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Islet or insulinoma amyloid polypeptide (IAPP) is a 37-amino acid monomeric polypeptide isolated from pancreatic amyloid (Cooper et al., 1987). Such amyloid is commonly found in the islets of patients with diabetes mellitus type II (269200) and in insulinomas. A specific immunoreactivity with antibodies to IAPP is found in islet amyloid and in cells of the islets of Langerhans, where it colocalizes with insulin in islet B cells. (At the end of the last century, Eugene Opie (1900) observed hyalinization of the islets of Langerhans in diabetics. The story of the contributions of Opie, who was a member of the first graduating class from the Johns Hopkins Medical School, was engagingly recounted by Harvey (1974).) Islet amyloid is a feature of spontaneous diabetes in domestic cats and macaques, as well as in humans.
IAPP has cysteine residues in positions 2 and 7, a feature found in all known calcitonin gene-related peptides (114130). IAPP shows 46% amino acid sequence homology with CGRP II (114160). Since IAPP has been demonstrated immunochemically in normal beta cells of several mammals, it probably has an important role in respect to pancreatic islet function. Cooper et al. (1988) presented evidence that the 37-amino acid peptide may be a hormone present in normal individuals; hence, 'diabetes-associated peptide' is an inappropriate designation. Cooper et al. (1988) synthesized whole amylin by using solid-phase techniques, with formation of the disulfide linkage by oxidation in dilute aqueous solution and recovery of the peptide by lyophilization. The effects of amylin on glucose metabolism were studied by 2 in vitro preparations: isolated rat soleus muscle strips and isolated rat adipocytes. In skeletal muscle, amylin resulted in a marked decrease in insulin-stimulated glycogen synthesis with resulting reduction in insulin-stimulated glucose uptake. In muscle, amylin resulted in a failure of response to the concentration of insulin required to stimulate glucose uptake half-maximally in untreated muscles. No effects were observed in isolated adipocytes. Amylin may be a factor in the etiology of the insulin resistance in type II diabetes mellitus. A correlation has been observed between the extent of islet amyloid deposition and the clinical severity of type II diabetes.
Mosselman et al. (1988) isolated and partially characterized the human IAPP gene. By hybridization to DNA from human-rodent somatic cell hybrids, Mosselman et al. (1988) demonstrated that the IAPP gene is located on 12pter-q14. Because of the striking parallelism in the genetic constitution of chromosomes 11 and 12, suggesting an ancient tetraploidization, the mapping of this calcitonin-related gene to 12 is of interest; 2 calcitonin genes are located on 11p. The amyloid in amyloid-producing medullary carcinoma of the thyroid, a feature of multiple endocrine neoplasia type II (171400), is derived from calcitonin. Sanke et al. (1988) showed that the islet amyloid polypeptide is derived from an 89-amino acid precursor by proteolytic processing. The processed peptide, 37-amino acids long, is bracketed at its NH(2) and COOH termini by lys-arg and gly-lys-arg, respectively. The data indicated that this amyloid peptide is generated by proteolytic processing similar to that for proinsulin and other islet prohormones and also that the peptide may be carboxyamidated. Mosselman et al. (1989) found that 2 exons, which are approximately 5 kb apart, encode the 89-amino acid pre-pro-IAPP. A putative signal sequence at the amino-terminus of the precursor suggested that IAPP is a secreted protein. From the DNA sequence of a partial cDNA clone and a phage lambda genomic clone of the coding region of the amylin gene, Roberts et al. (1989) concluded that this peptide is synthesized as a precursor peptide called proamylin. The sequences of the genes for amylin and the calcitonin gene-related peptides show strong similarity, especially in their 5-prime coding regions, where these peptides have a conserved intramolecular disulfide bridge, and also in their 3-prime coding regions, where the presence of a glycine codon strongly suggests that the carboxyl-terminal residue, like that of CGRP, is amidated. In a study of the biologic activity of amylin synthesized with or without the disulfide bridge and/or amidation, Roberts et al. (1989) demonstrated that both features are necessary for full biologic activity, thereby confirming the functional importance of those regions of the molecule that have been conserved at both protein and genetic levels.
Roberts et al. (1989) assigned the gene for IAPP to chromosome 12 by Southern analysis of somatic cell hybrid DNAs. By analysis of somatic cell hybrid DNAs and by in situ hybridization, Cockburn et al. (1989) assigned the IAPP gene to 12cen-q21.3. In combination with the earlier information on assignment, the location can be stated as 12cen-q14. Fan et al. (1989) localized the gene to 12p12.3 by in situ hybridization; see Nishi et al. (1989), who also reported assignment to chromosome 12 by Southern analysis of somatic hybrid cell DNAs. By in situ hybridization to metaphase chromosomes, Christmanson et al. (1990) found 2 distinct peaks on chromosome 12, at 12p13-p12 and at 12q13-q14. Southern blot analysis of genomic DNA, however, suggested a single IAPP locus. By fluorescence in situ hybridization, Hoovers et al. (1993) assigned the IAPP gene to 12p12.3-p12.1.
