Since particularly in type 2 diabetes the actual onset of the disease may often be preceded by a long period of unrecognized metabolic abnormality, it appears likely that neural dysfunction can be detected at the time of diagnosis of diabetes. Two studies have reported the frequency of neuropathy in type 2 diabetic patients who were examined within four weeks following the diagnosis of the disease. Lehtinen et al. [66] evaluated 132 patients aged 45-64 years in the district of Kuopio University Central Hospital and 142 controls randomly selected from the population registers. The rates of abnormal E/l ratio were 6.3% and 1.4%, respectively. A similar study was performed by Ratzmann et al. [34] in 95 newly diagnosed type2 diabetic patients who were representative of the East Berlin community. The prevalence of abnormal maximum/minimum heart rate during deep breathing was 7.3%.
In a clinic-based study we determined the prevalence of CAN in 120 healthy subjects and 130 newly diagnosed type 1 diabetic patients within 3-49 days after the initiation of insulin treatment with stable mean blood glucose levels. The prevalence of CAN defined by the strict criterion of at least three abnormal tests out of six was 7.7% in the patients and 0 in the controls. Two abnormal tests out of six were found in an additional 9.2% of the patients but in only 1.7% of the controls [67].
Thus, CAN cannot be generally regarded as a late complication of diabetes, but it should be borne in mind that subclinical cardiovascular autonomic dysfunction may be detected even in newly diagnosed type 1 diabetic patients if sensitive indices of spectral analysis are applied in conjunction with tests based on standard analysis of HRV.
Incidence an d Natural History
Only a few studies have evaluated the natural history of CAN in inception cohorts. Töyry et al. [68] followed 133 newly diagnosed type 2 diabetic patients and 144 control subjects over 10 years in Kuopio, Finland. CAN was assessed by the E/l ratio as an index of parasympathetic activity and the systolic blood pressure drop on standing as a measure of sympathetic activity. The prevalence of “parasympathetic neuropathy” rose from 5% in diabetic patients vs 2% in controls at baseline to 65% vs 28% after 10 years, while the prevalence of “sympathetic neuropathy” increased from 7% vs 6% at five years to 24% vs 9% after 10 years. Poor glycemic control and high insulin levels were significant predictors of the development of CAN [68]. Moreover, the presence of CAN at five years was an independent risk factor for the development of stroke after 10 years [69]. Clinic-based studies in patients with variable duration of type 2 diabetes showed a gradual increase in the prevalence of AFT score abnormalities from 41% at baseline to 64% after four years [70], and worsening of the AFT score in 57% of the patients after five years of follow-up [71].
There are no population-based studies including inception cohorts at the time of diagnosis of type 1 diabetes. In a clinic-based study we have shown that the natural evolution of abnormal HRV during the first five years following diagnosis of type 1 diabetes is clearly related to the degree of glycemic control [72]. The rates of abnormalities in HRV at five years were 5% in well-controlled patients and 23% in those who were poorly controlled. In type 1 diabetic children the prevalence of abnormal HRV at rest increased from 27% at the time of diagnosis to 56% after 10 years, but abnormal HRV during deep breathing changed only from 12% to 14% [73].
In longer-term teenage type 1 diabetic patients Young et al. [53] found an increase in the rates of abnormal HRV from 19% to 28% within 20-35 months in poorly controlled type 1 diabetic teenagers. Sampson and colleagues [74] noted a relatively slow decline in HRV of about 1 beat/min per year, approximately three times faster than in healthy subjects [39], over a decade in patients with initially normal HRV. Postural hypotension was persistent, but did not deteriorate in the majority of patients. In contrast, a six-year study has reported the relatively rapid development of postural hypotension in a small group of long-term diabetic patients, which was preceded by a decrease in E/l ratio [75]. In two recent studies in type 1 diabetic patients, AFTs and autonomic symptoms and signs had not changed after 5 and 9 years, respectively [76,77]. In a prospective study over 10-11 years, CAN has been shown to predict future deterioration in glomerular filtration rate in type 1 diabetic patients. It has been hypothesized that nocturnal rise in intraglomerular pressure could be one possible link between CAN and the observed deterioration in glomerular filtration rate [78].
There are no population-based studies reporting the prevalence or incidence of gastrointestinal symptoms or motor abnormalities in diabetic patients. A number of clinic-based studies reported relatively high rates of delayed gastric emptying in diabetic subjects, but most of these included small samples of highly selected populations subject to referral bias. Thus, the true prevalence of delayed gastric emptying is not known. Using the 13C-octanoic acid breath test, delayed gastric emptying has been shown in 16% of type 1 diabetic subjects without gastrointestinal symptoms, while the rate increased to 43% in those with these symptoms [79]. Several clinic-based studies reported the prevalence of gastrointestinal symptoms in diabetic and nondiabetic subjects [80–82] (Table 3.5). In type 1 diabetic patients only nausea, vomiting, early satiety, and fullness after meals occurred significantly more frequently than in the nondiabetic subjects in some studies. In type 2 diabetic patients nausea, early satiety, fullness after meals, diarrhea, and constipation were significantly more frequent than in the nondiabetic subjects. The prevalence of gastrointestinal symptoms such as dysphagia, heartburn, or bloating was comparable to that seen in nondiabetic subjects. However, there were considerable differences between the studies regarding the prevalence of the individual symptoms. For example, diarrhea was observed in 35% of the type 2 patients studied in Hong Kong vs 7% of those studied in Germany [80–82].
The gallbladder may become atonic in association with autonomic neuropathy, which increases the gallbladder volume by retention of bile. It is unknown whether these changes result in symptoms. It may be that biliary stasis explains the increased risk of gallstones shown by recent epidemiological data. In