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Studies were performed to examine the effects of various fractions of pineal gland origin upon rates of immunoreactive insulin release during short-term incubations of pancreatic islets from pinealectomized rats. Fractions of cerebral cortex were employed in control incubations. An ultrafiltrate of pineal extracts containing materials of molecular weight less than or equal to 1000 daltons stimulated insulin release while fractions of greater molecular weight were without effect. The stimulation of insulin release observed with the lower molecular weight pineal fraction was seen with both nonstimulatory (2 mM) and stimulatory (10 and 30 mM) medium glucose concentrations, but was abolished in the presence of 2,4-dinitrophenol (200 microM). Upon further fractionation of the low molecular weight pineal extract, fractions I (estimated molecular weight range 700-1000 daltons) and 11 (estimated molecular weight range 180-700 daltons) exhibited comparable stimulatory effects upon islet insulin release: similar effects were observed with cerebral cortical fractions in these molecular weight ranges. However, pineal fraction III (estimated molecular weight range less than 180 daltons) exhibited a striking inhibitory effect upon rates of insulin release compared to cerebral cortical fraction III. Potassium, dopamine, norepinephrine and epinephrine concentrations in both pineal and cortical tissue fractions were similarly low. We conclude that insulinotropic constituent(s) of similar molecular weight occur in pineal gland and cerebral cortex, and that the pineal insulinotropic activity stimulates active insulin secretion by the islets independently of concomitant stimulation by glucose; however, lower molecular weight insulinostatic constituent(s) are notable only in the pineal. It is suggested that mild hyperinsulinemia seen in pinealectomized rats under some circumstances may occur as a result of loss of the pineal insulinostatic factor(s).