Diabetes mellitus in the rat is associated with loss of pulsatile GH secretion. An interplay between hypothalamic GH-releasing factor (GRF) and inhibitory factor [somatostatin (SRIF)] secretion is thought to account for episodic pituitary GH release. An increase in SRIF tone/action or a decrease in GRF release/response in diabetic rats could account for the suppressed GH levels. Pituitaries from streptozotocin- diabetic rats contained less GH than controls (15.9 ± 2.5 vs. 29.5 ± 4.6 μg/mg; P < 0.05) despite normal somatotrope representation, as demonstrated using immunofluorescence studies. Basal GH secretion from monolayer culture of dispersed anterior pituitary (AP) cells from diabetic rats was proportionately decreased (150 ± 10 vs. 103 ± 10 ng/105 cells; P < 0.005). GRF (10-11-10-8 M)-induced release of GH from AP cells was decreased in diabetic rats (maximum response to 10-8 M GRF, 401 ± 60 vs. 618 ± 41 ng/105 cells; P < 0.01); however, sensitivity to GRF was unchanged (EC50, 79 ± 41 vs. 128 ± 67 pM). By contrast, SRIF (10-7-10-10)-induced inhibition of GRF (10-8 M)-mediated GH release was impaired in AP cells of diabetic rats compared to that in controls (IC50, 112 ± 33 vs. 55 ± 31 pM; P < 0.05) associated with a decrease in AP plasma membrane SRIF recep-tor concentration (63.4 ± 15.6 us. 160.3 ± 13.7 fmol/mg protein; P < 0.05), with no change in affinity. These findings are con-sistent with chronic exposure to increased hypothalamic SRIF influence. GH synthesis has been shown to be independent of SRIF regulation; however, insulin-like growth factor-I and GRF inhibit and stimulate GH synthesis, respectively. In diabetic rats insulin-like growth factor-I levels were decreased, appropriate to low GH status, in serum (290 ± 66 vs. 1662 ± 92 ng/ml; P < 0. 001) and hypothalamus (6.8 ± 1.0 vs. 13.0 ± 0.4 pg/mg wet wt; P < 0.001) and, thus, did not seem to account for the low AP GH content. Hypothalamic GRF content in diabetic rats (1.11 ± 0.10 ng/hypothalamus) did not differ from that in controls (1.16 ± 0.17 ng/hypothalamus). GRF mRNA levels, however, were reduced by 80% in diabetic rats compared to controls. Taken together these data support a combined role for decreased hypothalamic GRF and increased SRIF in mediating alterations of GH synthesis and secretion in streptozotocin-induced diabetes.