THE BIOSYNTHESIS OF INSULIN AND A PROBABLE PRECURSOR OF INSULIN BY A HUMAN ISLET CELL ADENOMA

Because of the occurrence of two polypeptide chains in the insulin molecule, it has been proposed by several investigators, most recently by Givol et al.,I that it may be synthesized in vivo as a single large polypeptide chainwhich is converted byproteolysis to insulin after the native conformation has been established. This mechanism would undoubtedly ensure correct and efficient assembly in vivo. However, high yields of insulin have been obtained in vitro by recombination of separated or synthetic chains, especially when directing groups are employed.2 The results of Humbel3 also are consistent with a separate parallel synthesis of the two chains of angler fish insulin. Furthermore, Wang and Carpenter4 have looked for a "proinsulin" in pancreatic extracts but have concluded that if such exists, it comprises less than 10 per cent of the total insulin in the pancreas. The preponderant acinar tissue in the mammalian pancreas and its proteolytic enzymes has restricted most studies of insulin biosynthesis to a few species of teleost fish in which the islet tissue is separate from the pancreas.5' 6 Insulinproducing tumors of the islets of Langerhans, which occasionally occur in humans, are uniquely suited for the study of insulin biosynthesis since they are composed mainly of fB cells and are well separated from the surrounding acinar tissue. We recently obtained part of an islet cell adenoma that was removed from the pancreas of a patient with severe hypoglycemic episodes. When slices from this tumor were incubated with tritiated leucine or phenylalanine, the amiho acids were incorporated into insulin. A second labeled protein was separated from the acid-alcohol soluble fraction which could be shown to be related immunologically and chemically to insulin. Treatment of the second fraction with trypsin resulted in its conversion to a form that could not be distinguished from insulin. The results suggest that there is a precursor in the synthesis of insulin and that the precursor is a larger protein than insulin.