Amyloid and polypeptide hormones: What is their

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was observed in some endocrine tissues and tumors at an ... All types of hitherto described polypeptide hormone- ... loid while the exocrine tissue is spared. .... fibrils elongate as new secretory granules are released (E and F). .... makes up the main part of the amyloid has changed this ..... cally is that in the pituitary gland.
Amyloid: Int. J. Exp. Clin. Invest. 1 (1994)

Amyloid and polypeptide hormones: what is their interrelationship? Per Westermark

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Department of Pathology University of Linkoping Linkoping, Sweden

KEY WORDS: AMYLDID, POLYPEPTIDE HORMONES

Abstract Amyloid deposits are common in certain polypeptideproducing tissues and are sometimes a characteristicfeature of diseases afecting these tissues. Recent years have given us increasing knowledge about the nature of this type of amyloid and its pathogenesis. A hyaline stmma, diflerent in appearancefrom collagen, was observed in some endocrine tissues and tumors at an early date1r2.Fairly soon, the amyloid nature of this stroma was discussed and designations like “atypical amyloid or “paraamyl~id”~ were used. For a long time, the amyloid was regarded as a non-specifc product of degeneration but when the nature of some systemic amyloids started to become elucidated in 1971, there was a growing suspicion that the amyloid in endocrine tissues reflected a specifc pathologic event. This suspicion was verifed in 1976 with the clarification of the hormonal nature of the amyloid (calcitonin derived) in a medullary carcinoma of the thyroid. Since then, three more polypeptide hormones have been identified as major amyloid fibril proteins. (islet amyloid polypeptide (IAPP); atrial natriuretic factor derived amyloid (ANF); insulin derived amyloid).



General Aspects Deposits as amyloid All types of hitherto described polypeptide hormonederived (PHD) forms of amyloid have in common an ultrastructural fibrillar appearance similar to what is seen in any other amyloid, although some variability exists. As in all types of amyloid, these fibrils have certain characteristic properties, such as affinity for Congo red and green birefringence on polarization microscopy after this staining. The PHD-amyloids are also characteristically deposited extracellularly. The earlier discussions whether the

designation amyloid is justified for the localized small deposits in endocrine tissues should have come to an end and now there seems to be general agreement that the hyaline material belongs to the group of amyloids.

The localized nature of PHD-amyloid All PHD-amyloids are strictly localized and are deposited in close vicinity to their producer cells, i.e. the endocrine active cells, irrespective of whether these are neoplastic or not. This is very evident in the islets of Langerhans, where sometimes most islets contain amyloid while the exocrine tissue is spared. Distant deposits are unknown, except for the iatrogenic insulin-derived amyloid. This localized nature is not surprising considering the very low concentrations of the amyloid-forming hormones in the circulation but is in notable contrast to the low incidence of amyloid deposits at the sites of synthesis of most other fibril-precursor proteins such as those in the systemic amyloidoses (see below). Site offibril formation Early discussions occurred as to whether fibrils in systemic amyloidoses are formed intra- or extracellularly4. The question has not been definitely settled, although in experimental AA-amyloidosis, there is evidence that the first fibrils are formed in lysosomal complexes5.The same problem occurs in PHD-amyloids. In these forms, at least the chemically defined ones, the amyloid deposits are always extracellular, but do they start there? The problem has been most extensively studied in IAPP-derived amyloidosis. Small, and therefore probably early, deposits are found extracellularly in close contact to the beta cell membrane. Characteristic small bundles of parallel fibrils run perpendicularly to the cell into deep plasma membrane pockets in the beta cells6 (Fig.1). The same phenomenon is usually found also with neoplastic beta

Correspondence: Per Westermark, M.D., Department of Pathology I, University Hospital, S-81 85 Linkoping, Sweden Tel. 46-1322 1501; Fax 46-13-132257

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Westermark

FIGURE 1. Electron micrograph showing bundles of islet amyloid penetrating the basement and beta cells membranes. Autopsy material from a nondiabetic individual. Reproduced from Reference 6.

