Visceral fat area and remnant cholesterol in type 2 diabetes: Nonlinear associations and thresholds

Table 1 Baseline characteristics of the study population across visceral fat area tertiles

Characteristic	T1, n = 392	T2, n = 387	T3, n = 401	P value
Age (years)	55.00 (48.00-61.00)	56.00 (47.00-63.00)	52.00 (42.00-61.00)	< 0.001
Sex				< 0.001
Female	182 (46.43)	156 (40.31)	100 (24.94)
Male	210 (53.57)	231 (59.69)	301 (75.06)
Current drinking				0.003
No	280 (74.27)	243 (67.13)	226 (60.75)
Yes	91 (25.73)	118 (32.87)	153 (39.25)
Current smoking				0.016
No	244 (69.91)	203 (62.85)	178 (57.05)
Yes	97 (30.09)	119 (37.15)	146 (42.95)
DBP (mmHg)	74.00 (68.00-78.00)	75.00 (70.00-80.00)	77.00 (72.00-85.00)	< 0.001
SBP (mmHg)	124.00 (116.75-131.00)	126.00 (118.00-137.00)	126.00 (120.00-137.00)	< 0.001
HbA1c (%)	9.30 (7.47-11.34)	9.07 (7.43-10.66)	9.61 (7.71-11.00)	0.163
TC (mmol/L)	4.49 (3.94-5.42)	4.68 (3.84-5.55)	4.73 (4.00-5.46)	0.187
HDLC (mmol/L)	1.16 (0.98-1.39)	1.09 (0.94-1.28)	1.00 (0.87-1.20)	< 0.001
LDL-C (mmol/L)	2.71 (2.07-3.45)	2.71 (2.08-3.47)	2.66 (2.05-3.40)	0.741
TG (mmol/L)	1.52 (1.04-2.62)	1.92 (1.27-3.23)	2.49 (1.54-4.17)	< 0.001
RC (mg/dL)	15.85 (2.71-26.30)	17.79 (6.96-30.16)	22.43 (10.44-42.92)	< 0.001
RCII	0.92 (0.00-3.42)	2.03 (0.00-6.75)	4.05 (0.00-12.65)	< 0.001
eGFR (mL/minute/1.73 m2)	103.43 (94.76-112.33)	102.15 (92.24-111.39)	105.33 (93.33-115.27)	0.209
SUA (μmol/L)	287.70 (235.42-348.33)	310.50 (262.60-375.30)	353.70 (303.05-417.40)	< 0.001
AST (U/L)	16.60 (13.97-21.30)	19.00 (15.70-26.35)	22.20 (16.70-34.20)	< 0.001
ALT (U/L)	18.70 (13.20-28.90)	23.20 (15.70-38.50)	31.10 (20.50-55.75)	< 0.001
CRP (mg/L)	1.15 (0.50-2.67)	1.67 (0.80-3.34)	2.62 (1.17-5.07)	< 0.001
WBC (× 109/L)	5.90 (5.07-7.30)	6.30 (5.20-7.40)	6.50 (5.50-7.80)	< 0.001
WC (cm)	83.10 (78.55-87.00)	89.00 (85.00-93.00)	97.30 (93.00-102.00)	< 0.001
VFA (cm2)	63.00 (50.00-70.00)	92.00 (86.00-100.00)	130.00 (117.00-152.00)	< 0.001
SFA (cm2)	124.50 (101.00-151.25)	162.00 (137.00-198.00)	219.00 (183.00-265.00)	< 0.001
FT3 (pmol/L)	3.87 (3.52-4.22)	3.96 (3.62-4.31)	4.05 (3.75-4.41)	< 0.001
FT4 (pmol/L)	12.54 (11.68-13.76)	12.57 (11.70-13.64)	12.59 (11.79-13.56)	0.860
TSH (μIU/mL)	1.47 (0.91-2.11)	1.34 (0.93-1.94)	1.40 (1.01-2.06)	0.724
BMI (kg/m2)	22.95 (21.40-24.40)	25.00 (23.70-26.60)	28.00 (26.30-30.80)	< 0.001
25(OH)D (ng/mL)	22.44 (17.00-27.66)	21.73 (16.70-27.16)	20.30 (16.15-24.39)	0.004

