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Gene Review

IAPP  -  islet amyloid polypeptide

Homo sapiens

Synonyms: AMYLIN, Amylin, DAP, Diabetes-associated peptide, IAP, ...
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Disease relevance of IAPP

  • IAPP from human insulinoma contained 37 amino acid residues and had a theoretical molecular mass of 3850 Da [1].
  • Pancreatic amyloid plaques formed by the pancreatic islet amyloid polypeptide (IAPP) are present in more than 95% of type II diabetes mellitus patients, and their abundance correlates with the severity of the disease [2].
  • This nidus of amyloid fibrils then allows the progressive accumulation of IAPP-containing fibrils and the eventual replacement of beta-cell mass by amyloid and contributes to the development of hyperglycemia [3].
  • We conclude that exogenous E2 administered to male mice may block human IAPP-mediated beta-cell loss both by direct action on beta-cells and by decreasing insulin demand through inhibition of weight gain or increasing insulin action [4].
  • BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by a deficit in beta-cell mass, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP) [5].
  • We propose that amylin levels and hypertension may be linked by a novel mechanism involving the capacity of amylin to induce endothelial dysfunction by interfering with nitric oxide-mediated responses [6].

Psychiatry related information on IAPP


High impact information on IAPP

  • CGRP is a 37-amino acid neuropeptide, primarily released from sensory nerves, whilst AM is produced by stimulated vascular cells, and amylin is secreted from the pancreas [11].
  • Since IAPP may cause insulin resistance, its overproduction may contribute to the diabetes that occurs in these patients [12].
  • Pancreatic cancers contained IAPP, but the concentrations were lower than in normal pancreatic tissue (17 +/- 16 vs. 183 +/- 129 pmol per gram, P < 0.001) [12].
  • Islet amyloid polypeptide (IAPP), a hormonal factor secreted from the pancreatic beta cells, reduces insulin sensitivity in vivo and glycogen synthesis in vitro [12].
  • The latter possibility is supported by studies demonstrating that IAPP production by islet beta cells is increased in normoglycemic cats with impaired glucose tolerance [13].

Chemical compound and disease context of IAPP


Biological context of IAPP

  • Interspecies variations in the amino acid sequence of residues 20-29 of IAPP may account for the presence of amyloid deposits in the islets of humans and cats and their absence in rats and mice [17].
  • We previously reported the nucleotide sequence of a human cDNA, which indicated that IAPP is a C-terminally amidated peptide derived by proteolytic processing of an 89-amino acid precursor [17].
  • The results indicate that the reported ability of IAPP to induce insulin resistance cannot be due to decreased skeletal muscle blood flow [18].
  • We tested the hypothesis that impaired processing of the IAPP precursor proIAPP contributes to amyloid formation and cell death [19].
  • No evidence for overproduction of IAPP in diabetic subjects has been found thus far, but much more work is necessary to define its normal secretory rates and clearance [20].

Anatomical context of IAPP

  • Although IAPP amyloid deposits are associated with areas of pancreatic islet beta-cell dysfunction and depletion and are thought to play a role in disease, their structure is unknown [21].
  • The resultant 2350-2C0 and 2511 cell lines produce human as well as mouse IAPP-like immunoreactivity (IAPP-LI) and immunoreactive insulin (IRI) [22].
  • Since PDX-1 is highly enriched in beta and delta cells, these results suggest that this factor plays a principal role in defining islet beta cell- and delta cell-specific expression of the IAPP gene [23].
  • Other proposed actions of IAPP include serum calcium-lowering effects and smooth muscle relaxation; the latter effect might promote the uptake of insulin into the circulation within the islets [20].
  • The pancreas and intestine contained a single 0.7 kilobase (kb) IAPP transcript while two transcripts, 0.7 kb and 0.9 kb, were detected in brain [24].

Associations of IAPP with chemical compounds

  • A C-terminal pro-IAPP fragment (residues 41-67) had no specific affinity for either heparin or heparan sulfate, and the N- or C-terminal fragments had only weak affinity for chondroitin sulfate [25].
  • The N- and C-terminal cleavage sites where pro-IAPP is processed by prohormone convertases contain a series of basic amino acid residues that we hypothesized may interact with heparan sulfate proteoglycans [25].
  • The main component of these deposits, islet amyloid polypeptide (IAPP), is a hormone involved in glucose metabolism and is normally co-secreted with insulin by the beta-cells of the pancreas [26].
  • The observation that proline substitutions outside the putative core domain effectively abolish amyloid formation indicates that models of IAPP aggregation must consider contributions from other regions [27].
  • Thioflavin T binding assays confirmed that this effect was not mediated by interference with h-IAPP oligomerization [5].

Physical interactions of IAPP

  • This complex was displaced with an antiserum to IUF-1, confirming that IUF-1 binds to the human IAPP promoter in vitro [28].
  • CHO-P cells provide an environment conducive to a low, but significant, level of amylin binding with either hCTR isoform alone, unlike in COS-7, where RAMP coexpression is imperative for amylin binding [29].
  • These findings suggest that specific IAPP binding sites exist which differ from the CGRP receptors in rat tissues [30].
  • The different behavior of human and rat IAPP could be due to differences in the 20-29 region or due simply to the fact that multiple proline residues destabilize amyloid fibrils [27].

Co-localisations of IAPP

  • IAPP was colocalized with insulin and glucagon in the immature and nondifferentiated cell granules in both species [31].

