Cardiometabolic risk factors as determinants of peripheral nerve function: the Maastricht Study

Abstract

Aims/hypothesis: We aimed to examine associations of cardiometabolic risk factors, and (pre)diabetes, with (sensorimotor) peripheral nerve function.

Methods: In 2401 adults (aged 40-75 years) we previously determined fasting glucose, HbA_1c, triacylglycerol, HDL- and LDL-cholesterol, inflammation, waist circumference, blood pressure, smoking, glucose metabolism status (by OGTT) and medication use. Using nerve conduction tests, we measured compound muscle action potential, sensory nerve action potential amplitudes and nerve conduction velocities (NCVs) of the peroneal, tibial and sural nerves. In addition, we measured vibration perception threshold (VPT) of the hallux and assessed neuropathic pain using the DN4 interview. We assessed cross-sectional associations of risk factors with nerve function (using linear regression) and neuropathic pain (using logistic regression). Associations were adjusted for potential confounders and for each other risk factor. Associations from linear regression were presented as standardised regression coefficients (β) and 95% CIs in order to compare the magnitudes of observed associations between all risk factors and outcomes.

Results: Hyperglycaemia (fasting glucose or HbA_1c) was associated with worse sensorimotor nerve function for all six outcome measures, with associations of strongest magnitude for motor peroneal and tibial NCV, β_{fasting glucose} = -0.17 SD (-0.21, -0.13) and β_{fasting glucose} = -0.18 SD (-0.23, -0.14), respectively. Hyperglycaemia was also associated with higher VPT and neuropathic pain. Larger waist circumference was associated with worse sural nerve function and higher VPT. Triacylglycerol, HDL- and LDL-cholesterol, and blood pressure were not associated with worse nerve function; however, antihypertensive medication usage (suggestive of history of exposure to hypertension) was associated with worse peroneal compound muscle action potential amplitude and NCV. Smoking was associated with worse nerve function, higher VPT and higher risk for neuropathic pain. Inflammation was associated with worse nerve function and higher VPT, but only in those with type 2 diabetes. Type 2 diabetes and, to a lesser extent, prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were associated with worse nerve function, higher VPT and neuropathic pain (p for trend <0.01 for all outcomes).

Conclusions/interpretation: Hyperglycaemia (including the non-diabetic range) was most consistently associated with early-stage nerve damage. Nonetheless, larger waist circumference, inflammation, history of hypertension and smoking may also independently contribute to worse nerve function.

Keywords: Cardiometabolic risk factors; Diabetes status; Electrophysiological; Nerve conduction test; Neuropathy; The metabolic syndrome.

Fig. 1

Standardised associations (expressed as β with 95% CIs) of cardiometabolic risk factors and nerve function. (a) Associations with the sum-score of nerve function. Associations in model 1 (light blue) were adjusted for sex, height, age (with the exception of associations of age), educational level and skin temperature. Associations in model 2 (dark blue) were additionally adjusted for alcohol consumption, mobility limitations, CVD (history) and kidney function. In addition, all associations in model 2 were adjusted for each of the other risk factors with multivariate regression, with the exception of HbA_1c. Further, HbA_1c was not adjusted for fasting glucose. (b) Associations with individual measures of nerve function. Red squares represent sural SNAP amplitude, grey squares represent sural NCV, red circles represent peroneal CMAP amplitude, grey circles represent peroneal NCV, red triangles represent tibial CMAP amplitude and grey triangles represent tibial NCV. Associations are adjusted as in model 2 in (a)

Fig. 2

(a) Standardised associations (expressed as β with 95% CIs) of cardiometabolic risk factors and VPT. A higher threshold indicates worse score. (b) Standardised associations (expressed as ORs with 95% CIs) of cardiometabolic risk factors and neuropathic pain (OR >1 indicates greater likelihood for neuropathic pain). Associations in model 1 (grey) were adjusted for age, sex, height, educational level and skin temperature. Associations in model 2 (dark blue) were additionally adjusted for alcohol consumption, mobility limitations, CVD (history) and kidney function. In addition, all associations in model 2 were adjusted for each of the other risk factors with multivariate regression, with the exception of HbA_1c. Further, HbA_1c was not adjusted for fasting glucose

Fig. 3

Standardised associations (expressed as β [or OR for outcome neuropathic pain] with 95% CIs) of prediabetes and type 2 diabetes with (a) nerve function, (b) VPT and (c) neuropathic pain, adjusted for age, sex, height, skin temperature, education, smoking, alcohol consumption, mobility, CVD (history), kidney function, waist circumference and inflammation. The p values indicate linear trend analysis among NGM, prediabetes and type 2 diabetes. Red squares represent sural SNAP amplitude, grey squares represent sural NCV, red circles represent peroneal CMAP amplitude, grey circles represent peroneal NCV, red triangles represent tibial CMAP amplitude and grey triangles represent tibial NCV