cells’ and is not specifically associated with IAPP amyloid. A similar relationship can be found between calcitonin-amyloid fibrils and medullary carcinoma cells (known to produce calcitonin) (Fig. 2). The occurrence of strictly intracellular IAPP-derived amyloid fibrils has never been proven in man. The extracellular location of even very small IAPP amyloid deposits indicate a primarily extracellular fibril formation, probably directly after exocytosis*.In contrast to this view, a theory, including incomplete lysosomal processing of secretory granules leading to intracellular amyloid precursor polymerization, has been proposedg.This theory is mainly based on the finding of IAPP-immunoreactivity in lysosomal structures10.The two proposed pathways do not necessarily rule each other out. A plausible model could include first, a minimal lysosomal fibril formation, followed by fibril exocytosis. Such small protein aggregates could, theoretically, act as niduses to which

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fiuther amyloid fibril protein units could be added with fibril extension as a result. Such a scenario could explain why parallel fibrils run into pockets. This could be due to a backward growth of the fibrils as new molecules stick to the fibril ends (Fig. 3). This model would fit the increasing experimental evidence that amyloid deposits form on already existing fibrils1’J2.Thus, under certain conditions, synthetic amyloid-like fibrils can be made in vitro from pure peptidesI3J4 (Fig. 4) corresponding to whole amyloid proteins such as calcitonin, IAPP and ANF, or parts thereof. Such fibrils, when used as seed, can speed up fibril formation in vitro. This is a well-known phenomenon in insulin chemistry and has been used as an insulin purification method15. Evidence of intracellular amyloid formation has been obtained in some PHD-amyloid forms and perhaps most convincingly in the ANF-derived IAA since small intracellular deposits often are encountered in atrial my~cytes’~J’.

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Amyloid: In#. J Exp. Clin. Invest. 1 (1994)

FIGURE 2. Electron microscope photo of calcitonin-derived amyloid in medullary carcinoma of the thyroid. The amyloid is extracellular, but bundles of parallel amyloid fibrils run into shallow cytoplasmic pockets of a tumor cell.

Factors of importance in the amyloidogenesis in PHDamyloids The common occurrence of amyloid deposits in polypeptide hormone producing tissues and tumors point to the existence of certain mechanisms in the fibrillogenesis common to these tissues. So far, two factors of importance in the PHD amyloidogenesishave been unravelled: the occurrence of amyloidogenic sequences in polypeptide hormones and the importance of the precursor concentration. Whether or not a polypeptide can make fibrils is obviously a determining factor in amyloidogenesis (see below). The second factor, the local concentration of the fibril precursor, most probably also is important. It is known from in vitro experimentsthat the rate of the fibrillogenesis is concentration-dependent"J2.However, even if the concentration of an amyloid fibril precursor is of importance, there are many examples that this is not enough for amyloid formation. Thus in AA and TTR amyloidoses, liver amyloidosis is rarely a major feature in spite of the syn-

thesis of SAA and TTR in the liver. Likewise, the bone marrow involvement in AL amyloidosis is usually very slight, if any. In these three systemic amyloidoses, an explanation for the lack of amyloid infiltration at the production site of the precursor may depend on a need of partial degradation to make the proteins amyloidogenic since in all three, split products make up a significant part of the fibrils. Interestingly, in the PHD-amyloids, the fulland insulength hormones ANF'*J9,calcitonin20,IAPP21*22 lin23924 have been identified as the major or only fibril protein, thus demonstrating that these full-length polypeptides are amyloidogenic per se. What then is the reason why polypeptide hormones polymerize to amyloid fibrils? There is no certain answer to the question yet, but it seems unlikely that concentration in combination with amyloidogenic polypeptides alone is the reason. Interaction with other substances such as proteoglycans andor amyloid P-component, which are present in PHD-amyloid2s.26may be important. Another possibility, at present being investigated in our laboratory,

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Westermark

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C

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FIGURE 3. Proposed mechanism for the formation of the cytoplasmic pockets seen in Figures 1 and 2. The hormone precursors are stored in secretory granules (A). Directly after exocytosis (B) amyloid fibrils form (C). New granules fuse with the cytoplasmic membrane (D) and the fibrils elongate as new secretory granules are released (E and F). The walls of the pockets are formed by granule-membranes, which have fused with the cytoplasmic membrane at exocytosis.

is that there are normally factors interacting with the polypeptide hormone molecules and thereby hindering a potential fibril formation.

