alt="Image"/> Hyperglycemia
The central role of hyperglycemia has been demonstrated in a range of studies. Mean HbA1c was approximately 1% higher in men with newly diagnosed type 2 diabetes who went on to develop DSP 10 years later, than in those who did not[33]. The risk of developing DSP (as measured by the odds ratio) has been calculated to rise by approximately 10-15% for every I mmol/l rise in fasting plasma glucose or every 1% rise in HbA1c[6,17]. The importance of hyperglycemia has of course been confirmed in interventional studies. The DCCT demonstrated that intensive glycemic control led to a 64%reduction in the five-year risk of developing DSP [2] in patients with type 1 diabetes. In the similar but smaller Stockholm Diabetes Intervention Study, symptoms of DSP developed in only 14% of those who were intensively treated, compared to 32% in the conventional treatment arm [95]. The effect of glucose lowering in type 2 diabetes is less clear. In the large UKPDS study, strict glycemic control had no significant impact on the development of DSP over the first 12 years [46]. Among the relatively small number of subjects who were followed to 15 years, a significant risk reduction was apparent, but only in those in the main study. Amongst the overweight subjects, whose intensive therapy was primarily with metformin, there was no impact of intensive therapy at all on DSP [96].
In the Rochester Diabetic Neuropathy Study, mean HbA1, severity of diabetic retinopathy, and a term calculated mean In (24-hour proteinuria multiplied by duration of diabetes) were the main covariates for severity of DSP at the 7-year follow-up [97].
Thus, the etiological link between hyperglycemia and DSP seems sound, but while it is clear that glucose lowering protects against the development of neuropathy in type 1 diabetes, the case is not yet proven in type 2 diabetes.
DSP, like the other specific diabetic complications, 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.
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 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 HbA1c [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 [
