Effect of Metabolic Health and Obesity Phenotype on Risk of Diabetes Mellitus: A Population-Based Longitudinal Study

Figures & data

Figure 1 Flowchart for selection of study participants.

Table 1 Baseline Characteristics of the Body Mass Index-Metabolic Status Phenotypes

Variables	Metabolically Healthy (N=2080)			Metabolically Unhealthy (N=1561)			F/χ^2/H	P ^a
	Normal Weight	Overweight	Obesity	Normal Weight	Overweight	Obesity
	n=1040	n=845	n=195	n=253	n=783	n=525
Demographic characteristics
Age (y), n (%)
(mean±SD)	50.85±9.52	50.98±8.77	49.60±9.35^▲	53.63±7.90*	52.91±7.58*	51.99±8.49	10.98	<0.001
<50	421 (40.48)	347 (41.07)	83 (42.56)	71 (28.06)*	243 (31.03)*	183 (34.86)	43.89	<0.001
50–59	382 (36.73)	318 (37.63)	82 (42.05)	108 (42.69)*	357 (45.59)*	221 (42.10)
≥60	237 (22.79)	180 (21.30)	30 (15.38)	74 (29.25)*	183 (23.37)*	121 (23.05)
Gender, n (%)
Male	380 (36.54)	347 (41.07)	81 (41.54)	73 (28.85)^▲	284 (36.27)	208 (39.62)	15.83	0.007
Female	660 (63.46)	498 (58.93)	114 (58.46)	180 (71.15)^▲	499 (63.73)	317 (60.38)
Education level, n (%)
Junior high school or below	884 (85.00)	717 (84.85)	156 (80.00)	219 (86.56)	685 (87.48)	450 (85.71)	7.95	0.160
Senior high school or above	156 (15.00)	128 (15.15)	39 (20.00)	34 (13.44)	98 (12.52)	75 (14.29)
Drug history, n (%) ^b
No	734 (70.58)^▲	568 (67.22)^▲	122 (62.56)^▲	152 (60.08)*^▲	448 (57.22)*^▲	243 (46.29)*	140.36	<0.001
Yes	257 (24.71)^▲	234 (27.69)^▲	64 (32.82)^▲	89 (35.18)*^▲	314 (40.10)*^▲	268 (51.05)*
Unclear	49 (4.71)^▲	43 (5.09)^▲	9 (4.62)^▲	12 (4.74)*^▲	21 (2.68)*^▲	14 (2.67)*
History of chronic disease, n (%) ^c
No	709 (68.17)^▲	535 (63.31)^▲	107 (54.87)*	154 (60.87)^▲	401 (51.21)*	234 (44.57)*	108.97	<0.001
Yes	331 (31.83)^▲	310 (36.69)^▲	88 (45.13)*	99 (39.13)^▲	382 (48.79)*	291 (55.43)*
Family history of diabetes, n (%)
No	830 (79.81)	659 (77.99)	155 (79.49)	203 (80.24)	611 (78.03)	414 (78.86)	8.83	0.548
Yes	161 (15.48)	151 (17.87)	29 (14.87)	42 (16.60)	137 (17.50)	97 (18.48)
Unclear	49 (4.71)	35 (4.14)	11 (5.64)	8 (3.16)	35 (4.47)	14 (2.67)
Behavioral characteristics
Smoking status, n (%)
Never	785 (75.48)	637 (75.38)	142 (72.82)	203 (80.24)	623 (79.57)	404 (76.95)	8.72	0.121
Ever	255 (24.52)	208 (24.62)	53 (27.18)	50 (19.76)	160 (20.43)	121 (23.05)
Drinking status, n (%)
Never	790 (75.96)	617 (73.02)	144 (73.85)	205 (81.03)	558 (71.26)	394 (75.05)	12.19	0.032
Ever	250 (24.04)	228 (26.98)	51 (26.15)	48 (18.97)	225 (28.74)	131 (24.95)
Regular physical activity, n (%)
No	808 (77.69)^▲	603 (71.36)*	142 (72.82)	192 (75.89)	553 (70.63)*	369 (70.29)*	18.04	0.003
