BACKGROUND: Type 2 diabetes mellitus is characterized by defective glucose- induced and glucose-potentiated insulin secretion. Chronic elevation of glucose levels are considered to be a cause of impaired insulin secretion. It has been suggested that such defects in insulin secretion can be related to the alteration in stimulus-secretion coupling. Recent studies have provided evidences for the existence of guanine nucleotide-binding protein (G protein), and the regulatory role of G protein and GTPase activity in stimulus-secretion coupling in pancreatic islets. This study was performed to determine whether the exposure to high glucose concentration alters GTPase activity with decreased insulin secretion in pancreatic islets isolated from normal rats. METHODS: Pancreatic islets isolated from normal Sprague-Dawley rats were incubated in high (20 mM) and low (5 mM) glucose concentration for 48 hours. After incubation, glucose (20 mM) induced insulin secretion was measured. Then subcellular fractions of islets by homogenization and differential centrifugation were obtained and glucose induced inhibition of GTPase activities in each fraction was measured. RESULTS: 1) After 48 hour exposure to 5 mM and 20 mM glucose, insulin secretion in response to 20 mM glucose were 134.4+/-16.8 fmol/10 islets/hr and 90.0+/-10.2 fmol/10 islets/hr, respectively. After the exposure to high glucose, glucose-induced insulin secretion significantly decreased (p<0.05). 2) In each subcellular fraction, there was no significant difference between the islets exposed to 5 mM and 20 mM glucose in the degree of inhibition of GTPase activities by high glucose. CONCLUSION: The exposure to high glucose for 48 hours decreased insulin secretion without any significant differences in the degree of inhibition of GTPase activities. This results suggest that impaired insulin secretion by high glucose is not associated with the change in GTPase activity.