Rocca et al. reported first that the secretion of incretins, particular GLP-1 in rat is regulated by the enteric nervous system, the afferent and efferent vagus nerves [1]. Further, Kazakos et al. [2] reported that autonomic nerve disturbance (AND) in patients with T2DM impaired the incretin effect owing to decreased GLP-1 secretion. However, Toft-Nielsen et al. [3] reported that the decreased GLP-1 responses in the patients with type 2 diabetes mellitus (T2DM) are unlikely to be related to the AND and, thus, did not support the results of Rocca et al. and Kazakos et al. Recently, Yabe at al. [4] also observed the same observations in Japanese patients with T2DM. Meanwhile, Jin et al. reported that administration of DPP-IV inhibitor recovered the disturbance of diabetic nerve dysfunction in rat [5]. However, it is unknown whether the administration of DPP-IV inhibitor effects on the AND in human, although many studies are performed to investigate the effect of the DPP-IV inhibitors on glycemic control.

Accordingly, it is significant to reinvestigate an effect of DPP-IV inhibitor on glycemic control and autonomic neuropathy in diabetic patients.

Autonomic nerve disturbance (AND) is estimated to use coefficient of variance of electrocardiographic beat-to-beat intervals (C.V. R-R). Maximal change of the C,V. R-R with from usual breathing to deep breathing at the resting was used for the evaluation of AND. Less than 2.0 % of the maximal value is estimated to have a positive to AND.

Glycemic control is estimated to measure change of HbA1c value once three months per year.

Inclusion Criteria:

type 1 and 2 diabetes mellitus patients

• Patients who have AND determined by C.V. R-R.
• Outpatients regularly visiting hospital
• Patients 20 years old (gender is disregarded)

Exclusion Criteria:

Patients with a serious complication in the heart, liver or kidney

• Pregnant or possibly pregnant patients, or lactating patients
• Patients complicated with a malignant tumor at present.
• Patients participating in other clinical study.
• Other than the above, patients judged inappropriate as the subjects of this study by the investigator

Type 1 and 2 diabetic patients who have AND determined by C.V. R-R, outpatients regularly visiting hospital and more than 20 years old (gender is disregarded). Type 1 diabetic patients are treated with Epalrestat 50 mg. 150 mg t.i.d., while type 2 diabetic patients are treated with DPP-IV inhibitors.