Diabetic Neuropathy. Friedrich A. Gries

is rare at the outset of type 1 diabetes. It is more common amongst people with established type 2 diabetes than among those with newly diagnosed diabetes [5,6]. This association between disease duration and the risk of diabetes is strong, has been confirmed in a variety of studies in both type 1 and type 2 diabetes, and remains after adjustment for age [5,14,17,49]. In a UK study, the prevalence of DSP rose from 21% in those with a diabetes duration of less than five years to 37% in people with a duration of over 10 years [8]. In a Spanish study, the prevalence rose from 14% at under five years' duration to 44% at a duration of more than 30 years [19]. Interestingly, in one study the association between DSP and duration of diabetes was not seen in those over the age of 54, but was strong in those aged under 54 [3]. This, however, has not been reported elsewhere.

Age

      Advancing age has been widely reported to increase the risk of DSP. In a large sample (6487 subjects) of UK diabetic hospital outpatients, the prevalence of DSP rose from 5% in the 20-to 29-year age group to 44% in the 70- to 79-year age group [8]. Amongst a population-based sample from Egypt, DSP was detected in 8% of those aged 20-44, and in 23% of those aged45 years or over [6]. In this study, the risk of DSP independently attributed to age approximately doubled for every 10 year increment in age. A number of other studies have also documented age as an independent risk factor for DSP neuropathy [11,14,17,20]. However, the influence of age may not be straightforward. Neurological function, especially vibration perception threshold (VPT), deteriorates with advancing age even in the normal, nondiabetic population [98,99]. Whilst some studies have adjusted for the effects of age on VPT, this is not universal. Furthermore, diagnostic criteria for DSP often include other parameters, such as clinical signs, monofilament sensitivity and electrophysiology, which are not adjusted for age. Interestingly, in a study from France, where VPT was adjusted for age, height, and gender, there was no relationship between neuropathy and age [3]. Data from Mauritius confirmed the increase in VPT with age in both diabetic and nondiabetic subjects [5]. However, when neuropathy was defined as having a VPT above the normal range (mean plus 2 standard deviations in the nondiabetic population) defined separately in each of three age categories, there was no relationship between age and neuropathy in either cross-sectional or prospective analyses [5]. Thus, the influence of age may have been overestimated in some studies.

Hypertension

      Hypertension is attractive as an etiological factor in DSP, as it could be viewed as lending weight to the vascular theory of the pathophysiology of DSP. Hypertension has been associated with DSP in several studies, most notably in the data from the Pittsburgh cohort of type 1 diabetes [49]. In this study, hypertension was the single strongest predictor of DSP, and was associated with an approximately four-fold risk of developing DSP over six years. In the EURODIAB Prospective Complications Study, systolic blood pressure was shown to be one of the predictors of the development of DSP after adjustment for age, duration of diabetes, and HbA_1c [50]. Reports in type 2 diabetes, however, have been conflicting [17,20,33,61,100], but mainly have not confirmed this association. In a small interventional study (including subjects with both type 1 and type 2 diabetes), treatment with the ACE inhibitor trandolapril reduced progression of electrophysiological parameters of DSP, and also lowered systolic blood pressure [101]. However, the UKPDS reported that intensive blood pressure lowering with a variety of agents had no effect in ameliorating the progression to DSP [102].

Hypoinsulinemia

      Partanen et al. [33] have suggested a link between hypoinsulinemia and DSP, which they believed resulted from the possible beneficial effects of insulin and C-peptide on neuronal metabolism and function [103]. They found that baseline fasting and 2-hour insulin levels were lower in newly diagnosed Finnish male subjects with type 2 diabetes who developed DSP 10 years later than in those who remained free of DSP. In the San Luis Valley Study [47], these findings were also evident (using C-peptide), but this univariate association disappeared when diabetes duration was taken into account. Our own data from Mauritius [5] also suggested a similar association with hypoinsulinemia, but, perhaps because of the low prevalence of DSP in that study, the association was not apparent in all analyses.

      Diabetes duration almost certainly has an important confounding effect on the assessment of this potential relationship, since it might be expected both to increase the prevalence of DSP and to reduce insulin levels. It is difficult to account for duration in type 2 diabetes, as the date of disease onset is not usually known. Only a study in a population in which the time of onset of type 2 diabetes can be accurately estimated will allow better insight into the role of hypoinsulinemia.

Hyperinsulinemia

      Several population-based studies suggest that high insulin levels are associated with disturbed autonomic nervous system activity. High insulin levels were significant predictors of the development of CAN 10 years after the diagnosis of type2 diabetes, irrespective of obesity and glycemia [68]. In the Atherosclerosis Risk in Communities (ARIC) Study patients with the metabolic syndrome (hypertension, type 2 diabetes, and/or dyslipidemia) showed significantly lower HRV indices than did those without these disorders. An increase in fasting insulin of 1 SD was associated with 88% higher odds of having lower HRV [104]. In nondiabetic individuals an inverse association was observed between serum fasting insulin and parasympathetic activity [105].