[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 583 type 1 diabetic patients who were followed over 1-11.5 years, both abnormal NCV and abnormal AFTs were associated with an increased risk of mortality. Mortality rates after 10 years in the groups with normal and highly abnormal NCV were 10% and 50% respectively, while the corresponding percentages were 10% and 43% respectively for the AFTs. Combining NCV and AFTs into a total neuropathy score resulted in an even stronger predictor of mortality than each of the two measures alone [117]. Thus, there is accumulating evidence to suggest that not only surrogate markers of microangiopathy, such as albuminuria, but also those used for polyneuropathy, such as NCV and VPT, may predict mortality in diabetic patients, but clearly further studies are needed to assess the prognostic role of polyneuropathy in diabetes. In diabetic patients with ultimate clinical endpoints of neuropathy such as foot ulcers the risk of death was increased to 12 per 100 person-years of follow-up, compared to 5 per 100 person-years in those without foot ulcers [118].
A number of largely clinic-based prospective studies have demonstrated increased mortality among diabetic patients with symptomatic CAN or those with abnormal cardiovascular reflex tests. Their major findings are summarized in Table 3.8 [68,74,117,119 128]. The overall mortality rates over periods up to 10 years were about 26% in diabetic patients with CAN compared with 4% in those without evidence of CAN. However, it must be kept in mind that autonomic dysfunction may also be found in the absence of diabetes as a consequence of common cardiovascular diseases such as coronary artery disease, myocardial infarction, and heart failure. It has been shown that reduced HRV is an independent indicator of poor prognosis in these patients [129]. Since cardiovascular diseases represent the major cause of death in diabetic patients [130], the impact of diabetes and, for example, coronary sclerosis on the autonomic nervous system may overlap in a number of patients to such a degree that CAN may at least not be the only factor responsible for the increased mortality [127]. On the other hand, there is evidence that CAN contributes to the poor prognosis in diabetic patients as an independent factor [122].
The mechanisms by which CAN leads to the increased mortality remain a matter of debate, but two hypotheses have been suggested [123,131]. A number of studies have shown an association between CAN and QT interval prolongation, and a recent metaanalysis revealed a 2.3-fold increased risk of CAN in diabetic patients showing a prolonged QT interval [132], leading to the speculation that, in analogy to the QT prolongation encountered in the idiopathic long QT syndrome, which is characterized by recurrent episodes of syncope or cardiac arrest due to torsades de pointes [133], CAN might also predispose patients to malignant ventricular arrhythmias and sudden death. A recent five-year study from Italy showed a considerably increased risk of mortality in type 1 diabetic patients with QTc prolongation (odds ratio: 24.6 [95% CI: 6.5-92.9]) which requires further confirmation [128]. Although the studies listed in Table 3.8 were not sufficiently large to allow unequivocal conclusions regarding an increased incidence of sudden death in CAN, recent evidence indicates an important role of the autonomic nervous system in triggering sudden death in both nondiabetic and diabetic subjects with low HRV. A marked decrease in HRV in nondiabetic patients with coronary artery disease was present immediately before the onset of the ST shift precipitating ischemic sudden death, suggesting that sympathovagal imbalance may trigger fatal arrhythmias during acute myocardial ischemia [134]. HRV was also diminished in nondiabetic survivors of sudden death not associated with coronary artery disease, indicating that abnormal autonomic activity may trigger malignant arrhythmia independently of coronary artery disease [135]. In subjects with inducible ventricular tachycardia (VT), 42% of whom were diabetic, HRV was markedly lower than in those without evidence of VT [136]. In unselected patients a 2.6-fold higher relative risk of sudden death within two years (after adjustment for age, left ventricular dysfunction, and history of myocardial infarction) was observed among patients with reduced HRV than in those with normal HRV. Among
