To clarify the mechanism of an increased response of diabetic D-cells to arginine, we studied the changes in responsiveness of pancreatic D-cell to this agent with the passage of time after the onset of diabetes and the effect of chronic insulin substitution on the altered D-cell function utilizing the perfused pancreas of streptozotocin diabetic rats. The magnitude of somatostatin (SRIF) response to arginine (10 mM) was progressively increased with the duration of diabetes. The integrated response of SRIF during a 20 min period of an arginine infusion one week after the injection of streptozotocin was not different from that in the normals, but it was increased by 240% at 8 weeks and by 390% at 15 weeks. The exaggerated pancreatic SRIF release observed in 8 week diabetic rats was partially ameliorated with the daily insulin replacement (15.0 +/- 1.0 units/kg of B.W.). This was accompanied by a partial recovery from growth failure. The integrated amount of SRIF secreted during an arginine-stimulated period (20 min) was inversely correlated with an increase in body weight during an 8 week period (r = -0.741, p less than 0.001). From these results, it might be concluded that the alteration in diabetic D-cell function may be related to the metabolic and hormonal abnormalities of diabetes, rather than insulin deficiency itself.