Association Between Aspartate Aminotransferase to Alanine Aminotransferase Ratio and Incidence of Type 2 Diabetes Mellitus in the Japanese Population: A Secondary Analysis of a Retrospective Cohort Study

Figures & data

Figure 1 Flowchart of study participants.

Table 1 The Baseline Characteristics of Participants

AST/ALT	Q1 (0.27–0.78)	Q2 (0.78–0.98)	Q3 (0.98–1.24)	Q4 (1.24–2.20)	P-value
Participants	3796	3388	4284	3823
Age (years)	42.73 ± 8.07	44.14 ± 8.82	44.32 ± 9.09	43.64 ± 9.42	<0.001
BMI (kg/m2)	23.97 ± 3.28	22.52 ± 2.99	21.41 ± 2.70	20.77 ± 2.54	<0.001
WC (cm)	82.00 ± 8.92	77.72 ± 8.84	74.36 ± 8.16	72.42 ± 7.52	<0.001
AST/ALT	0.64 ± 0.10	0.88 ± 0.05	1.10 ± 0.08	1.50 ± 0.22	<0.001
HDL (mmol/l)	1.28 ± 0.37	1.42 ± 0.39	1.53 ± 0.40	1.59 ± 0.39	<0.001
TC (mmol/l)	5.29 ± 0.86	5.18 ± 0.89	5.06 ± 0.84	5.00 ± 0.85	<0.001
HbA1C (%)	5.19 ± 0.33	5.15 ± 0.33	5.16 ± 0.32	5.18 ± 0.31	<0.001
FPG (mmol/l)	5.33 ± 0.38	5.20 ± 0.40	5.10 ± 0.41	5.03 ± 0.40	<0.001
SBP (mmHg)	119.19 ± 14.76	115.61 ± 14.75	112.71 ± 14.66	111.05 ± 14.44	<0.001
DBP (mmHg)	74.57 ± 10.61	72.46 ± 10.36	70.45 ± 10.27	69.20 ± 9.98	<0.001
ALT (U/L)	27.00 (21.00–37.25)	19.00 (16.00–24.00)	15.00 (13.00–19.00)	12.00 (10.00–14.00)	<0.001
AST (U/L)	18.00 (13.00–23.00)	17.00 (14.00–21.00)	17.00 (14.00–20.00)	18.00 (15.00–21.00)	<0.001
GGT (U/L)	23.00 (16.00–35.00)	16.50 (12.00–24.00)	14.00 (11.00–18.00)	12.00 (10.00–15.00)	<0.001
TG (mmol/l)	1.04 (0.70–1.54)	0.80 (0.55–1.21)	0.67 (0.45–0.97)	0.58 (0.41–0.81)	<0.001
Ethanol consumption (g/w)	12.00 (1.00–84.00)	2.80 (0.00–84.00)	1.00 (0.00–60.00)	1.00 (0.00–36.00)	<0.001
Sex					<0.001
Male	3120 (82.19%)	2171 (64.08%)	1929 (45.03%)	1163 (30.42%)
Female	676 (17.81%)	1217 (35.92%)	2355 (54.97%)	2660 (69.58%)
Fatty liver					<0.001
No	2197 (57.88%)	2754 (81.29%)	3922 (91.55%)	3681 (96.29%)
Yes	1599 (42.12%)	634 (18.71%)	362 (8.45%)	142 (3.71%)
Exercise					<0.001
No	3248 (85.56%)	2776 (81.94%)	3429 (80.04%)	3154 (82.50%)
Yes	548 (14.44%)	612 (18.06%)	855 (19.96%)	669 (17.50%)
SMOKING					<0.001
Never smoker	1632 (42.99%)	1788 (52.77%)	2740 (63.96%)	2744 (71.78%)
Ever smoker	923 (24.32%)	721 (21.28%)	758 (17.69%)	530 (13.86%)
Current smoker	1241 (32.69%)	879 (25.94%)	786 (18.35%)	549 (14.36%)

Note: Values are n (%) or mean±SD or medians (quartiles).

Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HbA1c, hemoglobinA1c; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; WC, waist circumference; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyltransferase.

