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

Diabetic neuropathy is one of the most common complications of diabetes mellitus [1], and a major cause of reduced quality of life, gait disturbances, foot ulceration, fall-related injuries and disability [2]. During their lifetimes, up to 50% of patients with type 2 diabetes are affected by some form of neuropathy, of which distal symmetric polyneuropathy is most common [3, 4]. Moreover, neuropathy was already present in 10–20% of patients at the time of diagnosis of type 2 diabetes [5], suggesting that neuropathy is initiated in early stages of the pathogenesis of diabetes. Indeed, studies have demonstrated that neuropathy is present in the prediabetic stage [6‐8], although not consistently [9, 10].

Traditionally, it has been suggested that hyperglycaemia is the main driver of microvascular damage and subsequent neuropathy. Therefore, glycaemic control is considered fundamental in its prevention [11]. However, a study in patients with type 2 diabetes showed that the aggregation of components for the metabolic syndrome was significantly associated with sensory neuropathy [12]. In subsequent studies, the metabolic syndrome has been associated with neuropathy regardless of the presence of (pre)diabetes [13‐17], but not consistently [7].

As increased blood glucose levels, even in the non-diabetic range, as well as other cardiometabolic risk factors could contribute to microvascular dysfunction, we postulated that each of these factors contributes to a progressive decline of nerve function, before the development of type 2 diabetes or overt neuropathy. To examine this, studies are needed that do not dichotomise risk factors (such as the presence of the metabolic syndrome) or dichotomise outcomes (such as the presence of neuropathy), but that analyse risk factors and outcomes as continuous variables. In addition, estimates of the prevalence of neuropathy may vary depending on the methods used, which may have contributed to the discrepancies in reported associations between metabolic risk markers and neuropathy [7, 18, 19]. Assessing nerve function as a continuous measure with objective electrophysiological techniques may therefore be more relevant to study the aforementioned associations [18]. However, such population-based studies are scarce and mainly focus on components of the metabolic syndrome [14, 20].

In light of the above, our aim was to examine the associations of multiple classical and newer cardiometabolic risk factors and mildly elevated blood glucose levels (such as in prediabetes [i.e. impaired fasting glucose and/or impaired glucose tolerance]) with measures of motor and sensory nerve function assessed by electrophysiological techniques in a large, population-based cohort: the Maastricht Study. In addition, we assess their associations with clinical measures such as vibration perception threshold (VPT) and neuropathic pain. We hypothesised that unfavourable cardiometabolic risk and elevated blood glucose levels within the prediabetic range are associated with impaired nerve function, independently of fasting glucose and of each other.

To our knowledge, this is the largest population-based study examining mutually independent associations of individual cardiometabolic risk factors with peripheral motor and sensory nerve function using electrophysiological techniques as well as clinical measures such as VPT and neuropathic pain. Older age, higher glucose levels, HbA_1c, antihypertensive medication, inflammation and smoking were associated with worse sensory and motor nerve function, without any major differences between these two types of nerves. By and large, the same patterns were seen for VPT and neuropathic pain, except that older age and higher waist circumference were more strongly associated with a poorer VPT and there was no association of age and neuropathic pain. These associations were similar for men and women. While type 2 diabetes was, as expected, clearly and consistently associated with worse nerve function and neuropathic pain, trend analyses showed that prediabetes also appeared to be associated with worse nerve function and neuropathic pain.

Previous studies on the relation between prediabetes and nerve function were inconsistent in their findings, which may be due to discrepancies in defining neuropathy or by dichotomising neuropathy as outcome [6‐10]. We used continuous, electrophysiological measures of large-fibre nerve function, in different type of nerves (sensory and motor), as primary outcome in order to detect changes at an early stage. In addition, we studied VPTs (a clinical measure of large-fibre dysfunction) and neuropathic pain, which is more related to small-fibre dysfunction. Higher levels of fasting glucose and HbA_1c, even within the normal range, were associated with lower nerve function. Associations with post-load glucose appeared to be somewhat weaker, which was in line with the Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Research in the Region of Augsburg (KORA) study [28]. In contrast, in participants without diabetes, fasting and post-load glucose were not associated with VPT and neuropathic pain.

In accordance with our results, waist circumference (or obesity) has previously been associated with neuropathy and diminished nerve function in people with and without diabetes [14, 20, 29, 30]. This effect might be mediated by low-grade inflammation, as inflammation is associated with diminished nerve function in patients with diabetes [31] and in the general population [32, 33]. Interestingly, in our study, inflammation was associated with diminished nerve conduction and higher VPT only in people with type 2 diabetes, suggesting that inflammation is a consequence of long-term metabolic damages that start before overt diabetes and is not a risk factor that initiates large-fibre damage. However, once present, neuro-inflammation might contribute to further progression of nerve damage. Our results on neuropathic pain are partially in line with the higher circulating Il-6 levels in painful diabetic neuropathy as reported in the KORA F4 study, although we observed no association with sICAM-1 [34]. To further delineate the role of inflammation in the development of small-fibre damage, objective techniques such as corneal confocal microscopy or skin biopsy will be needed.

The metabolic syndrome has also been associated with diminished nerve function [13‐15, 17, 20, 30, 35]. However, this is not unexpected as individual components of the metabolic syndrome (glucose, waist circumference and, to a lesser extent, antihypertensive medication) were associated with worse nerve function.

