ISLET AMYLOID POLYPEPTIDE IN HUMAN INSULINOMAS - EVIDENCE FOR INTRACELLULAR AMYLOIDOGENESIS

Amyloid deposits that characteristically form in the pancreatic islets of patients with non-insulin-dependent diabetes mellitus (NIDDM) and in insulinomas are both derived from islet amyloid polypeptide (IAPP). Evidence from previous studies has suggested that deposition of IAPP- derived amyloid is related to inherent amyloidogenic sequences present within normal human IAPP, together with an increased production and l ocal concentration of IAPP. However, whether the aggregation of IAPP t o form amyloid fibrils is primarily an intra- or extracellular event i s not clear. To address this question, we studied 20 human insulinomas by light end electron microscopy. By light microscopy, amyloid deposi ts were demonstrated in 13 of 20 (65%) human insulinomas. Furthermore, evaluation of Congo red-stained tumor sections showed small, globular or irregular, congophilic amyloid deposits within the cytoplasm of ma ny tumor cells in 10 of 13 (77%) amyloid-containing insulinomas. Dense , punctate areas of IAPP immunoreactivity within tumor cells correspon ded with the congophilic intracellular deposits. Ubiquitin immunoreact ivity also was observed as punctate intracellular labeling and within large extracellular amyloid deposits. Among the 10 insulinomas availab le for electron microscopic evaluation, pathological IAPP-immunoreacti ve (immunogold) deposits were found in 3 of 5 insulinomas in which amy loid was demonstrated by light microscopy and in none of 5 tumors foun d negative for amyloid by light microscopy. Morphology of IAPP-immunor eactive deposits varied from those with the classical distinct 7- to 1 0-nm diameter nonbranching fibrils to those with distinct but faint fi brillarity to those without discernable fibrils. In each of the 3 tumo rs with ultrastructurally demonstrable amyloid deposits, intracellular aggregates of IAPP-immunoreactive amyloid fibrils were observed eithe r free in the cytoplasmic matrix or in membrane-bound structures. Intr acellular IAPP-immunoreactive deposits were up to 10 mu m in the great est dimension. Free intracellular aggregates of amyloid fibrils someti mes contained degenerating secretory vesicles and fragments of membran ous organelles. These observations suggest that IAPP-derived amyloid d eposits are initially formed intracellularly and are subsequently rele ased to the extracellular space by exocytosis of the membrane-bound st ructures and/or after necrosis of the tumor cells. Our observations ra ise the possibility that IAPP-derived islet amyloid deposits (characte ristically present in NIDDM patients) also may be initially formed wit hin the cytoplasm of beta-cells, thus leading to beta-cell necrosis an d a reduction of beta-cell mass as seen in NIDDM.