Yes	232 (22.31)^▲	242 (28.64)*	53 (27.18)	61 (24.11)	230 (29.37)*	156 (29.71)*
Anthropometric characteristics
BMI (kg/cm^2) (mean±SD)	21.93±1.35^▲	25.67±1.09*^▲	30.13±2.27*^▲	22.64±1.06*^▲	26.07±1.12*^▲	30.55±2.56*	2797.63	<0.001
SBP (mmHg) (mean±SD)	127.91±18.74^▲	130.54±17.21*^▲	131.82±19.01^▲	139.84±17.49*^▲	141.33±17.51*	144.10±17.86*	94.29	<0.001
DBP (mmHg) (mean±SD)	78.37±10.80^▲	80.39±10.53*^▲	82.03±12.81*^▲	84.28±10.78*^▲	85.97±10.60*	87.70±10.48*	79.36	<0.001
WC (cm) ^d
(mean±SD)	77.16±6.72^▲	84.37±6.70*^▲	91.03±8.59*^▲	83.04±6.17*^▲	88.09±6.31*^▲	95.47±8.10*	572.77	<0.001
Normal	902 (86.73)^▲	479 (56.69)*^▲	55 (28.21)*^▲	101 (39.92)*^▲	159 (20.31)*^▲	39 (7.43)*	1300.00	<0.001
Non-standard	138 (13.27)^▲	366 (43.31)*^▲	140 (71.79)*^▲	152 (60.08)*^▲	624 (79.69)*^▲	486 (92.57)*
Waist-to-height ratio ^e
<0.5	673 (64.71)^▲	179 (21.18)*^▲	17 (8.72)*^▲	71 (28.06)*^▲	57 (7.28)*^▲	5 (0.95)*	1100.00	<0.001
≥0.5	367 (35.29)^▲	666 (78.82)*^▲	178 (91.28)*^▲	182 (71.94)*^▲	726 (92.72)*^▲	520 (99.05)*
Waist-to-hip ratio ^f
Normal	626 (60.19)^▲	311 (36.80)*^▲	50 (25.64)*^▲	69 (27.27)*^▲	118 (15.07)*	54 (10.29)*	590.89	<0.001
Non-standard	414 (39.81)^▲	534 (63.20)*^▲	145 (74.36)*^▲	184 (72.73)*^▲	665 (84.93)*	471 (89.71)*
Biochemical characteristics
FPG (mmol/L) (mean±SD)	5.55±0.49^▲	5.55±0.49^▲	5.44±0.43*^▲	5.87±0.47*	5.85±0.46*	5.86±0.46*	81.40	<0.001
2hPG (mmol/L) (mean±SD)	6.44±1.50^▲	6.56±1.43^▲	6.79±1.49*^▲	7.02±1.60*^▲	7.17±1.57*^▲	7.71±1.67*	62.49	<0.001
HbA1c (%) (mean±SD)	5.26±0.40^▲	5.32±0.40*^▲	5.32±0.39^▲	5.34±0.43^▲	5.41±0.39*	5.45±0.39*	21.15	<0.001
AST (U/L) (mean±SD)	24.88±14.43	25.27±15.57	27.09±15.46	25.38±9.54	25.60±12.53	26.70±10.40	1.85	0.099
ALT (U/L) (median, IQR)	15 (12–21)^▲	18 (13–25)*^▲	20 (15–30)*	17(13–26)*^▲	20 (15–28)*^▲	23 (17–33)*	250.61	<0.001Ϯ
GGT (U/L) (median, IQR)	13 (9–19)^▲	15 (11–24)*^▲	19 (12–30)*	14 (10–23)*^▲	18 (12–29)*^▲	22 (15–35)*	326.95	<0.001Ϯ
STB (μmol/L) (mean±SD)	14.97±5.69^▲	14.33±5.61	13.20±4.82*	14.26±6.42	14.29±5.34	13.70±5.12*	5.80	<0.001
TC (mmol/L) (mean±SD)	4.68±0.90^▲	4.75±0.95^▲	4.72±0.75^▲	4.87±0.93*	4.97±0.94*	5.00±0.98*	14.46	<0.001
LDL-C (mmol/L) (mean±SD)	2.47±0.66^▲	2.63±0.67*^▲	2.68±0.57*	2.65±0.66*	2.72±0.70*	2.77±0.71*	18.65	<0.001
HDL-C (mmol/L) (mean±SD)	1.68±0.36^▲	1.57±0.31*^▲	1.50±0.30*^▲	1.42±0.42*	1.40±0.37*	1.38±0.34*	86.87	<0.001
TG (mmol/L) (median, IQR)	0.96 (0.74–1.29)*^▲	1.12 (0.85–1.44)*^▲	1.15 (0.91–1.49)*^▲	1.85 (1.27–2.56)*	1.92 (1.33–2.65)*	1.93 (1.33–2.76)*	1063.16	<0.001Ϯ

