We reported that insulin sensitivity is inhibited by interruption of the hepatic parasympathetic reflex by surgical denervation of the liver or pharmacological blockade of the cholinergic neurotransmitter in rats (1,2,3). Therefore, we tested the hypothesis that parasympathetic neuropathy is associated with insulin resistance in type 2 diabetic patients.

At the present time, only one method is available to directly measure autonomic nerve activity (4), and there are no methods available to measure hepatic parasympathetic nerve activity in humans. Thus, we used the deep breathing test to evaluate a cardiovascular parasympathetic nerve function. Hepatic parasympathetic neuropathy will often occur in parallel with cardiovascular parasympathetic neuropathy, because diabetic autonomic neuropathy is a systemic distal polyneuropathy.

A total of 42 patients with type 2 diabetes (age [means ± SD] 37 ± 9.7 years, HbA1c 9.8 ± 2.2%, duration of diabetes 7.1 ± 7 years) were divided into two groups: those with obesity (BMI ≥25 kg/m2) and those without obesity (BMI <25). Insulin sensitivity was tested using a hyperinsulinemic-euglycemic clamp (5,6). Parasympathetic nerve function was assessed by the deep breathing test, which assesses the heart rate response to deep breathing at 6 cycles/min. The results were expressed as the mean of the difference between the inspiratory heart rate and the expiratory heart rate in each respiratory cycle. Patients were grouped into two categories: those with parasympathetic neuropathy showing <15 beats/min in the deep breathing test, and those without parasympathetic neuropathy showing ≥15 in the test. There was no difference in age, HbA1c, or duration of diabetes between the patients with and without parasympathetic neuropathy who were with and without obesity.

Because glucose infusion rates (GIR) correlated with BMI (r = −0.326, P = 0.035), we compared the GIR of patients with and without parasympathetic neuropathy, adjusted for BMI using minimum square average (analysis of covariance).

As shown in Fig. 1, the GIR of patients with parasympathetic neuropathy was marginally lower than that of those without parasympathetic neuropathy among the total subjects (3.39 ± 0.64 vs. 4.72 ± 0.43 mg · kg–1 · min–1 [means ± SEM], P = 0.07). The GIR of patients with parasympathetic neuropathy was lower than that of those without parasympathetic neuropathy in obese subjects (1.99 ± 0.7 vs. 3.71 ± 0.56 mg · kg–1 · min–1, P = 0.08). On the other hand, there was no difference in GIR between the patients with and without parasympathetic neuropathy in the nonobese subjects.

Gottsater et al. (7) reported that parasympathetic neuropathy is associated with hyperinsulinemia in type 2 diabetic patients. We reported that insulin sensitivity is affected by hepatic parasympathetic nerve (1,2,3). The results of this study support these reports, and we speculate that diabetic parasympathetic neuropathy affects the insulin resistance in type 2 diabetic patients with obesity.

We thank Prof. W. W. Lautt (Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba) and Dr. Mari Takayama (Second Department of Internal Medicine, Chiba University School of Medicine) for helpful comments.

A portion of this study was presented at the 60th Annual Meeting of the American Diabetes Association, San Antonio, TX, June 2000.

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Address correspondence to Shinichiro Takayama, Diabetes Center, Tokyo Women’s Medical University School of Medicine. 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan, 162-0054. E-mail: s-taka@ceres.dti.ne.jp.