Review of some discrete polypeptide hormone-derived amyloids Atrial natriuretic factor-derived amyloid (A-ANF) Atrial natriuretic factor (or peptide) is expressed by cardiac myocytes as a prepropolypeptide. The propolypeptide is stored in cytoplasmic granules, principally in atrial myocytes, as a 126 amino acid precursor. In connection with release, this proform is cleaved to yield ANF, which is the 28 amino acid carboxyterminal segment of the precursor. The exact cellular (or extracellular) site of cleavage is unknown27.Experimentally, ANF

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acts as a potent diuretic hormone and it has also hemodynamic effects. Its physiological role is, however, still under debatez7.ANF is a member of a polypeptide family, also including brain natriuretic hormone (BNP) and Ctype natriuretic ~ e p t i d eIt~ ~ should . be mentioned that not only ANF but also BNP is normally expressed by atrial myocyte~~~'. Isolated atrial amyloidosis (IAA) was separated in 1979 from other cardiac amyloidoses for morphologic reasons: it was identified as a local amyloidosis, limited to the atria, where it has a different tissue distribution pattern as compared to senile systemic amyloidosis and is tryptophannegative2*.Earlier, all senile cardiac amyloidosis had erroneously been regarded as one entity, that could start locally but eventually spread to the ventricles and possibly to other organs. The amyloid in IAA occurs usually as fine linear deposits along the sarcolemma and beneath the

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Amyloid: Int. J. Exp. Clin. Invest. 1 (1994)

FIGURE 4. Synthetic fibrils made from porcine insulin. The fibrils are thin and rigid. Like native amyloid fibrils, they show green birefringence on polarization microscopy after staining with Congo red. Electron micrograph, negatively contrasted.

endocardium and in the walls of small vessel^^^^^^. Larger tients with congestive heart failure occurs as antiparallel deposits, that can be seen macroscopically, are rare. dimers3’. In addition, brain natriuretic hormone predomiBiochemical analyses of purified IAA fibrils have nates in the atria in this disease38.Therefore, in addition shown that they consist mainly of A N F ’ * S ~ ~ to . increased release and possibly increased expression of Immunohistochemically, besideANFSoJ8, there is evidence ANF, altered expression of the different natriuretic pepof both proANFI7, (Johansson et a]., unpublished) and tide forms may be of importance in the pathogenesis of BNPI7 as minor components in IAA deposits. Synthetic IAA. ANF can form fibrils in vitroI6. Thus IAA occurs in certain heart diseases. On the other IAA is one of the most prevalent localized amyloids. It hand, so far no certain consequences of the amyloid itself appears at a low frequency in the fourth decade and the on the atrial function have been described. prevalence then increases3’.In one series, 61% of autopsy In Calcitonin-derived amyloid (ACal) patients over 70 years old had some degree of another series, an even higher prevalence was obtained3’. Amyloid is one of the cardinal findings in medullary Several different heart conditions are connected to IAA. carcinoma of the thyroid, occurring in 82% of the tumors Thus, an increased frequency of IAA is found in individuin a large seried9.Therefore, demonstration of amyloid in an endocrine tumor is of some diagnostic ~ a l u e ~ Like ~.~’. als with congestive heart failure32and chronic rheumatic in other endocrine tumors, the amyloid deposits are usuheart disease3),These are diseases often leading to distension of the atria, which is a major signal for ANF really small, although extensive amyloid infiltration some1 e a ~ e ) ~Furthermore, J~. elevated levels of ANF are found times occurs. Calcitonin secreted by non-neoplastic thyin the plasma of patients with congestive heart failure36. roid C-cells (the origin of the medullary carcinoma) has Interestingly, a major part of ANF in the plasma of panot been described to give rise to amyloid deposits.

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Westermark Amyloid fibrils have been extracted from two medullary thyroid carcinomas and the major amyloid fibril proteins have been purified and analyzed by amino acid sequence. In both cases, calcitonin-sequenceswere obtained. In one of the tumors, only processed, full-length calcitonin was identifiedz0while in the other, the size and amino acid composition of the major fibril molecule indicated a proform of calcitonin”. Calcitonin is expressed as a 141 amino acid long prepr~hormone~~, which undergoes several posttranslational modifications to yield the 32 amino acid C-terminally aminated calcitonin4. In the propeptide, calcitonin is flanked by one long N-terminal and one shorter C-terminal peptide, which are cleaved off at basic amino acid residues. Amino acid analysis of protein ACal from the second tumor indicated that this consisted of calcitonin with a piece of the N-terminal ~ e p t i d e ~ ~ . Like the other polypeptide hormones occurring as amyloid, calcitonin has an inherent fibril forming capacity in that both porcine45and salmon4 calcitonin form amyloidlike fibrils in vitro.

