The responses of the pancreatic alpha- and beta-cells to small changes in glucose were examined in overnight-fasted conscious dogs. Each study consisted of an equilibration (-140 to -40 min), a control (-40 to 0 min), and a test period (0 to 180 min), during which BAY R3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally, either alone to create mild hypoglycemia or with peripheral glucose infusion to maintain euglycemia or create mild hyperglycemia. Drug administration in the hypoglycemic group decreased net hepatic glucose output (NHGO) from 8.9 +/- 1.7 (basal) to 6.0 +/- 1.7 and 5.8 +/- 1.0 pmol x kg(-1) x min(-1) by 30 and 90 min. As a result, the arterial plasma glucose level decreased from 5.8 +/- 0.2 (basal) to 5.2 +/- 0.3 and 4.4 +/- 0.3 mmol/l by 30 and 90 min, respectively (P < 0.01). Arterial plasma insulin levels and the hepatic portal-arterial difference in plasma insulin decreased (P < 0.01) from 78 +/- 18 and 90 +/- 24 to 24 +/- 6 and 12 +/- 12 pmol/l over the first 30 min of the test period and decreased to 18 +/- 6 and 0 pmol/l by 90 min, respectively. The arterial glucagon levels and the hepatic portal-arterial difference in plasma glucagon increased from 43 +/- 5 and 4 +/- 2 to 51 +/- 5 and 10 +/- 5 ng/l by 30 min (P < 0.05) and to 79 +/- 16 and 31 +/- 15 ng/l by 90 min (P < 0.05), respectively. In euglycemic dogs, the arterial plasma glucose level remained at 5.9 +/- 0.1 mmol/l, and the NHGO decreased from 10 +/- 0.6 to -3.3 +/- 0.6 pmol x kg(-1) x min(-1) (180 min). The insulin and glucagon levels and the hepatic portal-arterial differences remained constant. In hyperglycemic dogs, the arterial plasma glucose level increased from 5.9 +/- 0.2 to 6.2 +/- 0.2 mmol/l by 30 min, and the NHGO decreased from 10 +/- 1.7 to 0 pmol x kg(-1) x min(-1) by 30 min. The arterial plasma insulin levels and the hepatic portal-arterial difference in plasma insulin increased from 60 +/- 18 and 78 +/- 24 to 126 +/- 30 and 192 +/- 42 pmol/l by 30 min, after which they averaged 138 +/- 24 and 282 +/- 30 pmol/l, respectively. The arterial plasma glucagon levels and the hepatic portal-arterial difference in plasma glucagon decreased slightly from 41 +/- 7 and 4 +/- 3 to 34 +/- 7 and 3 +/- 2 ng/l during the test period. These data show that the alpha- and beta-cells of the pancreas respond as a coupled unit to very small decreases in the plasma glucose level.