IAPP in animal species IAPP is a conserved molecule and is expressed in mammals (26,27) (Figure 2), birds (28), ﬁshes (29,30), and reptiles (Westermark and Westermark, unpublished) although islet amyloid is seen only in a limited number of species. As mentioned in the intro- duction, islet amyloid does not appear in mouse or rat islets. It is, however, a typical alteration in diabetes in many non-human primate species (31,32) as well as in cat species (33–35). Structural studies of islet amyloid in several mammalian species revealed that IAPP is a strongly conserved molecule but that there are con- siderable species variations in a middle segment of the peptide. It turned out that mouse and rat IAPP, which are identical, carry three proline residues in the 20– 29 segment, where the human molecule has none and the cat has one (26,36). While a synthetic peptide corresponding to human IAPP 20–29 is extremely ﬁbrillogenic in vitro, that corresponding to the rat/ mouse molecule is not (37). Consequently, it turned out that the reason why islet amyloid is not found in these rodents is simply that their IAPP is not amyloi- dogenic. Parenthetically, it may be mentioned that these species discrepancies have been utilized by a pharmaceutical company to make a non-ﬁbrillogenic IAPP variant, used for treatment of type 1 and type 2 diabetes. Amyloid in the degu: an interesting exception There is a remarkable exception from the rule that islet amyloid does not occur in species with apparently non-ﬁbrillogenic IAPP, and that is the South Amer- ican hystricomorphous rodent degu (Octodon degus). This animal is prone to develop diabetes in captivity Amyloid in the islets of Langerhans 83 (38). Degu IAPP has proline residues at positions 28 and 29 (39). In spite of this, islet amyloid is common in elderly and diabetic animals (Figure 3). Direct amino acid sequence analysis of puriﬁed degu islet amyloid revealed surprisingly that the ﬁbril pro- tein in this species is derived from insulin (40). In a way, this ﬁnding closed the circle, since insulin was, for natural reasons, believed to be the ﬁbril protein in human islet amyloid (41) before IAPP was discov- ered. Insulin is an amyloid protein also in human, although an iatrogenic one; amyloid ‘tumors’ may appear at the site of repeated insulin injections in type 1 diabetic subjects (42,43). Morphology of islet amyloid Islet amyloid is restricted to the islet area and is not found systemically or in other parts of the pancreas. In human, islet amyloid is extracellular, and it has been difﬁcult to ﬁnd certain intracellular amyloid. When the deposits are small, amyloid can be seen as thin layers between endocrine cells and capillaries and are tapestrying the outside of the islet. When larger, the deposits can form large masses completely remodel- ing the islets (Figure 4). Amyloid can be visualized with ordinary amyloid dyes such as Congo red and shows the typical birefringence that can vary between yellow and green (Figure 5), although erroneously often referred to as ‘apple green’ (44). It should be noted that the afﬁnity of this kind of amyloid for Congo red often is weak or very weak, making it easy to underestimate the amount of deposited mate- rial or even to totally miss the amyloid. By deﬁnition, islet amyloid consists of thin ﬁbrils, around 10 nm in width, but with an undetermined length. Within the deposits, the ﬁbrils are not organized, but close 20 µm 50 µm Figure 2. Pancreatic section of a common shrew (Sorex araneus), labeled with antibodies against IAPP. There is a strong reaction with the b-cells, which constitute the majority of islet cells. Figure 3. Pancreatic section of a degu (Octodon degus) with heavy amyloid deposits at the islet periphery, stained with Congo red.