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In Vitro Studies of the Rate of Proinsulin and Insulin Turnover in Seven Human Insulinomas

Summary. Human insulinoma tissue excised from seven patients was incubated with glucose (3.0 mg/ml) and 3H‐leucine (100 μCi/ml) for a 15 min. pulse period. One third of the tissue was homogenized immediately in 0.3 M sucrose (pH 6.0), one third was homogenized after a 20 min. chase (with L‐leueine 37S μg/ml) and the remaining third after an 80 min. chase. Subcellular fractions (cell debris, mitochondria, secretory granules, microsomes and S‐100) were prepared by centrifugation. Their identity was confirmed by ultrastructural examination. Since only tumours revealing typical β‐granules were investigated the secretory granule fractions contained the same types of granules as found in the normal human B‐cell.—The S‐100 contained approximately 40% of the immuno‐reactive insulin (IRI). The secretory granule samples from five tumours were fractionated by sucrose gradient ultracentrifugation. At the three time intervals examined, a peak of radioactivity and IRI was located at 1.60 M sucrose in three of the tumours. The different granule types were not separable in the sucrose gradients. Endogenous proinsulin‐like components (proinsulin) and insulin were released throughout the incubation. During incubation of tumour tissue the ratio of IRI release to content was significantly higher than that from isolated human pancreatic islets. Newly synthesized proinsulin was detected in the medium after the 15 min. pulse in five of the tumours; radioactive proinsulin and insulin were present in all the media after the 20 and 80 min. chase periods. Islets isolated from the pancreatic tissue of two insulinoma patients showed a much slower proinsulin and insulin turnover.—These data support the conjecture that human insulinomas have a more rapid turnover of proinsulin and insulin than normal pancreatic islet tissue, apparently as the consequence of defective IRI storage and release mechanisms.