Amyloid derivedfrom islet amyloid polypeptide (AIAPP) Among the polypeptide hormone-derivedamyloids, that occurring in the islets of Langerhans has recently gained much interest but it has not always been like that. Before the nature of islet amyloid was elucidated, only scattered investigations were performed, mainly by pathologists. The finding that a previously unknown polypeptide, produced by islet beta cells and of probable hormonal nature, makes up the main part of the amyloid has changed this situation completely and opened up a new field in diabetology. Islet amyloid was the first PHD-amyloid to be described, although as “hyaline”I. Only after the study by Ehrlich and RatneP7, who showed that islet hyaline has amyloid properties when stained with Congo red, and by Lacfa, who demonstrated the fine fibrillar ultrastructure of the material, typical of all a m y l ~ i dthe ~ ~ islet , deposits were accepted as a form of amyloidosis. When the composition of some systemic amyloids was determined and it became clear that these amyloids consisted of small, polymerized proteins, an insulin-nature of the amyloid in the islets of Langerhans was strongly suspected. The suspicion was supported by the demonstration that insulin fibrilsSoexhibit amyloid proper tie^^'-^^. Furthermore, immunohistochemically, a reaction with insulin B-chain antiserum was obtaineds3.Interestingly, it was shown later that insulin can give rise to real amyloid deposits (see below). When the nature of islet (and insulinoma) amyloid finally was elucidated in 198654,the finding of a novel, previously unknown polypeptide was completely unexpected. The polypeptide, now known as islet amyloid polypeptide (IAPP) or amylin, was shown to be a 37 amino-acid residue polypeptidc21.22 with 43-

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46% identity with the calcitonin gene-related peptide (CGRP)43.In humans, IAPP is expressed as an 89 amino acid prepropolypeptide, consisting of a 22 amino acid leader sequence and IAPP, flanked by two short p r ~ p e p t i d e s ~by ~ ~a ’gene ~ ~ ~on ~ ,chromosome 1258~S9@. The mature I M P is formed by cleavage at double basic amino acid residues, amidation of the C-terminus and formation of an intramolecular disulfide bridge. IAPP is synthesized almost exclusively by islet beta cells and is stored together with insulin in the secretory granules. IAPP is also released from the beta cells together with insulin.The plasma concentration of IAPP is less than 10% of that of insulin61. The function of IAPP is virtually unknown and is a matter of considerable debate. The subject is outside the scope of this review but it can be mentioned that autocrine and paracrine effects as well as many effects on peripheral tissues have been obtained experimentally. Most but not all of the putative functions involve the glucose metabolism. There are several recent reviews dealing with these problem^^^^^^^.

Relation between primary structure of IAPP and amyloidogenicity IAPP is a highly conserved polypeptide and the organization of the prepromolecule is the same in all studied mammals. Within the mature IAPP molecule, the N- and C-terminal segments are almost completely conserved while there is a central segment (positions 17-30) which varies strongly between species. The relationship between the primary structure and the amyloid formation capacity of IAPP is better known than with any other polypeptide hormone. The variability between species in the 20-29 segment of IAPP was already hinted at from immunohistochemical results when an antiserum to human IAPP(2029) was tested on pancreatic tissues from different mammalian species. It was then found that only beta cells from species in which islet amyloid occurs reacted with the antiserum, indicating that an amyloidogenic sequence was present in the 20-29 segment of IAPPs6.Comparison of the primary structures obtained by direct amino acid sequencing or DNA sequencing revealed that species with islet amyloid (human, monkey, cat, raccoon) contain the sequence GAILS (GTILS in monkey) while species without islet amyloid have different sequences (Fig. 5)63,”~6s~66~67~68~6g~70~71. Specifically, islet amyloid-lacking species have one or two proline residues within this segment of IAPP. Direct in vitro experiments with synthetic full length human IAPP and human IAPP(20-29) showed that both of these had an equally strong fibril forming capacityI4.Cat IAPP(20~ IAPP(2029) was also amyloidogenic in v i t r ~but~ not 29) of mousehat or hamster“’ or full-length rat IAPPI4. With the aid of hybrid peptides, in which one or two resi-

