Little is known about the occurrence and predictive factors of autonomic neuropathy and its relationship to cardiovascular mortality in NIDDM patients, and no long-term follow-up studies including nondiabetic control subjects are available. A total of 133 patients with newly diagnosed NIDDM (70 men) and 144 control subjects (62 men) were examined at baseline and after 5 and 10 years of follow-up. Deep-breathing tests (baseline, 5-year, and 10-year) and active orthostatic tests (5- and 10-year) were performed. Criteria for autonomic neuropathy were parasympathetic (expiration-to-inspiration ratio ≤1.10), sympathetic (systolic blood pressure decrease ≥30 mmHg in the orthostatic test), and combined autonomic neuropathy (parasympathetic with sympathetic neuropathy). The frequency of parasympathetic neuropathy (NIDDM patients versus control subjects) was 4.9 vs. 2.2% (P = 0.224) at baseline, 19.6 vs. 8.5% (P = 0.017) at 5 years, and 65.0 vs. 28.0% (P < 0.001) at 10 years of follow-up. The frequency of sympathetic neuropathy was 6.8 vs. 5.6% (P = 0.709) at 5 years and 24.4 vs. 9.0% (P = 0.003) at 10 years of follow-up. These figures for combined autonomic neuropathy were 2.1 vs. 1.8% (P = 0.869) at 5 years and 15.2 vs. 4.2% (P = 0.007) at 10 years of follow-up. NIDDM patients with parasympathetic neuropathy at the 10-year examination showed worse glycemic control and higher insulin values than those without parasympathetic neuropathy. Furthermore, in our subjects, women were more prone to have parasympathetic neuropathy than men. Parasympathetic neuropathy at baseline was more frequent in those who died from a cardiovascular cause than those who did not (13 vs. 3%, P = 0.045). Similarly, sympathetic autonomic nervous dysfunction at the 5-year examination predicted the 10-year cardiovascular mortality. In conclusion, the frequency of autonomic neuropathy in NIDDM patients increases sharply with time. The development of autonomic neuropathy is connected with poor glycemic control. Interestingly, a high insulin level seems to have a predictive role in the development of parasympathetic autonomic neuropathy irrespective of obesity and glycemia.

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