Notes: Data was presented as mean±SD (standard deviation) or median (IQR) for continuous variables when appropriate; number (percentage) for categorical variables. ϮThe Kruskal–Wallis H-test was used to examine the differences of ALT, GGT and TG among six body mass index-metabolic status phenotypes because of heterogeneity of variance. *Multiple comparison with Bonferroni-adjusted P-value <0.05 when compared with metabolically healthy normal weight group. ^▲Multiple comparison with Bonferroni-adjusted P-value <0.05 when compared with metabolically unhealthy obese group. ^a χ ² test, One-way analysis of variance or Kruskal–Wallis H-test was used to examine the difference of six groups (Metabolically healthy normal weight vs Metabolically healthy overweight vs Metabolically healthy obese vs Metabolically unhealthy normal weight vs Metabolically unhealthy overweight vs Metabolically unhealthy obese) when appropriate. ^bDrugs included antihypertensive agent, antilipemic agent, antithrombotic agent, antineoplastic agent, steroid hormone drugs. ^cHistory of chronic disease included hypertension, coronary heart disease, dyslipidemia, stroke, kidney disease, hepatic diseases, malignant tumor. ^dWC≤80cm for female or WC≤90cm for male was considered as normal. ^eWaist-to-height ratio≥0.5 was considered as central obesity. ^fWaist-to-hip ratio<0.85 for female or Waist-to-hip ratio<0.90 for male was considered as normal.

Abbreviations: y, years; n, number; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; WC, waist circumference; FPG, fasting plasma glucose;2hPG, 2-hour plasma glucose; HbA1c, glycosylated haemoglobin; AST, aspartate aminotransferase; ALT, alanine transaminase; GGT, gamma glutamyl transferase; STB, serum total bilirubin; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride; IQR, inter-quartile range.

Table 2 Diabetes Incidence Density at the End of Follow-Up (Until August, 2020) Among Six Body Mass Index-Metabolic Status Phenotypes at Baseline

BMI-Metabolic Status	Follow-Up Time (Person-Year)	Events (n)	Incidence Density (%)
Metabolically healthy normal weight	1688	90	5.33
Metabolically healthy overweight	1388	58	4.18
Metabolically healthy obesity	322	16	4.97
Metabolically unhealthy normal weight	414	35	8.45
Metabolically unhealthy overweight	1317	113	8.58
Metabolically unhealthy obesity	853	103	12.08
Total	5982	415	6.94
P for trend			<0.001

Abbreviation: BMI, body mass index.

Table 3 The Association of Body Mass Index, Metabolic Status and Adult Treatment Panel III Components with Diabetes

