Autonomic neuropathy (AN) in patients with newly diagnosed type 1 diabetes was first described by Fraser et al. (1). Of the six patients examined, two had evidence of AN. In this study, autonomic dysfunction detected during the initial metabolic derangement in newly diagnosed diabetic patients was not reversible after a prolonged period of improved control, indicating that established alterations may occur from the time of diagnosis onward. Other authors (2,3) have also shown that standard cardiovascular reflex tests are able to detect AN in newly diagnosed diabetic patients. A relationship between the severity of AN and prolongation of the corrected QT interval has also been noted (4).
According to the results of the EURODIAB IDDM Complications Study, the development of neuropathy is related to cardiovascular risk factors (5). The EURODIAB Prospective Complications Study (6) also confirms this finding.
However, there are no data regarding potential risk factors of nerve dysfunction in patients with newly diagnosed type 1 diabetes. We examined 40 patients with newly diagnosed type 1 diabetes with a mean (± SD) age of 34.7 ± 11.3 years. The control group comprised 25 healthy subjects (age 38.3 ± 14.8 years). The five standard tests of cardiovascular autonomic function were applied (7). Heart rate tests (heart rate responses to deep breathing, the 30:15 ratio, and the Valsalva ratio) mainly reflect parasympathetic function, while blood pressure responses to sustained handgrip and standing primarily allow the assessment of sympathetic integrity. The results of each of the five tests were scored as 0 (normal), 1 (borderline), or 2 (abnormal). A final score was calculated (range 0–10) to express the severity of the overall autonomic disorder. Patients with at least one abnormal or two borderline cardiovascular tests (score ≥2) were considered to have autonomic neuropathy. Peripheral sensory function was characterized by the evaluation of the current perception threshold (CPT), with a neuroselective diagnostic stimulator (Neurotron, Baltimore, MD), which permits transcutaneous testing (8) at three sinusoidal frequencies (2 kHz, 250 Hz, and 5 Hz). Median and peroneal nerves (digital branches) were studied. All tests were performed after 9 days (range 3–34) of insulin therapy.
As multiple comparisons increase the risk of the error of first kind, we considered results at P ≤ 0.01 as statistically proven, while those at P ≤ 0.05 were regarded as marginally significant.
Twelve diabetic patients (30%) had at least one abnormal autonomic function test. Parasympathetic neuropathy was found in six patients, sympathetic nerve dysfunction was observed in three patients, and three subjects had both parasympathetic and sympathetic damage. A significant decrease of the 30:15 ratio (mean ± SE) was found in diabetic patients compared with control subjects (1.28 ± 0.03 vs. 1.42 ± 0.03, P = 0.003). The autonomic score was higher in diabetic patients (1.08 ± 0.24) than in control subjects (0.17 ± 0.08, P = 0.005).
At least one abnormal sensory parameter was observed in 10 patients (25%). Higher CPT values indicating hypesthesia were found in the diabetic group compared with control subjects at peroneal nerve testing at 250 Hz (1.6 ± 0.1 vs. 1.1 ± 0.07 mA, P= 0.03) and 5 Hz (1.1 ± 0.09 vs. 0.6 ± 0.06, P = 0.007), just as at median nerve testing at 5 Hz (0.6 ± 0.03 vs. 0.49 ± 0.05, P = 0.048).
Analyzing the relationship between blood pressure and autonomic function in diabetic patients, the 30:15 ratio correlated significantly negatively with the diastolic blood pressure values (r = 0.3240, P = 0.044). There was a significant positive relationship between systolic blood pressure and the CPT values testing median nerve at 5 Hz (r = 0.3988, P = 0.012). The decrease of systolic blood pressure after standing correlated significantly negatively with CPT values at the peroneal nerve at 2 kHz (r = −0.3436, P = 0.032), 250 Hz (r = −0.3893, P = 0.014), and 5 Hz (r = −0.3273, P = 0.042).
Assessing the relationship between smoking and autonomic function, a significant negative correlation was found between the duration of smoking and the deep breathing test (r = −0.3452, P = 0.006). The duration of smoking correlated significantly positively with the parasympathetic score (r = 0.3817, P = 0.002), just as with the autonomic score (r = 0.3398, P = 0.006). There was a significant correlation between plasma cholesterol and the parasympathetic score (r = 0.3937, P = 0.047).
A significant negative correlation was observed between the deep breathing test and the CPT values testing the median nerve at 2 kHz (r = −0.4452, P = 0.005) as well as at 250 Hz (r = −0.4048, P = 0.01).
In conclusion, autonomic and sensory nerve dysfunction are quite frequent complications in newly diagnosed type 1 diabetic patients and seem to be related to each other. Our data suggest that traditional cardiovascular risk factors (smoking, hypertension, and serum cholesterol) should be considered as potential risk factors for the development of neuropathy, even in newly diagnosed type 1 diabetic patients. These observations may confirm the role of vascular factors in the pathogenesis of neuropathy and may be important for the development of risk reduction strategies.
Footnotes
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