Table 2 Univariate Analysis Between Variables and Incidence of T2DM

	Statistics	HR (95% CI)	P value
Sex
Female	6908 (45.177%)	Ref
Male	8383 (54.823%)	2.555 (2.005, 3.255)	<0.00001
Age	43.717 ± 8.893	1.057 (1.044, 1.069)	<0.00001
BMI	22.134 ± 3.129	1.242 (1.216, 1.269)	<0.00001
Exercise
No	12,607 (82.447%)	Ref
Yes	2684 (17.553%)	0.743 (0.552, 1.001)	0.05105
WC	76.518 ± 9.117	1.093 (1.083, 1.103)	<0.00001
Ethanol consumption	47.938 ± 82.517	1.002 (1.001, 1.003)	0.00102
Smoking status
Never smoker	8904 (58.230%)	Ref
Ever smoker	2932 (19.175%)	1.665 (1.262, 2.196)	0.00031
Current smoker	3455 (22.595%)	2.600 (2.069, 3.269)	<0.00001
SBP	114.546 ± 14.974	1.032 (1.026, 1.037)	<0.00001
DBP	71.608 ± 10.504	1.049 (1.040, 1.058)	<0.00001
Fatty liver
No	12,554 (82.101%)	Ref
Yes	2737 (17.899%)	6.975 (5.667, 8.585)	<0.00001
ALT	20.126 ± 14.357	1.006 (1.005, 1.007)	<0.00001
AST	18.380 ± 8.608	1.008 (1.006, 1.010)	<0.00001
AST/ALT	1.035 ± 0.342	0.129 (0.088, 0.189)	<0.00001
GGT	20.387 ± 18.204	1.011 (1.009, 1.013)	<0.00001
HDL	1.460 ± 0.405	0.147 (0.108, 0.201)	<0.00001
TC	5.129 ± 0.865	1.496 (1.345, 1.665)	<0.00001
TG	0.915 ± 0.656	1.797 (1.681, 1.922)	<0.00001
HBA1C	5.171 ± 0.322	54.026 (39.285, 74.299)	<0.00001
FPG	5.162 ± 0.413	25.313 (18.642, 34.371)	<0.00001

Figure 2 Kaplan–Meier event-free survival curve based on AST/ALT ratio quartiles and the incidence of T2DM.

Notes: Kaplan–Meier event-free survival curve. Kaplan–Meier analysis of diabetes incident based on AST/ALT quartiles (log-rank, P < 0.0001).

Table 3 Association Between AST/ALT Ratio and the Incidence of T2DM in Different Models

Variable	Crude Model (HR, 95% CI, P)	Model I (HR, 95% CI, P)	Model II (HR, 95% CI, P)
Total
AST/ALT ratio	0.179 (0.118, 0.272) <0.00001	0.349 (0.226, 0.540) <0.00001	0.617 (0.405, 0.938) 0.02399
AST/ALT ratio (quartile)
Q1	Ref	Ref	Ref
Q2	0.480 (0.366, 0.631) <0.00001	0.574 (0.435, 0.757) 0.00009	0.720 (0.545, 0.953) 0.02143
Q3	0.397 (0.296, 0.533) <0.00001	0.565 (0.416, 0.767) 0.00024	0.810 (0.596, 1.102) 0.18039
Q4	0.300 (0.206, 0.437) <0.00001	0.503 (0.342, 0.742) 0.00051	0.730 (0.496, 1.074) 0.10988
P for trend	<0.00001	0.00001	0.06169
Female
AST/ALT ratio	0.136 (0.061, 0.304) <0.00001	0.362 (0.162, 0.806) 0.01290	0.597 (0.280, 1.277) 0.18362
AST/ALT ratio (quartile)
Q1	Ref	Ref	Ref
Q2	0.397 (0.221, 0.716) 0.00211	0.491 (0.271, 0.889) 0.01888	0.683 (0.371, 1.256) 0.21944
Q3	0.245 (0.138, 0.436) <0.00001	0.407 (0.224, 0.739) 0.00314	0.652 (0.353, 1.204) 0.17162
Q4	0.190 (0.103, 0.349) <0.00001	0.395 (0.208, 0.749) 0.00446	0.587 (0.309, 1.115) 0.10336
P for trend	<0.00001	0.00450	0.11511
Male
AST/ALT ratio	0.198 (0.122, 0.322) <0.00001	0.347 (0.205, 0.586) 0.00008	0.634 (0.381, 1.055) 0.07941
AST/ALT ratio (quartile)
Q1	Ref	Ref	Ref
Q2	0.478 (0.350, 0.651) <0.00001	0.566 (0.413, 0.776) 0.00041	0.702 (0.511, 0.964) 0.02900
Q3	0.461 (0.329, 0.646) <0.00001	0.617 (0.433, 0.878) 0.00731	0.867 (0.607, 1.239) 0.43285
Q4	0.379 (0.235, 0.609) 0.00006	0.588 (0.358, 0.964) 0.03543	0.866 (0.528, 1.422) 0.57024
P for trend	<0.00001	0.00087	0.26053

Notes: Crude model: we did not adjust other covariates. Model I: we adjust age, WC, BMI, exercise, ethanol consumption, smoking status, SBP; DBP. Model II: we adjust age, WC, BMI, exercise, ethanol consumption, smoking status, SBP, DBP, TC, HDL, TG, FPG.

