84 P. Westermark Figure 4. Human islet from a diabetic subject. Most of the islet has been converted into amyloid, but there are still cords of cells, a majority being b-cells, most probably dysfunctional. Congo red. Bar: 50 mm. to b-cells there is often an orientation of bundles of ﬁbrils towards the cell membrane (24). Typically, bundles of ﬁbrils run into deep pockets of b-cells, seemingly penetrating the cell membrane (Figure 6). A conspicuous feature of b-cells close to islet amyloid is the distortion of the architecture of the outer part of the cells and loss of an evident basement mem- brane (24). The lack of intracellular amyloid in b-cells of diabetic individuals does not necessarily mean that aggregation of IAPP to ﬁbrils may not take place here. In models with more rapidly devel- oping islet amyloid, e.g. in human islets transplanted A B into nude mice or in islets cultured in vitro, small amyloid deposits develop within a few days or weeks (45,46). This very ﬁrst amyloid is intracellular. We have suggested that this ﬁrst amyloid leads to apo- ptosis of the cell, leaving the amyloid, which is resis- tant to degradation, extracellularly where it seeds further amyloid formation from exocytosed IAPP (46). Such an event might explain the deep pockets into b-cells formed by the ﬁbrils when these are elongated by addition of new IAPP molecules at the cellular side (47). The spreading of islet amyloid An interesting phenomenon is that even very small amyloid deposits are widely spread throughout an individual islet (10), although other islets in the neighbourhood are free. This might indicate that the abnormality has affected all cells in the islet. Amyloidogenesis is a nucleation-dependent phenom- enon and does not start until a nucleus has formed (48). However, when the ﬁrst ﬁbrils have assembled, the process moves on rapidly as long as the peptide is present above a critical concentration. The widely spread amyloid in single islets may simply reﬂect such events. Whether or not islets may communicate so that amyloid can spread from one islet to another is still an open question. Why does IAPP form amyloid in type 2 diabetes? The pathogenesis of any localized form of amyloid is not clear. Although most human proteins contain segments that in theory are able to assemble into amyloid ﬁbrils, most such parts are hidden in the molecules and may be exposed only after cleavage 200 µm 200 µm Figure 5. Section from the pancreas of a diabetic subject with severe islet inﬁltration of amyloid in all islets, visualized with Congo red. The section in A is seen in ordinary light, while in B polarized light with crossed polars has been used. A bright yellow birefringence is evident.