To investigate the role of ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, in diabetic gastroparesis, we evaluated the plasma ghrelin profile during the oral glucose tolerance test in 55 patients with diabetes (men/women: 36/19, mean +/- SE of age: 55.1 +/- 1.7 years) with or without gastroparesis (diagnosed by the (13)C-acetate breath test). We also further examined cardiac autonomic neuropathy by assessing 24-hour variation of the R-R interval in randomly selected 32 patients with diabetes (men/women: 23/9, mean +/- SE of age: 54.2 +/- 2.5 years), and evaluated the influence of autonomic neuropathy on ghrelin. The fasting plasma ghrelin level was significantly lower in diabetes mellitus with gastroparesis than in healthy controls (7.9 +/- 0.7 fmol/ml versus 16.6 +/- 5.3 fmol/ml, p = 0.006). Patients with diabetes with gastroparesis showed no decrease of plasma ghrelin after glucose loading, unlike patients without gastroparesis or healthy controls. Diabetes mellitus with autonomic neuropathy, but not those without it, also showed no decrease of plasma ghrelin after glucose loading. Diabetic gastroparesis may be related to ghrelin-associated neurohormonal abnormalities, but the pathophysiological meaning of this abnormal ghrelin response needs further clarification.