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Amyloid: Int. J. Exp. Clin. Invest. I (1994)

FIGURE 5. Amino acid sequences of IAPP from three species in which islet amyloid occurs (human, macaque and cat) and three without occurrence of islet amyloid (rat, mouse and degu). The N- and C-terminal parts of the molecules are conserved while there is a considerable variation in the central part. The GAILS (GTILS in non-human primates) is believed to be important in the fibrillogenesis. (Data from references 56, 64, 65, 66, 70, and 103)

dues in human IAPP(2CL29) were substituted with corresponding rat residues, it was possible to show that proline at position 28 is of specific importance for the hindrance of fibril formation14. The main protein in the amyloid of cerebral plaques and vessels in Alzheimer's disease is the beta protein, which is derived from a receptor-like 695-770 amino acid p r e c ~ s o r ~A~notable * ~ ~ . but probably coincidental partial sequence identity is seen between IAPP, positions 10-27 and beta-protein, positions 15-32 (Fig. 6). Within this section of 18 amino acid residues, there is identity in 7 positions (39%)72,73. A further similarity is that in both peptides, charged amino acids occur in two identical positions and hydrophobicresidues in two other positions.This similarity between the parts of the two molecules probably does not mean that they are evolutionarily related since the base identity is only 24 of 54 (44%). However, properties hidden in these sequences may determine the similar fibrillogenic tendencies of IAPP and beta protein. Thus, the GAILS sequence, which seems to determine the fibrillogenicproperty of IAPP14.74 has a relative, GAIIG in the beta-protein. Notable is also that the beta protein segment QKLWF, containing the important fibril-determining sequence LVFF7S,is very similar to the corresponding IAPP segment QRLANF. These similarities may explain why beta protein and IAPP amyloids have such similar solubility proper tie^^^,^'. Human IAPP in transgenic mice As described above, human IAPP (hIAPP), but not mousehat IAPP, is fibrillogenic .In order to create a mouse model for the study of islet amyloid formation, several groups have made transgenic mice, carrying the gene coding for the human IAPP78e79. While at least most constructs including cDNA have failed to give expression of hIAPP

at the protein level, constructs of genomic hIAPP behind the rat insulin 1 or 2 promoter have resulted in animals with production of hIAPP almost exclusively in the islet beta cells. An overproduction of IAPP with plasma concentrations 5 times the normal has been obtained. In spite of this in none of the transgenic mice has the occurrence of islet amyloid been reported. In one series of experiments, hIAPP producing transgenic mice were subjected to long-term administration of corticosteroids, which is known to give rise to increased expression of IAPP in normal mice, or made diabetic by partial pancreatectomy. In order to increase crinophagy, animals were also treated with diazoxide which hinders exocytosis. None of these experiments led to islet amyloidosisB0which supports the hypothesis that further factors are needed in amyloidogenesis and/or that yet unknown preventing factors exist. The relation of islet amyloid to non-insulin-dependentdiabetes (NIDDM) It is well known that there is a relationship between islet amyloid and NIDDM and this has been shown in many investigation^^^^^^"^^"^,"^^^^^^^. Some degree of islet amyloid is seen in a majority of patients with NIDDM. However, the significanceof islet amyloid in diabetes has been questioned since it occurs commonly to some degree also in non-diabetic patients, although rarely affecting many isl e t ~ ~The ~ , "association ~. between islet amyloid and NIDDM is obviously more a quantitative than a qualitative one. Why islet amyloid forms preferentially in NIDDM is still unknown but a hyperproduction of IAPP in association with hyperinsulinemia in conjunction with insulin resistance has been proposed to be a major factor. An increase of plasma IAPP levels parallel to those of insulin has been found in obese NIDDM patients6'. How-

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Westermark

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10 15 20 25 Q R L A N F L V H S S N N F G A I L IAPP: CAG CGC CTG GCA AAT TTT TTA GTT CAT TCC AGC AAC AAC TTT GGT GCC ATT CTC BETA: CAA AAA TTG GTG TTC TTT GCA GAA GAT GTG GGT TCA AAC AAA GGT GCA ATC ATT Q K L V F F A E D V G S N K G A I I 15 20 25 30

