href="#ulink_c80953f3-417c-54fc-ace0-cee70631d918">102].
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.
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]. In the Zutphen Elderly Study fasting C-pepride and glucose tolerance were associated with a QTc prolongation which itself is related to CAN [106].
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
