Do high proinsulin and C-peptide levels play a role in autonomic nervous dysfunction?: Power spectral analysis in patients with non-insulin-dependent diabetes and nondiabetic subjects.

BACKGROUND: Immunoreactive insulin has been shown to predict the development of parasympathetic autonomic neuropathy. It is possible that constituents of immunoreactive insulin could explain this association. In this cross-sectional study, the relationship of specific insulin, C-peptide, and proinsulin with autonomic nervous dysfunction was evaluated in 57 NIDDM patients and 108 control subjects. METHODS AND RESULTS: The frequency-domain analysis of heart rate variability was determined by using spectral analysis from stationary regions of registrations while the subjects breathed spontaneously in a supine position. Total power was divided into three frequency bands: low (0 to 0.07 Hz), medium (MFP, 0.07 to 0.15 Hz), and high (HFP, 0.15 Hz to 0.50 multiplied by the frequency equal to the mean RR interval). In NIDDM patients, total power, the three frequency bands (P<.001 for each), and the MFP/HFP ratio (P=.016), which expresses sympathovagal balance, were reduced compared with control subjects. Fasting proinsulin (r(s)=-.324, P=.014 for diabetics and r(s)=-.286, P=.003 for control subjects), C-peptide (r(s)=-.492, P<.001 for diabetics and r(s)=-.304, P=.001 for control subjects), and total immunoreactive insulin (r(s)=-.291, P=.028 for diabetics and r(s)=-.228, P=.017 for control subjects) were inversely related to MFP/HFP. For proinsulin and C-peptide the results did not change after controlling for the effects of age, body mass index, and fasting glucose. CONCLUSIONS: Both proinsulin and C-peptide levels were significantly associated with the sympathovagal balance of autonomic nervous function in NIDDM patients and control subjects, but this study cannot determine whether these compounds are directly involved in autonomic nervous dysfunction.

Divergent development of autonomic and peripheral somatic neuropathies in NIDDM.

There is no information on the mutual occurrence and the development of autonomic and peripheral somatic neuropathies based on long-term follow-up of patients with non-insulin-dependent diabetes mellitus (NIDDM). We investigated the relation between the changes in autonomic function values and electrodiagnostic values, and the relation between the occurrence of autonomic neuropathy and peripheral somatic polyneuropathy in a group of patients with newly diagnosed NIDDM (n = 133, aged 45-65 years) at baseline and 5 and 10 years later. Parasympathetic autonomic neuropathy was diagnosed on the basis of heart rate variability during deep-breathing and sympathetic autonomic neuropathy on the basis of fall in systolic blood pressure while changing from supine to standing. Polyneuropathy was diagnosed on the basis of both clinical criteria and electrodiagnostic studies (nerve conduction velocity and response-amplitude values). In 10 years 36 patients died, mainly from cardiovascular causes. Altogether 78 patients completed the study. At 10 years, parasympathetic autonomic neuropathy was diagnosed in 61.3% of those with polyneuropathy and 66.7% of those without. Likewise, the frequency of sympathetic autonomic neuropathy was similar in those with polyneuropathy (21.9%) and those without (26.5%). The respective figures for combined (both parasympathetic and sympathetic) autonomic neuropathy were 10.0% and 18.8%. The worsening of parasympathetic and sympathetic autonomic function values was not related to the worsening in electrodiagnostic results with time. In conclusion, the development of autonomic and peripheral somatic neuropathies was divergent in patients with NIDDM suggesting different pathophysiological processes for these neuropathies.

Regional cerebral perfusion in cardiovascular reflex syncope.

Little is known about the regional cerebral perfusion in subjects with presyncope or syncope, and the impact that autonomic nervous dysfunction has on it. Seven subjects with cardiovascular vasodepressor reflex syncope were studied. A baseline test was performed with the patients standing in the 70 degrees upright position, while the passive head-up tilt table test with and without isoprenaline infusion was employed for provocation. Regional cerebral perfusion was assessed by means of single-photon emission tomography with technetium-99m labelled V-oxo-1,2-N, N1-ethylenedylbis-l-cysteine diethylester (baseline, and during blood pressure decline in the provocation test) and the autonomic nervous function by means of spectral analysis of heart rate variability (baseline, and before blood pressure decline in the provocation test). Every subject showed an abrupt decline in blood pressure in the provocation test (five with presyncope and two with syncope). The systolic and diastolic blood pressures decreased significantly (P<0.001) between the baseline and the provocation study time points (radiopharmaceutical injection and lowest systolic blood pressure). Mean cerebral perfusion as average count densities decreased upon provocation as compared with baseline (190+/-63 vs 307+/-90 counts/voxel, respectively, P=0.013). Hypoperfusion was most pronounced in the frontal lobe. These results suggest that cerebral perfusion decreases markedly during presyncope or syncope with systemic blood pressure decline in subjects with cardiovascular vasodepressor syncope. Furthermore, the autonomic nervous function remains unchanged before the systemic blood pressure decline.

Autonomic neuropathy predicts the development of stroke in patients with non-insulin-dependent diabetes mellitus.

BACKGROUND AND PURPOSE: Our aim was to determine the predictive factors for stroke in patients with non-insulin-dependent diabetes mellitus (NIDDM). METHODS: We studied 133 patients with NIDDM at the time of diagnosis and 5 and 10 years later. RESULTS: The number of new fatal or nonfatal strokes was 19 (14.7%; 14 after 5-year examination). High initial fasting blood glucose (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.04 to 1.4) and the use of beta-blocking agents (OR, 6.7; 95% CI, 2.1 to 21.5) at baseline and the presence of parasympathetic neuropathy (OR, 6.7; 95% CI, 1.5 to 29.9), or sympathetic autonomic nervous dysfunction (OR, 1.1; 95% CI, 1.01 to 1.2), hypertriglyceridemia (OR, 5.7; 95% CI, 1.1 to 31.0), or use of beta-blocking agents (OR, 6.4; 95% CI, 1.3 to 31.2), and high fasting plasma glucose (OR, 1.2; 95% CI, 1.0 to 1.5) determined at 5-year examination predicted the development of stroke. CONCLUSIONS: Autonomic neuropathy is an independent risk factor for stroke in NIDDM.

Occurrence, predictors, and clinical significance of autonomic neuropathy in NIDDM. Ten-year follow-up from the diagnosis.

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 /- 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.