In order to determine whether there is an abnormality in the pituitary responsiveness to GRF in the diabetic rat, we examined the in vivo and in vitro effects of hGRF-44 NH2 (hGRF) on growth hormone (GH) release in the spontaneously diabetic BB Wistar rat. Under pentobarbital anesthesia, hGRF was injected intravenously at a dose of 500 ng/kg in male diabetic BB Wistar rats (n = 11) and in male control Wistar rats matched for weight (n = 11). Basal serum GH concentrations were significantly lower in the diabetic group, (123 ± 5 ng/ml, mean ± SEM) than in the control group (362 ± 15 ng/ml). However, the GH response to hGRF was significantly greater in the diabetic group (GH increment 873 ± 153 ng/ml) than in the control group (268 ± 91 ng/ml). The effect of hGRF was further tested in a perifusion system of freshly dispersed anterior pituitary cells of diabetic BB Wistar rats and control Wistar rats. Basal secretion rate of GH from cells of diabetic rats (0.85 ± 0.06 µg/2 pituitaries · 2 min) was lower than that from cells of control rats (1.60 ± 0.18 µg/2 pituitaries · 2 min). The GH response to 2-min pulses of hGRF at concentrations of 1.56, 6.25, and 25 pM with and without somatostatin 10–9 M was significantly greater in the diabetic group than in the control group. In conclusion, there is in the spontaneously diabetic rat an increased in vivo and in vitro GH responsiveness to exogenous hGRF suggesting an abnormality of GH regulation at the pit