Hyperglucagonemia is commonly found in insulin-dependent as well as in non-insulin-dependent diabetes mellitus, and is likely to be caused by absolute or relative insulin deficiency. The aim of the present study was to evaluate whether a chronic glucagon exposure (1.0 microM for 4 h) modifies the insulin response to acute stimuli with glucagon (1.0 microM), arginine (10.0 mM) and glucose (16.7 mM), or the glucagon response to arginine and glucose, in human islets. Chronic exposure to glucagon did not affect the insulin response to glucose and arginine, but inhibited its response to glucagon (44.6 +/- 9.3 vs 168.6 +/- 52.3 pg/islet per 20 min, P < 0.05); the latter effect was not observed when exposure to glucagon was discontinuous (2.0 microM glucagon alternated with control medium for 30 min periods). The chronic exposure to glucagon also reduced the glucagon response to arginine (- 4.9 +/- 5.7 vs 19.9 +/- 7.9 pg/islet per 20 min, P < 0.05) without affecting the inhibition of glucagon release exerted by glucose. These data indicate that chronic exposure to glucagon desensitizes pancreatic alpha and beta cells in response to selected stimuli.