General and Abdominal Obesity and Incident Distal Sensorimotor Polyneuropathy: Insights Into Inflammatory Biomarkers as Potential Mediators in the KORA F4/FF4 Cohort

Sabrina Schlesinger; Christian Herder; Julia M. Kannenberg; Cornelia Huth; Maren Carstensen-Kirberg; Wolfgang Rathmann; Gidon J. Bönhof; Wolfgang Koenig; Margit Heier; Annette Peters; Christa Meisinger; Michael Roden; Barbara Thorand; Dan Ziegler

doi:10.2337/dc18-1842

Epidemiology/Health Services Research

General and Abdominal Obesity and Incident Distal Sensorimotor Polyneuropathy: Insights Into Inflammatory Biomarkers as Potential Mediators in the KORA F4/FF4 Cohort

Sabrina Schlesinger¹,² ⇑,
Christian Herder²,³,⁴,
Julia M. Kannenberg²,³,
Cornelia Huth²,⁵,
Maren Carstensen-Kirberg²,³,
Wolfgang Rathmann¹,²,⁴,
Gidon J. Bönhof³,
Wolfgang Koenig⁶,⁷,⁸,
Margit Heier⁵,
Annette Peters²,⁵,
Christa Meisinger⁵,⁹,
Michael Roden²,³,¹⁰,
Barbara Thorand²,⁵ and
Dan Ziegler²,³,¹⁰

¹Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
²German Center for Diabetes Research, München-Neuherberg, Germany
³Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
⁴Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
⁵Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
⁶Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
⁷German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
⁸Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
⁹Chair of Epidemiology, Ludwig-Maximilians-Universität München am UNIKA-T Augsburg, Augsburg, Germany
¹⁰Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Corresponding author: Sabrina Schlesinger, sabrina.schlesinger{at}ddz.de

S.S. and C.He. contributed equally to this work.
B.T. and D.Z. contributed equally to this work.

Diabetes Care 2019 Feb; 42(2): 240-247. https://doi.org/10.2337/dc18-1842

Article Figures & Tables

Tables

Table 1

Baseline characteristics of the study population in KORA F4 stratified by incidence of DSPN^*

Variable	No incident DSPN	Incident DSPN	P
N	386	127
Age (years)	67.9 ± 4.6	70.2 ± 5.0	<0.001
Men (%)	49.2	55.9	0.169
Socioeconomic status (%)^†			0.139
Low	23.6	27.0
Moderate low	21.2	19.8
Moderate	21.8	27.8
Moderate high	19.2	11.1
High	14.2	14.3
Height (cm)	166 ± 9	167 ± 9	0.016
BMI (kg/m²)	27.6 ± 3.9	29.2 ± 4	<0.001
BMI classes (%)			0.001
Normal weight (18.5 to <25 kg/m²)	27.5	11.0
Overweight (25 to <30 kg/m²)	46.1	52.8
Obese (≥30 kg/m²)	26.4	36.2
Waist circumference (cm)	94.7 ± 11.3	100.1 ± 11.4	<0.001
Waist circumference classes (%)			<0.001
WHO definition
Low (M: <102, W: <88 cm)	53.1	34.6
High (M: ≥102, W: ≥88 cm)	46.9	65.4
IDF definition			0.001
Low (M: <94, W: <80 cm)	24.1	11.0
High (M: ≥94, W: ≥80 cm)	75.9	89.0
WHR	0.90 ± 0.08	0.92 ± 0.08	0.004
WHR classes (%)			0.071
Low (M: <0.95, W: <0.8)	35.8	27.6
High (M: ≥0.95, W: ≥0.8)	64.2	72.4
HbA_1c (%)	5.66 ± 0.48	5.83 ± 0.69	0.014
HbA_1c (mmol/mol)	39 ± 6	40 ± 7	0.014
Diabetes status (%)			0.299
No diabetes	45.9	38.6
Prediabetes^§	40.2	40.9
Diabetes	14.0	20.5
Hypertension (%)^‡	56.5	65.4	0.452
Total cholesterol mmol/L (mmol/L)^¶	6.06 ± 1.01	5.82 ± 1.12	0.094
Fasting triglycerides (mmol/L)^¶	1.27 (0.97; 1.77)	1.29 (1.05; 1.67)	0.745
Use of lipid-lowering drugs (%)	23.1	26.8	0.643
eGFR (mL/min/1.73 m²)	80.2 ± 13.1	76.9 ± 14.3	0.498
Smoking status (%)
Never	51.6	54.3	0.002
Former	42.7	33.9
Current	5.7	11.8
Alcohol intake (%)^#
Abstainer	31.1	30.7	0.584
Moderate intake	52.3	51.2
High intake	16.6	18.1
Physically active (%)^‖	62.2	41.7	<0.001
Myocardial infarction (%)	5.2	7.1	0.850
Neurological conditions that might cause nerve damage (%)	15.1	20.5	0.084
Use of nonsteroidal anti-inflammatory drugs (%)^††	1.0	2.4	0.375
IL-6 (pg/mL)	1.33 (0.94; 1.96)	1.71 (1.22; 2.52)	0.005
TNF-α (pg/mL)	1.90 (1.39; 2.73)	2.09 (1.60; 3.43)	0.062
CCL7 (NPX)	1.83 ± 0.50	2.09 ± 0.64	<0.001
CXCL9 (NPX)	7.27 ± 0.75	7.68 ± 0.89	<0.001
CXCL10 (NPX)	9.32 ± 0.84	9.74 ± 1.09	<0.001
DNER (NPX)	8.32 ± 0.26	8.34 ± 0.26	0.084
CD40 (NPX)	10.19 ± 0.32	10.31 ± 0.34	0.001
TNFRSF9 (NPX)	6.19 ± 0.44	6.41 ± 0.47	<0.001

