Insulin secretion from the isolated perfused pancreas is characterized by pulses occurring every 5-15 min. The present experiments were performed to explore the role of glucose in regulating these pulses. The pancreata from 12 Wistar (W), 12 Zucker diabetic fatty (ZDF), and 6 nondiabetic lean Zucker control (ZC) male rats were isolated and perfused at 37 degrees C with an oxygenated Krebs Ringer solution containing bovine serum albumin and glucose. In W and ZDF, insulin secretion was pulsatile during constant glucose, as assessed by pulse analysis (ULTRA). The pulse period in W was significantly shorter than in ZDF (7.1 +/- 0.6 vs. 14.7 +/- 1.0 min; P < 0.001), whereas the median relative pulse amplitude was not different. When glucose was administered as a series of 10-min sine waves, spectral analysis showed that the normalized spectral power at 10 min was greater in W and ZC compared with ZDF (34.2 +/- 5.9 and 32.9 +/- 2.9 vs. 3.2 +/- 0.9; P < 0.0001), demonstrating entrainment of the insulin pulses to the exogenous glucose oscillations in W and ZC but not in ZDF. Furthermore, in ZDF, the insulin secretory rates were not higher when 28 mM rather than 7 mM glucose were used. In additional studies, islets of Langerhans from one W, three ZDF, and three ZC rats were isolated and perifused using an oscillatory glucose concentration. Single and groups of islets were studied. Islets from diabetic rats demonstrated the same lack of entrainment by glucose seen in the perfused pancreas, suggesting that the defect is at the cellular level.(ABSTRACT TRUNCATED AT 250 WORDS)