82 P. Westermark A resemblance to amyloid was noted at an early date, and when the nature of this substance was debated the name ‘para-amyloid’ was sometimes used for deposits like those in the islets (4). However, not until the studies by Ehrlich and Ratner (5) was the material accepted as a ‘real’ form of amyloid. It may be mentioned that the discussion about inclusion criteria for amyloid is still on-going (6). For a long time, the interest for this alteration, which is quite characteristic for type 2 diabetes, was generally low, but it was an enigma mainly for pathologists who noticed the islet alteration when examining autopsy specimens. The low interest in amyloid among researchers in the diabetes ﬁeld might have been due to the fact that islet amyloid is missing in mouse and rat models of diabetes. The reason for this absence became obvious soon after our description of the nature of human (and feline) islet amyloid (1,7). Another reason for the lack of interest is that islet amyloid is not solely seen in association with diabetes; it occurs also in non- diabetic subjects but less commonly and to a lower degree (8–10). The ﬁnding that islet amyloid is com- posed by a previously unknown polypeptide hormone immediately increased the interest in islet amyloid. The elucidation of the islet amyloid nature Gellerstedt, a professor of pathology at Uppsala University, noted already in 1938 that the Congo red staining property of islet amyloid was slightly different from that of systemic amyloid (4). Also histochemical studies indicated that the islet amyloid was different (11,12). However, only an amino acid sequence analysis could determine the nature of the material. It was not an easy task to extract, purify, and determine the nature of the main protein in islet amyloid. In 1971 the two ﬁrst ﬁbril proteins from systemic amyloidosis had been puriﬁed and deter- mined by Edman degradation. One was found to be of immunoglobulin light chain origin (13), while the second turned out to be a previously unknown pro- tein, now called AA (14). The third amyloid ﬁbril protein to be characterized was calcitonin (or procal- citonin) in the C-cell tumor thyroid medullary carci- noma (15). In all these instances, the tissue material serving for protein puriﬁcation was very rich in amy- loid, making identiﬁcation of the main protein com- paratively easy. Dealing with amyloid in the islets of Langerhans was a completely different problem. This amyloid is strictly limited to the around 1 million islets which constitute about 1% of the total pancreatic mass. A second problem was the unusual insolubility of this amyloid (12). Previously studied amyloid pro- teins had been puriﬁed after solubilization in guani- dine hydrochloride, but islet amyloid turned out to be completely insoluble in this solvent. After years of trials, the solution to the problem came with a b-cell tumor (insulinoma), rich in amyloid. With this material a new approach was used, including solubi- lization in concentrated formic acid, used for identi- ﬁcation of the Ab protein (16), a new puriﬁcation method with the aid of high-performance liquid chro- matography and access to a new sensitive gas phase sequenator. In this way, the nature of the protein was ﬁnally elucidated (1). Surprisingly, it turned out to be a novel b-cell protein, not related to insulin or its precursor. It was initially named insulinoma (or islet) amyloid peptide (IAP), which soon changed to islet amyloid polypeptide (IAPP) since the abbreviation IAP was already used. Further analyses, also of pro- tein puriﬁed from amyloid derived from human and cat islets (Figure 1), revealed a 37-amino acid residue polypeptide belonging to the calcitonin gene- related peptide (CGRP) family (7,17). Soon after- wards, our ﬁndings were veriﬁed by another research group (18). Parts of this group later named the pep- tide ‘amylin’ (19). By immunohistochemistry (7,20), immune electron microscopy (21,22), and later in-situ hybridization (23) it was shown that IAPP is a product of islet b-cells (24). IAPP is stored together with insulin in the secretory vesicles. It is located to the halo region where also proinsulin and C-peptide are located. Although most of the circulating IAPP is derived from islet b-cells, there is IAPP expression in some gastrointestinal endocrine cells, in certain peripheral ganglia, and in the brain (for review, see (25)). 50 µm Figure 1. Pancreatic section of case IsN13 with islets ﬁlled with amyloid, stained with Congo red. This material was used to purify the IAPP giving the ﬁrst amino acid sequence from human islet origin. There are signs of pronounced autolysis, which did not affect the quality of the puriﬁed peptide. There was also partial exocrine atrophy which was helpful in that it made the amyloid more concentrated.