Johnson et al. (1989) reviewed the relation between islet amyloid and diabetes mellitus, and discoveries that appear to link IAPP to both islet-amyloid deposition and diabetogenesis. Positions 20 through 29 of the IAPP molecule appear to be intrinsically amyloidogenic in some species including humans, cats, and raccoons. An increased beta-cell production of IAPP may predispose to the deposition of amyloid and may cause insulin resistance by opposing the action of insulin in peripheral tissues. Polymerization of IAPP to form amyloid may further contribute to the development of type II diabetes mellitus by destroying islet cells and by disrupting the passage of glucose and hormones to and from them.
Westermark et al. (1990) concluded that the sequence ala-ile-leu-ser-ser, corresponding to positions 25-29 of the human IAPP, is strongly amyloidogenic, and that a serine-to-proline substitution in position 28, as occurs normally in several rodents that do not develop IAPP-derived amyloid, almost completely inhibits formation of amyloid fibrils.
Hoppener et al. (1994) showed that the IAPP gene in both human and rat contains 3 exons, encoding precursor proteins of 89 amino acids and 93 amino acids, respectively.
Lorenzo et al. (1994) showed that human amylin is toxic to the beta-cells of the adult pancreas of rats and humans. They suggested that amylin fibril formation in the pancreas may cause islet cell dysfunction and death in type 2 diabetes mellitus. See the Animal Model section for further discussion.
Hoppener et al. (1994) studied the potential role of islet amyloid polypeptide overproduction in the pathogenesis of islet amyloid formation and type II diabetes, and they generated transgenic mice that overproduced either the amyloidogenic human islet amyloid polypeptide or the nonamyloidogenic rat islet amyloid polypeptide in their islet beta-cells. (In rat and mouse, diabetes-associated islet amyloid does not develop.) Despite elevated (up to 15-fold) plasma islet amyloid polypeptide levels, no marked hyperglycemia, hyperinsulinemia, or obesity was observed. This suggested to the authors that chronic overproduction of islet amyloid polypeptide per se does not cause insulin resistance. No islet amyloid deposits were detected in mice up to 63 weeks of age, but in every mouse producing human islet amyloid polypeptide (as in man), accumulation of islet amyloid polypeptide was observed in beta-cell lysosomal bodies. Hoppener et al. (1994) stated that this may represent an initial phase in intracellular amyloid fibril formation.
In view of the fact that the related beta-amyloid protein (104760) that forms fibrils in Alzheimer disease is toxic to neurons, Lorenzo et al. (1994) investigated whether amylin fibrils are toxic to pancreatic islet cells and play a role in the development of type 2 diabetes mellitus. Lorenzo et al. (1994) showed that human amylin is toxic to the beta-cells of the adult pancreas of rats and humans. The toxicity is mediated by the fibrillar form of the amylin peptide and requires direct contact of the fibrils with the cell surface. Cell death was characterized by plasma membrane blebbing, chromatin condensation, and DNA fragmentation, indicating that amylin induces islet cell apoptosis. Lorenzo et al. (1994) suggested that amylin fibril formation in the pancreas may cause islet cell dysfunction and death in type 2 diabetes mellitus.
In transgenic mice that expressed human IAPP in pancreatic beta cells, Verchere et al. (1996) found extensive amyloid deposits in the pancreatic islets of approximately 80% of male transgenic mice more than 13 months of age. Islet amyloid deposits were rarely observed in female transgenic mice (11%) and were never seen in nontransgenic animals. Ultrastructural analysis revealed that these deposits were composed of human IAPP-immunoreactive fibrils that accumulated between beta cells and islet capillaries. Approximately half of the mice with islet amyloid deposits were hyperglycemic. In younger male transgenic mice, islet amyloid deposits were less commonly observed but were always associated with severe hyperglycemia.
Janson et al. (1996) created homozygous transgenic mice with a high level of expression of human IAPP. Male transgenic mice spontaneously developed diabetes mellitus by 8 weeks of age, which was associated with selective beta-cell death and impaired insulin secretion. Approximately 20% of female transgenic mice spontaneously developed diabetes at 30+ weeks of age when beta-cell degeneration and both amorphous and amyloid deposits of IAPP were present. Large deposits of IAPP-derived amyloid did not appear to be important to the cytotoxicity, but early, small amorphous intra- and extracellular aggregates of human IAPP were consistently present at the time of beta-cell death and therefore may be the most cytotoxic form of IAPP.
Victor A. McKusick : 12/20/1988
terry : 11/12/1996terry : 11/1/1996terry : 5/10/1996terry : 5/10/1996terry : 5/7/1996terry : 4/30/1996terry : 11/17/1995mark : 7/30/1995davew : 6/28/1994warfield : 4/21/1994mimadm : 4/14/1994carol : 3/19/1993
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