The effect of synthetic human growth hormone-releasing hormone(1-40) (hGHRH-40) on the function of the endocrine pancreas and on glucose homeostasis in lean and genetically obese-diabetic (ob/ob) mice and normal rats has been examined. The addition of 1 mumol hGHRH-40/1 to incubated islets from normal lean mice increased insulin release by 90 and 37% at 5.6 and 16.7 mmol glucose/l respectively. Lower concentrations of hGHRH-40 did not affect insulin release. hGHRH-40 (1 mumol/l) increased pancreatic polypeptide release by 50% at 5.6 mmol glucose/l. A range of concentrations of hGHRH-40 (1 nmol/l-1 mumol/l) reduced glucagon release by 42-73% at 5.6 mmol glucose/l, and by 38-70% at 16.7 mmol glucose/l. Somatostatin release was increased (eightfold) by 1 mumol hGHRH-40/1 at 5.6 mmol glucose/1, but at 1 nmol hGHRH-40/1 somatostatin release was reduced (by greater than 50%). At 16.7 mmol glucose/litre 0.01-1 mumol hGHRH-40/1 increased somatostatin release (three- to fourfold), but 1 nmol hGHRH-40/1 produced a reduction of 50%. In vivo, administration of hGHRH-40 (50 micrograms/kg body weight i.p.) to fasted lean and ob/ob mice did not alter basal plasma concentrations of glucose and insulin, or the glucose and insulin responses to a concomitant i.p. glucose challenge. Intravenous injection of hGHRH-40 (20 micrograms/kg body weight) to anaesthetized rats increased plasma concentrations of insulin in the hepatic portal vein. A lower dose of hGHRH-40 (0.2 micrograms/kg) was ineffective, and neither dose of hGHRH-40 altered plasma glucose.(ABSTRACT TRUNCATED AT 250 WORDS)