Cigarette smoking has been identified as an independent risk factor for DSP in two different studies of type 1 diabetes, in which it was associated with an approximate doubling of the risk of DSP [14,49]. Smoking was also found to carry an independent risk in the San Luis Valley study of type 2 diabetes [47], but was actually associated with a protective effect in US veterans [17], and had only a weak (and not independent) association in the study from Mauritius [5].
Alcohol consumption has been associated with DSP on a number of occasions [17], but it may be difficult, at least in epidemiological studies, to differentiate between diabetic neuropathy in which alcohol is a risk factor, and alcoholic neuropathy in a person with diabetes.
DSP, like other metabolic, nutritional, and toxic neuropathies, is a distal disease which is first manifest in the feet. It is therefore, clearly a length-dependent process, although the pathophysiology underpinning this phenomenon is not understood. It seems logical, therefore, that height, as a surrogate measure of the length of the longest nerves, might be associated with DSP. This hypothesis has been borne out in a number of different cross-sectional and prospective studies [5,14,17,49].
There are no consistent findings that would indicate a relationship between gender and the risk of DSP.
High total cholesterol [6] and elevated triglycerides [14] have been reported as independent risk factors for DSP (after adjustment for HbAlc, age, and other potential confounders). Elevated LDL was also found to predict neuropathy in a study of type 1 diabetes, but the association was lost after adjustment for other risk factors [49]. In the EURODIAB Prospective Complications Study BMI, albuminuria, triglycerides, cholesterol, and systolic blood pressure were shown to be significant predictors of the development of DSP after adjustment for age, duration of diabetes, and HbAlc[50]. In type 2 diabetic patients the link between DSP and dyslipidemia must, however, remain tentative at this stage, as several studies have failed to observe such a relationship [5,33].
Physiological factors for which an inverse relationship to HRV has been described include age, heart rate, female gender, body mass index, sitting or standing body position, blood pressure, and pregnancy. Pathophysiological correlates unfavorably affecting HRV include the duration of diabetes, any of the chronic diabetic complications, metabolic syndrome, peripheral vasomotor abnormalities, medial arterial calcification, peripheral edema, reduced muscle sympathetic nerve activity (MSNA), cardiovascular risk factors such as high LDL cholesterol and smoking, as well as various drugs [107]. The population-based Hoorn Study, including subjects with NGT, IGT, and type 2 diabetes, recently reported that the strongest determinants of cardiovascular autonomic function were age and use of antihypertensive drugs in subjects with NGT, insulin levels in those with type 2 diabetes [108], and albuminuria in subjects with IGT or type 2 diabetes [109].
Striking ethnic and racial differences in the prevalence of nephropathy and macroangiopathy have been reported, but no such effects have been observed in the population-based surveys of diabetic neuropathy [20,26]. Although hyperglycemia and duration of diabetes are generally accepted to represent major contributory factors to the prevalence of diabetic neuropathy, many diabetologists have come across patients who do not develop neuropathy despite long-term poor glycemic control. Whole-genome screening and candidate gene strategies can be applied to the genetics of type 1 diabetes complications [110].The most significant results were obtained regarding a role for polymorphisms of the renin-angiotensin system in diabetic nephropathy [110]. In diabetic polyneuropathy, reduced Na+/K+-ATPase activity and increased aldose reductase activity have been suggested to play an important pathogenetic role. Na+/K+-ATPase is encoded by various genes, of which the ATP1 Al gene is expressed predominantly in peripheral nerves and erythrocytes. A case-control study found that type 1 diabetic patients bearing a restriction fragment length polymorphism (RFLP) of the ATP1 Al gene carried a 6.5-fold (95% CI: 3.3-13) increased risk of peripheral neuropathy. Moreover, these patients showed reduced erythrocyte Na+/K+-ATPase activity [111]. Another case-control study showed increased susceptibility to peripheral neuropathy in type 1 diabetic patients who had a polymorphism at the 5 end of the aldose reductase (ALR2)gene [112]. In contrast, a study in Japanese type 2 diabetic patients found an association of the ALR2 gene polymorphism in the 5 region with retinopathy but not peripheral and autonomic neuropathy or nephropathy [113].
Thus, at present only a low level of evidence for a role of these candidate genes obtained from case-control studies is available. Only prospective controlled trials using strata selected along a candidate gene would clarify whether polymorphisms might have therapeutic relevance in future.
Prognosis
Available information on the mortality associated with DSP is sparse. In a cohort of 134 type 2 diabetic patients randomly selected from the register of the Helsinki Diabetes Association followed prospectively over 9 years, neuropathy as assessed by NCV was identified as an independent predictor of mortality after adjusting for macroangiopathy, albumin excretion rate, and HbA1c [114]. In the Stockholm Diabetes Intervention Study 7.5-year mortality was predicted not only by albuminuria but also by sural sensory nerve action potential amplitude and sympathetic nerve function [115]. In a university hospital setting a 14-year observational study including 794 patients demonstrated that reduced VPT was the most significant predictor of mortality. Proteinuria and type 1 diabetes, but not HbA1c and smoking, were other important risk factors [116]. In a clinic-based cohort of