Data are presented as median (interquartile range) for continuous variables and n (%) for categorical variables, unless otherwise indicated. Differences across visceral fat area (VFA) tertiles (T1-T3) were assessed using the Kruskal-Wallis test for continuous variables and the χ² test (or Fisher’s exact test where appropriate) for categorical variables. VFA tertiles were defined according to the distribution of VFA in the study population (T1, lowest tertile; T3, highest tertile). HbA1c: Glycated haemoglobin; VFA: Visceral fat area; SFA: Subcutaneous fat area; BMI: Body mass index; WC: Waist circumference; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; TC: Total cholesterol; TG: Triglycerides; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; RC: Residual cholesterol; RCII: Residual cholesterol-inflammation index; SUA: Serum uric acid; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; CRP: C-reactive protein; WBC: White blood cell; FT3: Free triiodothyronine; FT4: Free thyroxine; TSH: Thyroid-stimulating hormone; 25(OH)D: 25-hydroxyvitamin D; eGFR: Estimated glomerular filtration rate.

Table 2 Associations of visceral fat area with residual cholesterol and the residual cholesterol-inflammation index in adults with type 2 diabetes

Exposure	Non-adjusted		Adjust I		Adjust II
	β (95%CI)	P value	β (95%CI)	P value	β (95%CI)	P value
RC
VFA	0.16 (0.10-0.21)	< 0.0001	0.14 (0.08-0.19)	< 0.0001	0.09 (0.01-0.17)	0.0330
VFA quartile
T1	1.0		1.0		1.0
T2	4.77 (-0.45 to 9.99)	0.0735	4.92 (-0.25 to 10.09)	0.0623	7.59 (0.65-14.53)	0.0325
T3	14.18 (9.01-19.36)	< 0.0001	12.28 (7.07-17.49)	< 0.0001	10.96 (3.50-18.42)	0.0041
P for trend	< 0.0001		< 0.0001		0.0036
RCII
VFA quartile	0.09 (0.04-0.15)	0.0018	0.08 (0.02-0.14)	0.0057	0.10 (-0.01 to 0.21)	0.0784
T1	1.0		1.0		1.0
T2	2.46 (-3.23 to 8.14)	0.3977	2.75 (-2.92 to 8.43)	0.3416	6.74 (-2.50 to 15.98)	0.1535
T3	9.19 (3.55-14.83)	0.0014	8.32 (2.61-14.04)	0.0044	12.56 (2.63-22.49)	0.0134
P for trend	0.0014		0.0044		0.0130

Data are β coefficients (95%CIs) and P values from linear regression models. Visceral fat area (VFA) was entered as a continuous variable and as tertiles (T1-T3), with T1 as the reference. The non-adjusted model included no covariates. Model 1 was adjusted for age and sex. Model 2 was additionally adjusted for current smoking, current drinking, glycated haemoglobin, free triiodothyronine, estimated glomerular filtration rate and alanine aminotransferase. P for trend across VFA tertiles was calculated by treating the tertiles as an ordinal variable. RC: Residual cholesterol; RCII: Residual cholesterol-inflammation index; VFA: Visceral fat area.

Table 3 Threshold effects of visceral fat area on residual cholesterol and the residual cholesterol to C-reactive protein ratio based on two-piecewise linear regression models

	Adjusted β (95%CI)	P value
RC
VFA (model I)	0.09 (0.01-0.17)	0.0330
VFA (model II)
Inflection point	126
VFA < 126	0.24 (0.12-0.35)	< 0.0001
VFA ≥ 126	-0.22 (-0.42 to -0.02)	0.0279
Difference (segment 2-1)	-0.46 (-0.73 to -0.19)	0.0007
Log likelihood ratio		< 0.001
RCII
VFA (model I)	0.10 (-0.01 to 0.21)	0.0784
VFA (model II)
Inflection point	118
VFA < 118	0.22 (0.05-0.39)	0.0105
VFA ≥ 118	-0.10 (-0.33 to 0.14)	0.4102
Difference (segment 2-1)	-0.32 (-0.66 to 0.02)	0.0623
Log likelihood ratio		0.060

