Decreased Serum Osteocalcin is an Independent Risk Factor for Metabolic Dysfunction-Associated Fatty Liver Disease in Type 2 Diabetes

Figures & data

Table 1 Characteristics of the Subjects According to Osteocalcin Quartiles

Variables	Q1 (n=472)	Q2 (n=469)	Q3 (n=473)	Q4 (n=475)	P value	^aP value
Serum OCN (μmol/L)	<9.78	9.78–12.52	12.53–16.28	≥16.29	—	—
Male (n, %)	338 (71.6)	281 (59.9)	261 (55.2)	209 (44.0)	<0.001	<0.001
Age (years)	58±13	59±12	59±13	59±13	0.870	0.245
*DD (months)	108 (36–168)	108 (36–168)	96 (36–108)	96 (36–156)	0.814	0.320
Hypertension (n, %)	263 (55.7)	264 (56.3)	269 (56.9)	229 (48.2)	0.023	0.015
Obesity (n, %)	248 (53.0)	224 (47.8)	223 (47.1)	200 (42.1)	0.010	0.011
Smoking (n, %)	186 (39.4)	168 (35.8)	146 (30.9)	121 (25.5)	<0.001	0.726
Drinking (n, %)	122 (25.8)	105 (22.4)	71 (15.0)	48 (10.1)	<0.001	<0.001
IIAs (n, %)	366 (77.5)	350 (74.6)	319 (67.4)	324 (68.2)	<0.001	<0.001
LLD (n, %)	255 (54.0)	243 (51.8)	242 (51.2)	224 (47.2)	0.198	0.192
Metformin (n, %)	334 (70.8)	310 (66.1)	298 (63.0)	253 (53.3)	<0.001	<0.001
Insulin sensitizers (n, %)	71 (15.0)	74 (15.8)	61 (12.9)	56 (11.8)	0.254	0.094
SBP (mmHg)	133±16	132±17	132±18	132±17	0.558	0.339
DBP (mmHg)	80±9	81±9	80±10	80±9	0.534	0.643
WC (cm)	91.9±11.2	90.4±9.8	90.8±10.4	88.9±9.8	<0.001	0.023
WHR	0.94±0.07	0.92±0.06	0.93±0.06	0.91±0.06	<0.001	0.001
BMI (kg/m^2)	25.4±3.5	25.0±3.4	25.0±3.4	24.6±3.2	0.005	0.005
*FPG (mmol/L)	8.56 (6.95–11.06)	7.46 (6.13–9.61)	7.49 (6.11–9.86)	7.22 (5.83–8.96)	<0.001	<0.001
*2h PPG (mmol/L)	14.33 (11.20–18.09)	13.11 (10.23–16.51)	13.02 (10.27–16.07)	12.39 (9.31–15.79)	<0.001	<0.001
HbA1C (%)	9.77±2.35	9.18±2.19	8.98±2.15	8.58±2.31	<0.001	0.870
*FCP (ng/mL)	1.78 (1.13–2.43)	1.66 (1.11–2.56)	1.87 (1.21–2.53)	1.77 (1.10–2.44)	0.283	0.459
Fins (μU/mL)	12.17 (8.10–19.51)	12.11 (7.85–20.22)	11.20 (7.42–18.50)	11.71 (7.11–20.05)	0.233	0.229
2hins (μU/mL)	48.41 (32.30–69.93)	51.81 (34.44–77.76)	49.04 (32.57–77.56)	54.46 (35.46–80.42)	0.119	0.113
*2h C-P (ng/mL)	3.29 (2.08–5.48)	3.72 (2.16–5.93)	4.21 (2.41–6.26)	3.96 (2.37–6.06)	0.001	0.005
*TG (mmol/L)	1.57 (1.01–2.56)	1.47 (0.99–2.24)	1.34 (0.94–2.06)	1.34 (0.94–1.98)	<0.001	<0.001
TC (mmol/L)	4.91±1.49	4.80±1.21	4.74±1.02	4.85±1.08	0.179	0.248
HDL-C (mmol/L)	1.05±0.30	1.10±0.29	1.10±0.30	1.15±0.35	<0.001	0.031
LDL-C (mmol/L)	2.91±0.98	2.99±1.00	2.94±0.83	2.96±0.91	0.604	0.535
*Lp (a)	9.70 (5.07–20.45)	10.40 (5.43–19.30)	10.80 (6.00–20.60)	11.80 (6.60–21.75)	0.050	0.179
*ALT (U/L)	20 (15–30)	21 (15–31)	20 (14–30)	18 (13–29)	0.002	0.008
*γ-GT (U/L)	26 (18–39)	25 (18–37)	24 (17–40)	22 (16–33)	<0.001	0.003
*Scr (μmol/L)	66 (54–80)	66 (55–77)	67 (54–79)	64 (54–76)	0.701	<0.001
*SUA (μmol/L)	325 (259–381)	314 (256–384)	305 (256–360)	294 (247–356)	<0.001	0.086
*UAE (mg/24h)	14.22 (7.42–49.03)	11.49 (6.67–28.87)	11.49 (6.79–28.51)	9.48 (6.18–23.90)	<0.001	<0.001
*eGFR (mL/min/1.73 m^2)	118 (92–142)	112 (94–138)	111 (90–132)	111 (94–133)	0.043	<0.001

Notes: Values are expressed as number (%), mean ± standard deviation, or median (interquartile range). P values: The P values were not adjusted for age and sex for the trend. ^aP values: The ^aP values were adjusted for age and sex for the trend. *The Mann-Whitney U–test was applied.

