Amyloid in the islets of Langerhans 85 Figure 6. Electron micrograph showing a part of a b-cell from a diabetic subject. There are bundles of typical amyloid ﬁbrils which penetrate deeply into the cells. Note that the cell is ﬁlled with characteristic insulin granules. (49). In the case of IAPP, aberrant cleavage is not necessary for ﬁbrillogenesis since only full-length molecules have been identiﬁed in the deposits, although small amounts of propeptides can be dem- onstrated by immunological techniques (50,51). Still, aberration in the cleavage of pro-IAPP as an initial step in amyloidogenesis cannot be ruled out (52). An increased local concentration of the ﬁbrillogenic pro- tein may be important. Over-production of insulin, often seen in type 2 diabetes as a response to insulin resistance, is associated with increased release also of IAPP since these two b-cell products are normally regulated in parallel (53). IAPP is a very ﬁbrillogenic peptide in vitro, and its native conformation must be controlled in vivo. Consequently, a further possible factor in amyloidogenesis might be a dysregulation of chaperones, normally hindering the strongly ﬁbrillo- genic molecule IAPP from making amyloid. It is not known exactly how IAPP is stored in granules and which factors normally inhibit ﬁbril formation, but, experimentally, insulin is a strong inhibitor (54–56). Although insulin is mainly stored in crystalline form in the granule core and IAPP in the halo region, it is possible that there is enough insulin in the halo to inhibit ﬁbril formation. Proinsulin, present in the halo, is also an inhibitor (54). Finally, there may be unknown inhibitors and promoters in IAPP amyloi- dogenesis. Among additional components present in all forms of amyloid and which may affect amyloido- genesis are heparan sulfate (57) and serum amyloid P-component (SAP) (58,59). Is islet amyloid of any importance in type 2 diabetes? This question can be rephrased as to whether aggre- gated IAPP in any form is pathogenically important since there is evidence that not fully developed amy- loid ﬁbrils but smaller, oligomeric assemblies exert toxic effects on b-cells and thereby kill them (60). It has even been suggested that the amyloid itself is innocent and that its formation rather is a protection mechanism by which the dangerous oligomeric spe- cies are taken care of (61). In this paper, I will not discuss oligomers more, and interested readers are referred to a recent review (25). However, when looking at a pancreatic section from a patient with type 2 diabetes where almost all of the islets are converted to amyloid (Figure 4), it is very difﬁcult to believe that the amyloid itself is without