Preparation and Properties of Hypothalamic Factors Capable of Altering Pancreatic Hormone Releasein Vitro*

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Abstract
Insulin release-inhibiting and glucagon-releasing activities previously detected in media in which rat ventromedial hypothalamic tissue had been incubated have now been detected in acid/acetone extracts of rat hypothalamic tissue. The activities from the two sources have identical responses to treatment with various proteolytic enzymes. They were treated with trypsin, chymotrypsin, carboxypeptidase, or pepsin and then tested in a pancreatic islet system for their ability to inhibit insulin and stimulate glucagon release. The insulin release-inhibiting activity was abolished by chymotrypsin, trypsin, carboxypeptidase, and pepsin treatment, whereas the glucagon-releasing activity was eliminated by carboxypeptidase and pepsin, was unaffected by trypsin, and was enhanced by chymotrypsin. These results indicate not only the peptidic nature of the two activities but also show that both extract and incubate preparations appear to contain the same two peptide agents. Gel filtration on Sephadex G-25 demonstrated that the insulin release-inhibiting and glucagon-releasing activities were associated with two distinct entities. The insulin release-inhibiting activity was eluted soon after the void volume, whereas the glucagon-releasing activity was considerably retarded; each was distinguished from neurotensin and substance P. While no physiological significance can yet be assigned to these two peptides for the control of insulin and glucagon secretion, their existence provides further evidence for a possible neurohormonal pathway in the regulation of the endocrine pancreas.