Abbreviations: OCN, osteocalcin; DD, diabetes duration; IIA, insulin or insulin analogue; LLD, lipid-lowering drug; SBP, systolic blood pressure; DBP, diastolic blood pressure; WC, waist circumference; WHR, waist-to-hip ratio; BMI, body mass index; FPG, fasting plasma glucose; PPG, postprandial plasma glucose; HbA1c, glycated hemoglobin A1c; FCP, fasting C-peptide; PCP, postprandial C-peptide; TG, triglycerides; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); ALT, alanine aminotransferase; γ-GT, γ-glutamyltransferase; Cr, creatinine; SUA, serum uric acid; UAE, urinary albumin excretion; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein.

Figure 1 Comparisons of MAFLD prevalence and serum OCN levels stratified by sex, age, and DD. (A) Overall prevalence of MAFLD in the subjects and comparison of the MAFLD prevalence between men and women (P = 0.003). (B) Comparison of the MAFLD prevalence among the subjects stratified by age after controlling for sex and diabetes duration (DD) (P < 0.001 for trend). (C) Comparison of the MAFLD prevalence among the subjects stratified by DD after controlling for sex and age (P < 0.001 for trend). (D) Comparison of serum osteocalcin (OCN) levels between men and women (P = 0.001). (E) Comparison of serum OCN levels among the subjects stratified by age after controlling for sex and DD (P = 0.057 for trend). (F) Comparison of serum OCN levels among the subjects stratified by DD after controlling for sex and age (P = 0.091 for trend).

Figure 2 Comparisons of metabolic dysfunction-associated fatty liver disease (MAFLD) prevalence. (A) Comparisons of the prevalence of MAFLD across the serum osteocalcin (OCN) quartiles after controlling for sex, age, and diabetes duration (P < 0.001 for trend). (B) Comparisons of serum OCN levels between the type 2 diabetes mellitus patients with and without MAFLD (P < 0.001).

Figure 3 Comparisons of liver enzymes. (A) Comparisons of alanine aminotransferase (ALT) between type 2 diabetes mellitus (T2DM) patients with and without metabolic dysfunction-associated fatty liver disease (MAFLD) after controlling for age, sex, and diabetes duration (DD) (P < 0.001). (B) Comparisons of ALT across the serum osteocalcin quartiles after controlling for age, sex, and DD (P = 0.007 for trend). (C) Comparisons of γ-glutamyltransferase (γ-GT) between T2DM patients with and without MAFLD after controlling for age, sex, and DD (P < 0.001). (D) Comparisons of γ-GT across the serum OCN quartiles after controlling for age, sex, and DD (P = 0.001 for trend).

Figure 4 Comparisons of insulin resistance parameters and C-reactive protein (CRP). (A) Comparison of homeostasis model assessment of insulin resistance (HOMA-IR) between the type 2 diabetes mellitus (T2DM) patients with and without metabolic dysfunction-associated fatty liver disease (MAFLD) after controlling for age, sex, and diabetes duration (DD) (P < 0.001). (B) Comparisons of HOMA-IR across the serum osteocalcin (OCN) quartiles after controlling for age, sex, and DD (P = 0.001 for trend). (C) Comparison of HOMA2-IR between the T2DM patients with and without MAFLD after controlling for age, sex, and DD (P < 0.001). (D) Comparisons of HOMA2-IR across the serum OCN quartiles after controlling for age, sex, and DD (P = 0.068 for trend). (E) Comparison of serum CRP levels between the T2DM patients with and without MAFLD after controlling for age, sex, and DD (P < 0.001). (F) Comparisons of serum CRP levels across the serum OCN quartiles after controlling for age, sex, and DD (P < 0.001 for trend).

Table 2 The Association of Serum Osteocalcin Levels with MAFLD

	B Statistic	OR	95% CI	P value
Model 1	−0.208	0.812	0.729–0.904	<0.001
Model 2	−0.193	0.825	0.739–0.920	0.001
Model 3	−0.219	0.804	0.713–0.906	<0.001
Model 4	−0.184	0.832	0.719–0.962	0.013

Notes: Model 1: adjusted for age, sex, diabetes duration, smoking, drinking, history of hypertension and obesity. Model 2: further adjusted for the use of lipid-lowering drugs, metformin, insulin or insulin analogues and insulin sensitizers. Model 3: further adjusted for systolic blood pressure, diastolic blood pressure, waist circumference, waist-to-hip ratio and body mass index. Model 4: further adjusted for total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), creatinine, estimated glomerular filtration rate, serum uric acid, urinary albumin excretion, C-reactive protein, glycated hemoglobin A1c, fasting plasma glucose, 2-hour postprandial plasma glucose, fasting insulin, 2-hour postprandial insulin, homeostasis model assessment of insulin resistance (HOMA-IR), fasting C-peptide, 2-hour postprandial C-peptide and HOMA2-IR.

Abbreviations: OCN, osteocalcin; MAFLD, metabolic dysfunction-associated fatty liver disease; OR, odds ratio; CI, confidence interval.