Methods are described for the isolation in nearly pure form of bovine proinsulin, a single polypeptide chain precursor of insulin, and of intermediate forms of proinsulin having two polypeptide chains. The intermediate forms represent proinsulin molecules in which one or more cleavages have occurred at the site of attachment of the connecting peptide (C-peptide) to the A chain. A third fraction is apparently unrelated to proinsulin but appears instead to be an aggregate of insulin (possibly a covalent dimer) which behaves similarly to proinsulin during gel filtration. The purified fractions all react with antisera to insulin and all have been shown to have measurable biological activity. The purified intact proinsulin has very low biological activity, but can be converted to fully active deatanated insulin upon incubation with trypsin. The possible relevance of proinsulin to a fuller understanding of the β cell derangements in human diabetes is briefly discussed.

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