Results of cholesterol and blood pressure (and, to a lesser extent, triacylglycerol) should be interpreted with caution, as over one-third of the population used lipid-lowering and/or antihypertensive medication. In general, hypertension and hypercholesteraemia are treated early in the Netherlands. Consequently, in this relatively healthy and well-treated population, ranges of lipids and blood pressure might be too narrow to observe associations. Nevertheless, antihypertensive medication (which suggests a history of exposure to hypertension) was associated with lower nerve function and, to a lesser extent, with neuropathic pain. Hypertension may affect nerve function by damage of the (nerve) microcirculation. Moreover, as statin use is common in the treatment of diabetes, fasting LDL-cholesterol levels were actually lower in people with type 2 diabetes, compared with people with NGM. This may explain the unexpected finding that LDL-cholesterol was associated with better nerve function. In the Addition study, lower LDL levels were associated with a higher risk of developing diabetic polyneuropathy, and also these authors could not exclude an effect of statins in their analyses [29].

We used electrophysiology, enabling us to detect on a continuous scale differences in large-fibre nerve function that cannot be detected on clinical examination, and studied both motor and sensory nerves. In contrast to earlier studies, we could not observe a difference in the associations of cardiometabolic risk factors with sural or motor nerve function [19, 36]. Partly, this may be due to 165 cases of undetectable sural nerve response in our study. As an undetectable response indicates poor nerve function, this may have led to underestimation in effect size of the associations studied. Further, due to the cross-sectional design of our study, we cannot exclude that cardiovascular risk factors impact on the sural nerve at an earlier stage. For this we need longitudinal data.

Previous studies have indicated that axonal damage (typically reflected as lower CMAP or SNAP amplitudes) is more common in diabetes than demyelinating damage (typically reflected by lower NCV) [36]. Indeed, age and waist circumference had higher magnitudes of associations with low CMAP and SNAP amplitudes as compared with NCV, but these differences were not statistically significant. Thus, whether different cardiometabolic risk factors may affect nerve axons or myelin differentially is unclear from our results, but, if present, such a differential effect seems limited. Moreover, we did not examine small fibres with objective measures and it has been suggested that obesity/hyperlipidaemia and hyperglycaemia may have differential effects on small vs large nerve fibres [37].

A complex interplay between several mechanisms including hyperglycaemia, lipotoxicity, oxidative stress and inflammation is thought to play a central role in the pathogenesis of (diabetic) neuropathy [38]. We recently reported that microvascular function was diminished not only in people with type 2 diabetes, but also with prediabetes [39]; age, smoking and prior exposure to hypertension and dyslipidaemia, and in particular higher levels of glucose (also in the normal range), were all associated with microvascular function [40]. Observations in the current study are in line with these results, suggesting similar risk factors for generalised microvascular damage and early-stage nerve damage. Most likely, preventive or therapeutic measures that target all of these risk factors may be clinically beneficial. However, in contrast to several other microvascular complications, intensive blood glucose control had only a very modest effect in preventing large-fibre neuropathy in type 2 diabetes [41], and also multi-modal interventions, such as in the STENO-2 [42] or the Look AHEAD (Action for Health in Diabetes) studies [43], seemed unsuccessful. Hence, prevention of large-fibre neuropathy should probably start at the earliest signs of diabetes, maybe even in the prediabetic stage, and the role of inflammation in the progression of subclinical to clinical neuropathy should be further explored. Prediabetes is also associated with abnormalities of the central nervous system [44], and it remains to be determined whether the risk factors for central nerve abnormalities are the same as those for peripheral nerves.

Strengths of this study include the use of nerve conduction testing as an objective measure of nerve function that provides insight into nerve damage at very early stages. We investigated different types of nerve and anatomical parts of the nerve and we also included clinical measures in a large, population-based study of adults (aged 40–75 years). Lastly, our statistical models were mutually adjusted and adjusted for many potential confounders. Nonetheless, residual confounding by non-measured factors may still have occurred. Other limitations include its cross-sectional design, and thus inferences regarding causality should be made with caution. As we did not observe major differences between the individual nerves, we summarised our electrophysiological findings in a sum-score, but this should be viewed as a post hoc analysis. The clinical relevance of the observed associations should be investigated in future studies. Further, waist circumference is a crude measure for adiposity and the underlying biological mechanisms explaining the associations between waist circumference and nerve function should be scrutinised. Finally, the inclusion of a relatively healthy population in the Maastricht Study and the exclusion of participants with incomplete assessments of nerve function may have resulted in selection bias, as these participants were older and more often had diabetes. This may have led to an underestimation of the associations observed.

In conclusion, in adults aged 40–75 years, blood glucose (fasting glucose or HbA_1c), even in the non-diabetic range, was most consistently associated with (sensorimotor) peripheral nerve function and neuropathic pain. Similarly, those with type 2 diabetes, and to a lesser degree those with prediabetes, had worse nerve function. A larger waist circumference, smoking and use of antihypertensive medication (suggestive of history of exposure to hypertension), independent of glucose and other risk factors, were associated with worse nerve function, and similar patterns were observed with VPT and neuropathic pain. The association with low-grade inflammation was most pronounced in participants with type 2 diabetes. These results imply that early-stage nerve damage may result not only from glycaemic damage, but also from other cardiometabolic risk markers. Consequently, multifactorial approaches should be considered in the prevention of neuropathy, rather than a sole focus on blood glucose.