Data are shown as mean ± SD, median (interquartile range), or percentages. The P values are derived from logistic regression analysis (likelihood ratio tests comparing models with the respective variable and age and sex as independent variables to models with age and sex only). All analyses were adjusted for age and sex except associations with age (sex-adjusted only) or sex (age-adjusted only). Data from this table have been published in a previous report from the KORA study (10).
CD, cluster of differentiation; eGFR, estimated glomerular filtration rate; HbA_1c, glycated hemoglobin; M, men; W, women.
↵*DSPN defined by MNSI >3.
↵†Socioeconomic status based on a score including education, income, and occupation and classified as low (1–9 points), moderate low (10–12 points), moderate (13–15 points), moderate high (16–19 points), and high (>19 points).
↵§Prediabetes was defined as IFG and/or IGT.
↵‡Blood pressure of ≥140/90 mmHg or antihypertensive medication given that the subjects were aware of as hypertensive.
↵¶Individuals using lipid-lowering drugs excluded (n = 123).
↵#Classified as none (0 g/day), moderate (≥0 to <20 g/day for women and ≥0 to <40 g/day for men), or high (≥20 g/day for women and ≥40 g/day for men).
↵‖Defined as >1 h sports/week in summer and winter.
↵††Nonsteroidal anti-inflammatory drugs except acetylsalicylic acid used as platelet aggregation inhibitor.

Table 2

ORs and 95% CIs of incident DSPN according to anthropometric measures in KORA F4 (n = 513)

	N	Cases	Model 1^*	Model 2^†	Model 3^‡
BMI (kg/m²)
Normal weight (<25)	120	14	1	1	1
Overweight (25 to <30)	245	67	2.75 (1.45; 5.22)	3.06 (1.57; 5.97)	3.20 (1.57; 6.53)
Obese (≥30)	148	46	3.31 (1.70; 6.47)	3.47 (1.72; 7.00)	3.21 (1.50; 6.87)
P trend			0.001	0.002	0.017
BMI per 5 kg/m²	513	127	1.66 (1.27; 2.16)	1.68 (1.28; 2.22)	1.58 (1.17; 2.14)
Waist circumference (cm)
WHO definition
Low (M: <102, W: <88)	249	44	1	1	1
High (M: ≥102, W: ≥88)	264	83	2.17 (1.40; 3.36)	2.06 (1.30; 3.26)	1.87 (1.13; 3.08)
IDF definition
Low (M: <94, W: <80)	107	14	1	1	1
High (M: ≥94, W: ≥80)	406	113	2.60 (1.40; 4.84)	2.72 (1.42; 5.19)	2.55 (1.28; 5.05)
Waist circumference per 5 cm	513	127	1.25 (1.12; 1.39)	1.24 (1.11; 1.39)	1.21 (1.07; 1.36)
WHR
Low (M: <0.95, W: <0.8)	173	35	1	1	1
High (M: ≥0.95, W: ≥0.8)	340	92	1.62 (1.01; 2.61)	1.51 (0.91; 2.50)	1.30 (0.76; 2.23)
WHR per 0.1 units	513	127	1.83 (1.24; 2.68)	1.79 (1.20; 2.67)	1.60 (1.03; 2.49)
WHtR
WHtR per 0.1 units	513	127	1.73 (1.25; 2.38)	1.68 (1.19; 2.35)	1.51 (1.04; 2.18)

M, men; W, women.
↵*Model 1: adjusted for age and sex.
↵†Model 2: model 1 plus adjustment for socioeconomic status, smoking status, alcohol intake, physical activity, and height (not in models for BMI and WHtR).
↵‡Model 3: model 2 plus adjustment for HbA_1c, hypertension, HDL cholesterol, LDL cholesterol, and triglycerides.

