78%) | 281 (1.30%) | 393 (1.78%) | |
never | 4566 (22.09%) | 4275 (19.10%) | 3898 (18.07%) | 3903 (17.71%) | |
not recorded | 15464 (74.80%) | 17134 (76.57%) | 16294 (75.53%) | 16075 (72.96%) | |
Drinking status | | | | | < 0.001 |
current | 139 (0.67%) | 132 (0.59%) | 136 (0.63%) | 164 (0.74%) | |
ever | 547 (2.65%) | 761 (3.40%) | 996 (4.62%) | 1443 (6.55%) | |
never | 4523 (21.88%) | 4351 (19.44%) | 4148 (19.23%) | 4352 (19.75%) | |
not recorded | 15464 (74.80%) | 17134 (76.57%) | 16294 (75.53%) | 16075 (72.96%) | |
Values are n (%), median(Q1-Q3) or mean ± sd |
ALT alanine aminotransferase, AST aspartate transaminase, BMI body mass index, SBP systolic blood pressure, DBP diastole blood pressure, FPG fasting plasma glucose, LDL low-density lipoprotein cholesterol, HDL high density lipoprotein cholesterol, SCR serum creatinine |
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.
Table 2
Incidence rate of incident diabetes
Group | No of participants | No of DM events | Cumulative incidence (95% CI) | Per 100,000 person-years |
Total | 86659 | 1826 (2.11%) | 2.112 (2.016–2.208) | 671.79 |
ALT/AST (quartile) | | | | |
Q1 | 20468 | 205 (0.99%) | 0.992 (.0.857–1.127) | 318.73 |
Q2 | 22058 | 320 (1.43%) | 1.430 (1.274–1.586) | 452.34 |
Q3 | 21057 | 517 (2.40%) | 2.396 (2.192-2.600) | 761.29 |
Q4 | 21250 | 784 (3.56%) | 3.559 (3.314–3.803) | 1138.85 |
P-value for log-rank test | — | — | ༜0.001 | — |
Univariate analysis
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.
Table 3
The results of univariate analysis
| Statistics | HR(95%CI,P-value) |
Age (years) | 42.229 ± 12.819 | 1.070 (1.066, 1.073) < 0.00001 |
BMI (kg/m2) | 23.220 ± 3.303 | 1.232 (1.219, 1.245) < 0.00001 |
FPG (mmol/L) | 4.931 ± 0.615 | 10.323 (9.655, 11.036) < 0.00001 |
SBP (mmHg) | 119.241 ± 16.520 | 1.041 (1.039, 1.043) < 0.00001 |
DBP (mmHg) | 74.104 ± 10.847 | 1.048 (1.044, 1.051) < 0.00001 |
Cholesterol (mmol/L) | 4.693 ± 0.896 | 1.431 (1.370, 1.495) < 0.00001 |
Triglyceride (mmol/L) | 1.319 ± 1.011 | 1.258 (1.242, 1.275) < 0.00001 |
SCR (umol/L) | 71.207 ± 15.691 | 1.005 (1.004, 1.007) < 0.00001 |
ALT/AST | 0.917 ± 0.358 | 3.176 (2.847, 3.542) < 0.00001 |
Gender | | |
male | 48942 (56.477%) | 1.0 |
female | 37717 (43.523%) | 0.574 (0.519, 0.634) < 0.00001 |
HDL (mmol/L) | | |
low(0 to ≤ 1.23) | 16272 (18.777%) | 1.0 |
middle(1.24 to ≤ 1.46) | 15822 (18.258%) | 0.997 (0.871, 1.142) 0.96748 |
high(1.47 to ≤ 10.40) | 16965 (19.577%) | 0.933 (0.816, 1.066) 0.30476 |
not recorded | 37600 (43.388%) | 0.531 (0.471, 0.599) < 0.00001 |
LDL (mmol/L) | | |
low(0 to ≤ 2.42) | 16381 (18.903%) | 1.0 |
middle(2.42 to ≤ 2.98) | 16759 (19.339%) | 1.138 (0.985, 1.314) 0.07886 |
high(2.99 to ≤ 10.07) | 16758 (19.338%) | 1.572 (1.373, 1.799) < 0.00001 |
not recorded | 36761 (42.420%) | 0.628 (0.549, 0.719) < 0.00001 |
Family history of diabetes | | |
no | 84915 (97.988%) | 1.0 |
yes | 1744 (2.012%) | 1.632 (1.279, 2.084) 0.00008 |
Smoking status | | |
current | 4085 (4.714%) | 1.0 |