FIGURE 6. Amino acid sequences (one letter code) and DNA sequences of positions 10-27 of human IAPP and positions 15-32 of human protein A beta. The sequences have some striking similarities which may explain physico-chemical similarities between the two forms of amyloid. (Data from references 56 and 73)

ever, a paradoxical decrease in beta cell IAPP immunoreactivity is the rule in NIDDM in spite of apparently normal insulin s t ~ r a g although e ~ ~ ~ in ~ ~situ hybridization studies with an IAPP probe provide evidence of IAPP productionE9.Therefore, an aberration in the storage and/or secretion of IAPP may occur in NIDDM and be of importance in the amyloidogenesis. Stimulation of in vitro cultivated human islets resulted in an increased synthesis of both insulin and IAPP but increased secretion was only obtained with insulin while IAPP was retained in the isletsg0. Another unresolved problem concerns the importance of the islet amyloid itself. Although islet amyloid most probably is not a primary cause of diabetes, it is very likely that large deposits lead to a progressive islet destruction. The common need of insulin replacement therapy in patients with NIDDM of long duration9'may be an effect of such destruction (Fig. 7). The finding of a reduced number of beta cells in conjunction with islet amyloidosis in humanEz~E3 and in animal models (see below) support this conclusion. In two studies, NIDDM patients with insulin therapy have significantly more advanced islet a m y l o i d o s i ~One ~ ~ ~would ~ ~ . also expect the degree of islet amyloidosis to correlate with the duration of NIDDM. However, this has not been shown but may be related to the very insidious and indistinct start of the diabetes. Islet amyloid in animals The main reason for the comparative studies of the structure of IAPP was the finding that islet amyloid only occurs in certain species. Islet amyloidosis has been carefully studied in non-human primates by Howard et al.93 and by Clark et a1.%and in domestic cats by Johnson et a1.95396-97. These animal studies have also revealed a strong relationship between a form of diabetes, resembling human NIDDM, and islet amyloidosis. Both in diabetic

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monkeys and cats, there is a significant reduction of the beta cell mass94~9E,w. Islet amyloid tends to precede the diabetes and may be factor of importance in the proceeding destruction of islet cells%.The relation of IAPP structure to the species-specific occurrence of islet amyloid has been described previously. Amyloid derived from insulin Insulin was the first polypeptide-hormone that was shown to form fibrils50with a cross-p structure@ ' ' and green birefringence on polarization microscopy after Congo red stainingS1J2(Fig.4). Therefore, there was a rationale for the hypothesis that islet and insulinoma amyloid contained insulin. This was disproved but insulin-amyloid is now known to occur in two forms, both with certain interesting points. Amyloid occurs rarely as subcutaneous nodules at the site of insulin injections in diabetic individuals'O'. Thus, the main fibril protein in such a nodule turned out to be porcine insulin without signs of truncationz3.Like all amyloids, the iatrogenic insulin-amyloid contained amyloid P-componentz3and heparan sulfate proteoglycanlo2,components which may be of importance in the fibrillogenesis. Islet amyloid does occur in one rodent species, the South American degu, (Octodon degus). The primary structure of IAPP in this species indicated a non-fibril forming molecule with two proline residues in the 20-29 segment103. Purification and sequence analysis of a major degu islet amyloid fibril protein was therefore performed and yielded equimolar amounts of insulin A and B identical to the deduced amino acid sequence from genomic DNAfo3. The pathogenesis of islet amyloid in the degu is unknown but degu insulin has an unusual structure which may make it more amyloidogenic than most other insulins. A possible relationship between degu islet amyloid and diabetes has not been thoroughly studied.

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Other polypeptide-hormone derived amyloids One type of amyloid, that should be studied biochemically is that in the pituitary gland. Age-related amyloid here has a prevalence comparable to islet amy1oidosis1@'Jo5JM but no relationship to any disease is known. Pituitary adenomas also often contain amyloid107J08Jw, especially those producing growth hormone and p r o l a ~ t i n ~ ~ ~In J ~most ~ J ~histochemical J'~. studies, the pituitary amyloid has shown no reaction with antisera against pituitary horrnones1l0Jl1, although the opposite has been claimed on a few occasions"*. Considering the situation with islet amyloid, the nature of the pituitary amyloid should be regarded as unknown until chemically characterized. Finally, small amyloid deposits are very common in the parathyroid glands and in parathyroid adenomas111,113J 14, Thefuture of PolypeptideHormone Derived (PHD)Amyloid This review has only dealt with a few, known PHDamyloids. The family of peptide signal substances is large and still gowing. There is no reason to believe that there are no more PHD-amyloids to be discovered (see for examp1e reference 15) and it be 'wising if Some other signal substances did not give rise to amyloid deposits. These must not necessarily be located in any ma-

