Differences in amyloid deposition in islets of transgenic mice expressing human islet amyloid polypeptide versus...

Islet amyloid polypeptide (IAPP)-derived amyloid is frequently deposited in the islets of Langerhans in patients with chronic non-insulin-dependent diabetes mellitus (NIDDM). When human islets were implanted under the renal capsule in nude mice, amyloid occurred in 73% of the grafts within 2 weeks. In this study, we compare the deposition of amyloid in islets from a transgenic mouse strain expressing human IAPP (hIAPP) and in normal human islets after implantation in nude mice. The implantations were performed as follows: (1) nondiabetic recipients were given islets from transgenic mice alone, (2) human islets were implanted in the upper pole of the kidney and islets from transgenic mice were implanted in the lower pole of the kidney, (3) grafts containing a mixture of human and transgenic islets were implanted, and (4) transgenic islets and islets from nontransgenic littermates were implanted in therapeutic numbers into recipients made diabetic by a single injection of alloxan prior to implantation. The implants were removed after various periods from 4 days to 8 weeks. The implants were either fixed in Formalin, stained for amyloid, and viewed in polarized light, or processed for immunoelectron microscopy and studied after immunolabeling with specific antibodies against IAPP. We found that the course of amyloid deposition differed significantly between human islets and hIAPP-expressing mouse islets. In human islets, amyloid was mainly deposited intracellularly and only small amounts of amyloid were found extracellularly. In contrast, in islets from transgenic mice, amyloid was exclusively deposited extracellularly and deposition in this site was preceded by an aggregation of immunoreactive material along the basement membrane. These findings point to separate mechanisms for amyloid formation in these two models.