Table 3

Association between potential mediators and anthropometric measures in KORA F4 (n = 513)^*

Potential mediator	BMI (kg/m²)		Waist circumference (cm)
Potential mediator	β	95% CI	β	95% CI
IL-6 (pg/mL)	0.086	−0.158; 0.329	0.030	−0.062; 0.122
TNF-α (pg/mL)	0.161	−0.174; 0.496	0.069	−0.059; 0.196
CCL7 (NPX)	0.063	0.001; 0.125	0.025	0.001; 0.048
CXCL9 (NPX)	0.008	−0.080; 0.958	0.012	−0.021; 0.046
CXCL10 (NPX)	0.135	0.032; 0.239	0.059	0.020; 0.098
DNER (NPX)	−0.043	−0.072; −0.014	−0.018	−0.029; −0.007
CD40 (NPX)	0.008	−0.029; 0.045	0.003	−0.011; 0.017
TNFRSF9 (NPX)	0.046	−0.005; 0.098	0.014	−0.006; 0.034

Boldface type indicates statistically significant findings. The association was interpreted as statistically significant if the 95% CI of the β-estimate did not include the null value.
↵*Associations are adjusted for age, sex, socioeconomic status, smoking status, alcohol intake, physical activity, and height (not in models for BMI).

Table 4

Effect estimates (95% CI) for incident DSPN for 5-unit increase in anthropometric measure and estimated percent mediated by inflammatory biomarker^*

	Direct effect	Indirect effect	Total effect	Percent mediated^†
BMI (kg/m²)
TNF-α	0.013 (0.005; 0.021)	0.000 (0.000; 0.002)	0.014 (0.005; 0.021)	1.6 (−2.0; 9.7)
IL-6	0.014 (0.005; 0.024)	0.000 (−0.004; 0.003)	0.014 (0.005; 0.022)	1.3 (−18.6; 20.3)
CCL7	0.013 (0.005; 0.020)	0.001 (0.000; 0.004)	0.014 (0.005; 0.022)	6.8 (0.0; 22.2)
CXCL9	0.014 (0.005; 0.023)	0.000 (−0.003; 0.002)	0.014 (0.006; 0.021)	7.0 (−16.4; 14.2)
CXCL10	0.012 (0.005; 0.019)	0.002 (0.000; 0.006)	0.014 (0.005; 0.021)	10.5 (1.3; 32.8)
DNER	0.015 (0.006; 0.026)	−0.001 (−0.005; 0.000)	0.014 (0.005; 0.021)	−7.5 (−0.4; −25.6)
CD40	0.014 (0.005; 0.022)	0.000 (−0.002; 0.002)	0.014 (0.005; 0.021)	1.4 (−9.6; 11.3)
TNFRSF9	0.012 (0.005; 0.020)	0.001 (0.000; 0.004)	0.014 (0.006; 0.021)	7.8 (−1.7; 21.6)
Waist circumference (cm)
TNF-α	0.002 (0.000; 0.005)	0.000 (0.000; 0.000)	0.002 (0.000; 0.005)	1.9 (−1.1; 8.8)
IL-6	0.002 (0.000; 0.006)	0.000 (−0.001; 0.000)	0.002 (0.000; 0.005)	9.0 (−1.7; 15.2)
CCL7	0.002 (0.000; 0.004)	0.000 (0.000; 0.001)	0.002 (0.000; 0.005)	6.9 (0.7; 21.3)
CXCL9	0.002 (0.000; 0.005)	0.000 (0.000; 0.001)	0.002 (0.000; 0.005)	2.8 (−10.5; 15.6)
CXCL10	0.002 (0.000; 0.004)	0.000 (0.000; 0.001)	0.002 (0.000; 0.005)	11.2 (2.8; 30.2)
DNER	0.002 (0.000; 0.007)	0.000 (−0.001; 0.000)	0.002 (0.000; 0.005)	−9.2 (−1.3; −32.4)
CD40	0.002 (0.000; 0.005)	0.000 (0.000; 0.000)	0.002 (0.000; 0.005)	1.5 (−9.7; 13.0)
TNFRSF9	0.002 (0.000; 0.005)	0.000 (0.000; 0.001)	0.002 (0.000; 0.005)	5.4 (−5.4; 18.3)

Data are β (95% CI) unless otherwise indicated.
↵*Models adjusted for age, sex, socioeconomic status, smoking status, alcohol intake, physical activity, and height (not in models for BMI).
↵†Boldface type indicates statistically significant findings. The mediation effect was interpreted as statistically significant if the 95% CI of the percent mediated effect did not include the null value.