Data are regression coefficients (β) with 95%CIs and P values from two-piecewise linear regression models with a single inflection point for visceral fat area (VFA). The inflection points were 126 cm² for residual cholesterol (RC) and 118 cm² for RC-inflammation index, estimated using a likelihood-based approach. The rows labelled “< inflection point” and “≥ inflection point” represent the slopes of VFA below and above the inflection point, respectively; “β difference” denotes the difference between these two slopes. Likelihood ratio test P indicates the P value from the likelihood ratio test comparing the two-piecewise model with a simple linear model. All models were adjusted for age, sex, current smoking, current drinking, glycated haemoglobin, free triiodothyronine, estimated glomerular filtration rate and alanine aminotransferase. RC: Residual cholesterol; RCII: Residual cholesterol-inflammation index; VFA: Visceral fat area.

Table 4 Subgroup and interaction analyses

	n	β (95%CI)	P value	P for interaction
RC
Age (year)			0.6211
< 60	784	0.12 (-0.00 to 0.25)	0.0522
≥ 60	396	0.08 (-0.00 to 0.17)	0.0644
Gender				0.2134
Female	438	0.00 (-0.09 to 0.10)	0.9245
Male	742	0.12 (0.00-0.23)	0.0437
Smoking status				0.3918
No	749	0.05 (-0.04 to 0.14)	0.2501
Yes	362	0.17 (-0.02 to 0.35)	0.0754
Drinking status				0.8779
No	747	0.08 (-0.01 to 0.18)	0.0763
Yes	362	0.10 (-0.07 to 0.26)	0.2418
BMI (kg/m2)				0.0201
< 28	915	0.21 (0.10-0.32)	0.0002
≥ 28	265	-0.04 (-0.23 to 0.15)	0.6817
HbA1C (%)				0.8224
< 6.5	53	0.06 (-0.23 to 0.35)	0.6908
≥ 6.5	658	0.09 (0.00-0.18)	0.0479
RCII
Age (year)			0.2841
< 60	784	0.15 (-0.01 to 0.30)	0.0636
≥ 60	396	0.00 (-0.14 to 0.14)	0.9729
Gender				0.7762
Female	438	0.12 (0.04-0.21)	0.0065
Male	742	0.09 (-0.07 to 0.25)	0.2849
Smoking status				0.9594
No	749	0.05 (-0.03 to 0.14)	0.2140
Yes	362	0.13 (-0.17 to 0.44)	0.3958
Drinking status				0.8483
No	747	0.09 (0.01-0.18)	0.0358
BMI (kg/m2)				0.3370
< 28	915	0.15 (-0.01-0.30)	0.0635
≥ 28	265	0.01 (-0.20-0.21)	0.9599
HbA1C (%)				0.4256
< 6.5	53	-0.08 (-0.28-0.11)	0.4083
≥ 6.5	658	0.10 (-0.01-0.22)	0.0869

Data are regression coefficients (β) with 95%CIs and P values from multivariable linear regression models stratified by the indicated subgroups. Visceral fat area (VFA) was modelled as a continuous variable. All models were adjusted for age, sex, current smoking, current drinking, glycated haemoglobin, free triiodothyronine, estimated glomerular filtration rate (eGFR) and alanine aminotransferase (ALT), except for the stratifying variable itself. P for interaction was obtained by adding a multiplicative interaction term between VFA and the subgroup indicator into the corresponding model. Recoded and the interaction terms for following variables: Age, sex, eGFR, ALT. RC: Residual cholesterol; RCII: Residual cholesterol-inflammation index; BMI: Body mass index; HbA1c: Glycated haemoglobin.