ever | 965 (1.114%) | 0.909 (0.612, 1.352) 0.63882 |
never | 16642 (19.204%) | 0.510 (0.413, 0.629) < 0.00001 |
not recorded | 64967 (74.969%) | 0.650 (0.544, 0.777) < 0.00001 |
Drinking status | | |
current | 571 (0.659%) | 1.0 |
ever | 3747 (4.324%) | 0.443 (0.276, 0.710) 0.00072 |
never | 17374 (20.049%) | 0.407 (0.264, 0.628) 0.00005 |
not recorded | 64967 (74.969%) | 0.443 (0.291, 0.675) 0.00015 |
Values are n (%), median(Q1-Q3) or mean ± sd |
The Kaplan-Meier curves of the cumulative hazards of incident diabetes risk was depicted in Fig. 1 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
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. 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 1.04 times ascendant of the risk of incident diabetes than Q1 in full adjusted model with (P for trend = 0.00007).
Table 4
Relationship between AST/ALT and censor of diabetes at follow up in different models
Exposure | Crude Model (HR, 95%CI, P) | Minimally adjusted Model (HR, 95%CI, P) | Fully adjusted Model (HR, 95%CI, P) |
ALT/AST (per0.1 charge) | 3.176 (2.847, 3.542) < 0.00001 | 3.434 (2.980, 3.958) < 0.00001 | 2.535 (2.190, 2.934) < 0.00001 |
ALT/AST (quartile) | | | |
Q1 | 1.0 | 1.0 | 1.0 |
Q2 | 1.373 (1.152, 1.636) 0.00040 | 1.207 (1.011, 1.441) 0.03726 | 1.031 (0.863, 1.231) 0.73672 |
Q3 | 2.325 (1.978, 2.734) < 0.00001 | 1.851 (1.565, 2.191) < 0.00001 | 1.403 (1.185, 1.661) 0.00009 |
Q4 | 3.521 (3.019, 4.107) < 0.00001 | 3.037 (2.553, 3.612) < 0.00001 | 2.042 (1.717, 2.429) < 0.00001 |
P for Trend | < 0.00001 | < 0.00001 | 0.00007 |
Crude model: we did not adjust other covariant |
Minimally adjusted model: we adjusted age, gender, BMI, DBP, SBP, family history of diabetes, smoking status, drinking status |
Fully adjusted model: we adjusted age, gender, BMI, DBP, SBP, family history of diabetes, smoking status, drinking status, FPG, HDL, LDL, cholesterol, triglyceride, SCR |
CI: confidence, Ref: reference |
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 Fig. 2, 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). A 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.
Table 5
The results of two-piecewise linear regression model
| incident diabetes (HR,95%CI, P) |
Fitting model by standard linear regression | 2.535 (2.190, 2.934) < 0.0001 |
Fitting model by two-piecewise linear regression | |
Inflection point | 0.68 |
≤ 0.68 | 1.317 (0.514, 3.375) 0.5665 |
༞0.68 | 2.641 (2.257, 3.091) < 0.0001 |
P for log likelihood ratio test | 0.176 |
CI: Confidence interval |
We adjusted age, gender, BMI, DBP, SBP, family history of diabetes, smoking status, drinking status, FPG, HDL, LDL, cholesterol,triglyceride, CCR |
Subgroup analysis
In Table 6, 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 (< 24 kg/m2) and SBP (< 140 mmHg) was found to be the stronger association. On the contrary, the population with age (20 to < 30 years, > 50 years), BMI (≥ 24 kg/m2) and SBP (≥ 140 mmHg) was found to be the weaker association.
