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The biological activities were studied of a new protein, islets-activating protein (IAP), purified from the culture medium of Bordetella pertussis. Rats injected intravenously with 1 microgram of purified IAP exhibited markedly enhanced insulin secretory responses to glucose, glucagon, epinephrine, and sulfonylureas over a period from 3 to 10 days after the injection. The degree and duration of the enhancement were proportional to the dose of IAP; the maximal effect induced by 1-2 microgram of IAP persisted for as long as 2 months. There was a highly significant correlation between the enhancement of insulin secretion and suppression of epinephrine hyperglycemia over a wide range of doses of IAP, indicating that suppression of epinephrine hyperglycemia resulted from hypoglycemic action of insulin secreted in response to epinephrine challenge. Additional actions of IAP were observed in mice; mice treated with higher doses of IAP showed symptoms were observed when lower doses of IAP were injected into mice. Thus, it is concluded that IAP is a protein primarily possessing a unique action to potentiate insulin secretory responses of experimental animals to nutritional and hormonal stimuli.

The subunit structure was studied of islets-activating protein (IAP), a new protein recently isolated from the culture media of Bordetella pertussis and possessing a unique action, i.e., potentiating insulin secretory responses of animals, IAP dissociated into three subunits, F-1, F-2, and F-3, when incubated in 8M urea. Three subunits isolated by chromatography on CM-Sepharose and DEAE-Sepharose columns showed different molecular weights (F-1: 44,000, F-2: 20,000, F-3: 11,000) and different isoelectric points, but similar amino acid compositions. The F-1 subunit consisted of two polypeptide chains linked by S-S bonding(s), while the F-2 and F-3 subunits were single-chain peptides. These subunits, none of which was biologically active alone, associated upon incubation for 2 h at 37 degrees C and regained biological activities after association only when the F-3 subunit was present in the association product. Thus, the F-3 subunit was essential, and the F-1 and F-2 subunits were permissive, for the development of IAP activity in animals.

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