Variables	Crude RR (95% CI)	P	Adjusted RR (95% CI) ^a	P ^a	Adjusted RR (95% CI) ^b	P ^b
Adult Treatment Panel III components
Waist circumference (WC)
Normal	Reference		Reference		Reference
Elevated WC	1.47 (1.23–1.77)	<0.001	1.63 (1.35–1.96)	<0.001	1.46 (1.21–1.76)	<0.001
Fasting plasma glucose (FPG)
Normal	Reference		Reference		Reference
Elevated FPG or medication	3.20 (2.63–3.89)	<0.001	4.57 (3.75–5.58)	<0.001	4.23 (3.47–5.16)	<0.001
Low-density lipoprotein cholesterol (LDL-C)
Normal	Reference		Reference		Reference
Reduced HDL-C or medication	0.89 (0.71–1.13)	0.340	1.04 (0.83–1.31)	0.705	0.97 (0.78–1.22)	0.819
Triglyceride (TG)
Normal	Reference		Reference		Reference
Elevated TG or medication	1.59 (1.33–1.90)	<0.001	1.67 (1.44–1.98)	<0.001	1.51 (1.27–1.80)	<0.001
Blood pressure
Normal	Reference		Reference		Reference
Elevated blood pressure or mediation	2.15 (1.72–2.67)	<0.001	1.89 (1.50–2.36)	<0.001	1.55 (1.21–1.97)	<0.001
Number of components (n)
0	Reference		Reference		Reference
1	1.09 (0.68–1.77)	0.711	1.11 (0.69–1.79)	0.671	1.05 (0.65–1.70)	0.836
2	1.83 (1.18–2.82)	0.007	1.93 (1.25–2.99)	0.003	1.74 (1.12–2.71)	0.014
3	3.07 (2.01–4.68)	<0.001	3.50 (2.30–5.34)	<0.001	2.98 (1.94–4.59)	<0.001
4	4.16 (2.69–6.42)	<0.001	5.04 (3.27–7.79)	<0.001	4.11 (2.62–6.44)	<0.001
5	4.87 (2.87–8.25)	<0.001	8.53 (5.09–14.31)	<0.001	6.74 (3.95–11.48)	<0.001
P for trend	<0.001
Body mass index
Normal weight	Reference		Reference		Reference
Overweight	1.14 (0.92–1.42)	0.237	1.22 (0.98–1.51)	0.076	1.12 (0.90–1.38)	0.318
Obese	1.85 (1.45–2.35)	<0.001	2.03 (1.60–2.58)	<0.001	1.70 (1.33–2.17)	<0.001
Metabolic status
Healthy	Reference		Reference		Reference
Unhealthy	2.45 (2.04–2.95)	<0.001	2.82 (2.35–3.38)	<0.001	2.48 (2.06–2.98)	<0.001
P for multiplicative interaction	0.015

Notes: Results are based on a generalized estimating equation (GEE) with diabetes vs no diabetes as binary outcome (analysis sample n=9623). ^aAdjusted for follow-up time, age (numeric) and gender. ^bAdjusted for follow-up time, demographic characteristics (age (numeric), gender, education level, drug history, history of chronic disease and family history of diabetes) and behavioral characteristics (smoking status, drinking status, regular physical activity).

Table 4 The Association Between Body Mass Index-Metabolic Status Phenotypes and Diabetes

BMI-Metabolic Status	Crude RR (95% CI)	P	Adjusted RR (95% CI) ^a	P ^a	Adjusted RR (95% CI) ^b	P ^b
Metabolically healthy normal weight	Reference		Reference		Reference
Metabolically healthy overweight	0.64 (0.46–0.89)	0.007	0.67 (0.49–0.93)	0.016	0.65 (0.47–0.90)	0.009
Metabolically healthy obesity	1.02 (0.65–1.61)	0.919	1.08 (0.69–1.68)	0.741	0.99 (0.63–1.53)	0.949
Metabolically unhealthy normal weight	1.63 (1.13–2.36)	0.009	1.99 (1.41–2.82)	<0.001	1.81 (1.28–2.55)	0.001
Metabolically unhealthy overweight	2.01 (1.56–2.61)	<0.001	2.34 (1.82–3.01)	<0.001	2.02 (1.57–2.61)	<0.001
Metabolically unhealthy obesity	2.55 (1.94–3.34)	<0.001	2.95 (2.26–3.86)	<0.001	2.48 (1.89–3.26)	<0.001
P for trend	<0.001

Notes: Results are based on a generalized estimating equation (GEE) with diabetes vs no diabetes as binary outcome (analysis sample n=9623). ^aAdjusted for follow-up time, age (numeric) and gender. ^bAdjusted for follow-up time, demographic characteristics (age (numeric), gender, education level, drug history, history of chronic disease and family history of diabetes) and behavioral characteristics (smoking status, drinking status, regular physical activity).

Abbreviation: BMI, body mass index.

Figure 2 The association of body mass index-metabolic status phenotypes with diabetes in an analysis stratified by age. Adjusted for follow-up time, demographic characteristics (gender, education level, drug history, history of chronic disease and family history of diabetes) and behavioral characteristics (smoking status, drinking status, regular physical activity).

Abbreviation: BMI, body mass index.

Figure 3 The association of body mass index-metabolic status phenotypes with diabetes in an analysis stratified by gender. Adjusted for follow-up time, demographic characteristics (age (numeric), education level, drug history, history of chronic disease and family history of diabetes) and behavioral characteristics (smoking status, drinking status, regular physical activity).

Abbreviation: BMI, body mass index.