Table 1

FIGURE 7. Percentage of islets containing amyloid deposits in 33 patients with perorally-treated and llpatients with insulin-treated NIDDM. There is a significantly (p=O.O03) more advanced islet amyloidosis in the insulintreated group. unpublished data)

Human polypeptide hormone derived (PHD)amyloid

Term

Polypeptide

Site of Synthesis

BiochemicalAnalysts

Amyloid Deposition

Prevalence

AANF

atrial natriuretic factorderived

atrial myocytes

28 amino acid C-terminal segment of the prepropolypeptide precursor

limited to atria of the heart; small deposits along sarcolemma and beneath endocardium and in walls of vessels

one of the most prevalent of localized amyloids; 61% of autopsy patientsover age 70 (28), associatedwith congestive heart failure

ACal

calcitoninderived thyroid C-cells

32 amino acid C-terminally amidated calcitonin or with N-terminal portion of the propeptide

limited to thyroid tumor tissue

82% of medullary carcinoma tumors

AIAPP

islet amyloid polypeptidederived (or amylin)

37 amino acid polypeptide from the 89 amino acid prepropolypeptide; 4 3 4 6 % identity with calcitoningene-related peptide (CGRP); amyloidogenicsequence present in 20-29 residue segment

limited to insulinomas and pancreatic islets; may be of importance in causing destruction of islet cells

some degree found in the majorityof patients with non-insulindependent diabetes mellitus; commonly found to a lesser degree in nondiabetic patients

Alns

insulin derived

porcine insulin

subcutaneous nodules rare at site of insulin injection

pancreatic islet beta cells

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Westermark ~~~

jor endocrine organ but, at least theoretically, may occur in any tissue producing signal substances, such as the brain or endothelium. These putative amyloid deposits may be very small and scattered and therefore easily escape detection. Even if the amyloids themselves are of no importance, identification of them could be valuable since they can lead to important knowledge of known or unknown polypeptide hormones.

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Acknowledgments The author’s work, cited in this review, has been supported by the Swedish Medical Research Council (project No. 5941), the Nordic Insulin Fund and the County of &ergotland.

References .I

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Opie, EL (1901). On relation of chronic interstitial pancreatitis to the islands of Langerhans and to diabetes mellitus. J Exp Med 5, 397428 Warren, S, LeCompte, PM and Legg, MA (1966). The Pathology of Diabetes Mellitus (Philadelphia: Lea & Febiger) Gellerstedt, N (1938). Die elektive, insulare (Para)Amyloidose der Bauchspeicheldriise. Zugleich ein Beitrag zur Kenntnis der “senilen Amyloidose”. BeifrPath Anat., 101, 1-13 Mandema, E, Ruinen, L, Scholten, H and Cohen, AS (1968), (eds) Amyloidosis (Amsterdam: Excerpta Medica) Shirahama, T and Cohen, AS (1975). Intralysosomal formation of amyloid fibrils. Am J Path, 81, 101-116 Westermark, P (1973). Fine structure of islets of Langerhans in insular amyloidosis. firchows Arch A , 359, 1-18 An, T and Kaye, GI (1978). Amyloid formation in insulinoma. Arch Path Lab Med., 102, 227-232 Westermark, P, Johnson, KH, O’Brien, TD and Betsholtz, C (1992). Islet amyloid polypeptide-+ novel controversy in diabetes research Diabetologia, 35, 297-303 Clark, A (1992). Islet amyloid-an enigma of type-2 diabetes. Diab Metabol Rev, 8, 117-132 Clark, A, Edwards, CA, Ostle, LR, Sutton, R, Rothbard, JR, Morris, JF and Turner, RC (1989). Localization of islet amyloid peptide in lipofuscin bodies and secretory granules of human p-cells and in islets of type-2 diabetic subjects. Cell lissue Res, 257, 179-185 Naiki, H, Higuchi, K, Nakakuki, K and Takeda, T (1991). Kinetic analysis of amyloid fibril polymerization in vitro. Lab Invest, 65, 104-1 10 Jarrett, JT and Lansbury, PT (1993). Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell, 73, 10551058

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