Table 6
Effect size of ALT/AST on incident diabetes in prespecified and exploratory subgroups
Characteristic | No of participants | HR (95%CI) P value P for interacion |
Age(years) 20 to < 30 30 to < 40 40 to < 50 50 to < 60 60 to < 70 ≥70 | 11723 33801 18235 12273 7668 2959 | 0.0384 1.802 (0.425, 7.578) 0.4218 3.502 (2.354, 5.211) ༜0.0001 2.597(1.906, 3.537) ༜0.0001 1.985(1.533, 2.570) ༜0.0001 1.583(1.115, 2.248) 0.0101 1.567 (0.866, 2.835) 0.1375 |
Gender | | 0.0999 |
male | 48942 | 2.394(2.038, 2.814) <0.0001 |
female | 37717 | 3.091 (2.348, 4.069) <0.0001 |
BMI (kg/m2) | | 0.0013 |
<18.5 | 4894 | 5.365(0.611, 47.123) 0.1297 |
≥18.5, < 24 | 47961 | 3.726 (2.774, 5.006) <0.0001 |
≥24, < 28 | 26663 | 2.521 (2.049, 3.100) <0.0001 |
≥28 | 7141 | 1.649 (1.247, 2.181) 0.0004 |
FPG (mmol/L) | | 0.0880 |
low(1.78 to ≤ 4.92) | 43228 | 2.171 (1.413, 3.335) 0.0004 |
high(4.93 to ≤ 6.99) | 43431 | 3.182 (2.738, 3.698) <0.0001 |
SBP (mmHg) | | 0.0003 |
<140 | 77553 | 2.944 (2.485, 3.487) <0.0001 |
≥140 | 9106 | 1.660 (1.266, 2.178) 0.0002 |
DBP (mmHg) | | 0.1968 |
<90 | 79689 | 2.667(2.265, 3.141) <0.0001 |
≥90 | 6970 | 2.127 (1.564, 2.893) <0.0001 |
HDL (mmol/L) | | 0.4873 |
low(0 to ≤ 1.23) | 16272 | 2.957 (2.308, 3.787) <0.0001 |
middle(1.24 to ≤ 1.46) | 15822 | 2.462 (1.839, 3.295) <0.0001 |
high(1.47 to ≤ 10.40) | 16965 | 2.491 (1.824, 3.402) <0.0001 |
not recorded | 37600 | 2.310 (1.855, 2.877) <0.0001 |
LDL (mmol/L) | | 0.2055 |
low(0 to ≤ 2.42) | 16381 | 3.285 (2.368, 4.556) <0.0001 |
middle(2.42 to ≤ 2.98) | 16759 | 2.801 (2.042, 3.841) <0.0001 |
high(2.99 to ≤ 10.07) | 16758 | 2.184 (1.668, 2.861) <0.0001 |
not recorded | 36761 | 2.314 (1.811, 2.956) <0.0001 |
Family history of diabetes | | 0.7528 |
no | 84915 | 2.542 (2.189, 2.951) <0.0001 |
yes | 1744 | 2.254 (1.082, 4.697) 0.0300 |
Smoking status | | 0.1793 |
current | 4085 | 1.507 (0.918, 2.475) 0.1052 |
ever | 965 | 2.425 (0.817, 7.197) 0.1103 |
never not recorded | 16642 64967 | 2.420 (1.664, 3.521) <0.0001 2.686 (2.272, 3.176) <0.0001 |
Drinking status | | 0.8861 |
current | 571 | 1.632 (0.356, 7.474) 0.5281 |
ever | 3747 | 2.406 (1.284, 4.510) 0.0062 |
never not recorded | 17374 64967 | 2.391 (1.693, 3.375) <0.0001 2.633 (2.225, 3.117) <0.0001 |
Note 1: Above model adjusted for age, gender, BMI, FPG, SBP, DBP, HDL, LDL, family history of diabetes, cholesterol, triglyceride, SCR, smoking status, drinking status |