Abbreviations: CI, confidence; Ref, reference.

Table 4 The Result of the Two-Piecewise Linear Regression Model

Incident Diabetes	Total (HR, 95% CI, P)	Female (HR, 95% CI, P)	Male (HR, 95% CI, P)
Fitting model by standard linear regression	0.617 (0.405, 0.938) 0.0240	0.597 (0.280, 1.277) 0.1836	0.634 (0.381, 1.055) 0.0794
Fitting model by two-piecewise linear regression
Inflection point of AST/ALT	0.882	1.368	0.9
≤Inflection point	0.287 (0.126, 0.655) 0.0030	0.458 (0.171, 1.225) 0.1198	0.251 (0.105, 0.598) 0.0018
>Inflection point	1.036 (0.561, 1.913) 0.9105	1.561 (0.163, 14.968) 0.6996	1.571 (0.708, 3.488) 0.2666
P for log likelihood ratio test	0.037	0.410	0.011

Notes: We adjusted age, WC, BMI, exercise, ethanol consumption, smoking status, SBP, DBP, TC, HDL, TG, FPG.

Abbreviations: HR, hazard ratios; CI, confidence intervals.

Figure 3 The non-linear relationship between AST/ALT and the incidence of diabetes.

Notes: The non-linear relationship between AST/ALT and the incidence of diabetes. A non-linear relationship between them was detected after adjusting for sex, age, WC, BMI, exercise, ethanol consumption, smoking status, SBP, DBP, TC, HDL, TG, FPG.

Table 5 Effect Size of AST/ALT on Diabetes in Prespecified and Exploratory Subgroups

Characteristic	No of Participants	HR (95% CI)	P value	P for Interaction
Age (years)				0.3503
<30	408	0.689 (0.004, 110.740)	0.8856
30 to <40	5111	0.505 (0.209, 1.221)	0.1294
40 to < 50	5722	0.561 (0.300, 1.048)	0.0698
50 to < 60	3348	0.695 (0.345, 1.399)	0.3080
≥60	702	0.932 (0.316, 2.749)	0.8981
Sex				0.4294
Male	8383	0.689 (0.419, 1.133)	0.1418
Female	6908	0.487 (0.234, 1.010)	0.0533
BMI				0.2618
<18.5	1602	0.790 (0.055, 11.294)	0.8621
≥18.5, <24	9943	0.449 (0.241, 0.837)	0.0118
≥24, <28	3056	0.769 (0.376, 1.572)	0.4719
≥28	690	0.884 (0.285, 2.742)	0.8309
WC group				0.7410
<90 in mela, <80 in female	13,292	0.628 (0.378, 1.043)	0.0721
≥90 in male, ≥80 in female	1999	0.542 (0.261, 1.127)	0.1009
Excise habit				0.0024
No	12,607	0.464 (0.290, 0.741)	0.0013
Yes	2684	2.361 (0.962, 5.792)	0.0607
Smoking status				0.3136
Never smoker	8904	0.753 (0.408, 1.388)	0.3626
Ever smoker	2932	0.644 (0.250, 1.657)	0.3618
Current smoker	3455	0.462 (0.224, 0.953)	0.0366
Ethanol consumption				0.8131
No (0 g/d)	4674	0.568 (0.260, 1.241)	0.1560
Yes (>0 g/d)	10,617	0.631 (0.393, 1.014)	0.0572
Fatty liver				0.7424
No	12,554	0.904 (0.501, 1.630)	0.7366
Yes	2737	0.785 (0.431, 1.431)	0.4297
SBP				0.9127
<140	14,508	0.657 (0.422, 1.023)	0.0627
≥140	783	0.609 (0.170, 2.184)	0.4466
DBP				0.9935
<90	14,534	0.632 (0.406, 0.983)	0.0418
≥90	757	0.628 (0.165, 2.400)	0.4968
GGT				0.1959
<40	14,022	0.565 (0.357, 0.894)	0.0148
≥40	1269	1.229 (0.428, 3.528)	0.7021
FPG				0.8191
Low	7412	0.599 (0.201, 1.783)	0.3571
High	7879	0.522 (0.328, 0.831)	0.0062

Notes: Note 1: Above model adjusted for sex, age, WC, BMI, exercise, ethanol consumption, smoking status, SBP, DBP, TC, HDL, TG, FPG. Note 2: In each case, the model is not adjusted for the stratification variable.