Regulatory relationships of IAPP


Other interactions of IAPP

  • The hypocalcemic potency of amylin was found to be second only to that of calcitonin (CT) and is 100-fold more potent than calcitonin gene-related peptide [36].
  • Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product [37].
  • The results of experiments cross-linking 125I-labeled amylin to RAMP 1/hCTR-transfected cells with bis succidimidyl suberate were suggestive of a cell-surface association of RAMP 1 and the receptors [37].
  • RAMP 2 or vector cotransfection did not cause significant increases in specific amylin binding [37].
  • Processing of pro-islet amyloid polypeptide (proIAPP) by the prohormone convertase PC2 [38].

Analytical, diagnostic and therapeutic context of IAPP

  • This possibility was tested using affinity chromatography by applying synthetic fragments of pro-IAPP to heparin-agarose and heparan sulfate-Sepharose [25].
  • Northern blot analyses demonstrated that chicken IAPP mRNA is expressed predominantly in intestine and brain but at a much lower level in pancreas [24].
  • Here, we use kinetic studies in conjunction with assessments of lipid binding and electron microscopy to investigate the interactions of IAPP with phospholipid bilayers and the morphological effects of membranes on IAPP fibers [39].
  • Gel permeation chromatography of the IAPP-LI revealed that, except in the carcinoid, more than 80% coeluted with synthetic human IAPP [40].
  • An aggregated but not necessarily fibrillar form of IAPP is toxic in cell culture, suggesting that prefibrillar oligomeric (protofibrillar) IAPP may be pathogenic [7].


  1. Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. Westermark, P., Wernstedt, C., Wilander, E., Hayden, D.W., O'Brien, T.D., Johnson, K.H. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  2. Amyloidogenicity and cytotoxicity of recombinant mature human islet amyloid polypeptide (rhIAPP). Lopes, D.H., Colin, C., Degaki, T.L., de Sousa, A.C., Vieira, M.N., Sebollela, A., Martinez, A.M., Bloch, C., Ferreira, S.T., Sogayar, M.C. J. Biol. Chem. (2004) [Pubmed]
  3. Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Kahn, S.E., Andrikopoulos, S., Verchere, C.B. Diabetes (1999) [Pubmed]
  4. Estrogen can prevent or reverse obesity and diabetes in mice expressing human islet amyloid polypeptide. Geisler, J.G., Zawalich, W., Zawalich, K., Lakey, J.R., Stukenbrok, H., Milici, A.J., Soeller, W.C. Diabetes (2002) [Pubmed]
  5. Activation of peroxisome proliferator-activated receptor-gamma by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by a phosphatidylinositol 3'-kinase-dependent pathway. Lin, C.Y., Gurlo, T., Haataja, L., Hsueh, W.A., Butler, P.C. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  6. Amylin and hypertension: association of an amylin -G132A gene mutation and hypertension in humans and amylin-induced endothelium dysfunction in rats. Novials, A., Rodriguez-Mañas, L., Chico, A., El Assar, M., Casas, S., Gomis, R. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  7. Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetes. Anguiano, M., Nowak, R.J., Lansbury, P.T. Biochemistry (2002) [Pubmed]
  8. Recovery and purification of highly aggregation-prone disulfide-containing peptides: application to islet amyloid polypeptide. Abedini, A., Singh, G., Raleigh, D.P. Anal. Biochem. (2006) [Pubmed]
  9. Anorexia following the intrahypothalamic administration of amylin. Chance, W.T., Balasubramaniam, A., Zhang, F.S., Wimalawansa, S.J., Fischer, J.E. Brain Res. (1991) [Pubmed]
  10. Central nervous system and other effects. Young, A. Adv. Pharmacol. (2005) [Pubmed]
  11. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Brain, S.D., Grant, A.D. Physiol. Rev. (2004) [Pubmed]
  12. Islet amyloid polypeptide in patients with pancreatic cancer and diabetes. Permert, J., Larsson, J., Westermark, G.T., Herrington, M.K., Christmanson, L., Pour, P.M., Westermark, P., Adrian, T.E. N. Engl. J. Med. (1994) [Pubmed]
  13. Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. Johnson, K.H., O'Brien, T.D., Betsholtz, C., Westermark, P. N. Engl. J. Med. (1989) [Pubmed]
  14. Islet amyloid polypeptide (IAPP). A short review. Stridsberg, M., Wilander, E. Acta oncologica (Stockholm, Sweden) (1991) [Pubmed]
  15. Chronic overproduction of islet amyloid polypeptide/amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia. Höppener, J.W., Verbeek, J.S., de Koning, E.J., Oosterwijk, C., van Hulst, K.L., Visser-Vernooy, H.J., Hofhuis, F.M., van Gaalen, S., Berends, M.J., Hackeng, W.H. Diabetologia (1993) [Pubmed]
  16. Adrenomedullin and calcitonin gene-related peptide interact with the same receptor in cultured human neuroblastoma SK-N-MC cells. Zimmermann, U., Fischer, J.A., Muff, R. Peptides (1995) [Pubmed]
  17. Conservation of the sequence of islet amyloid polypeptide in five mammals is consistent with its putative role as an islet hormone. Nishi, M., Chan, S.J., Nagamatsu, S., Bell, G.I., Steiner, D.F. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  18. Antagonistic effect of human alpha-calcitonin gene-related peptide (8-37) on regional hemodynamic actions of rat islet amyloid polypeptide in conscious Long-Evans rats. Gardiner, S.M., Compton, A.M., Kemp, P.A., Bennett, T., Bose, C., Foulkes, R., Hughes, B. Diabetes (1991) [Pubmed]
  19. Impaired NH2-terminal processing of human proislet amyloid polypeptide by the prohormone convertase PC2 leads to amyloid formation and cell death. Marzban, L., Rhodes, C.J., Steiner, D.F., Haataja, L., Halban, P.A., Verchere, C.B. Diabetes (2006) [Pubmed]
  20. Is islet amyloid polypeptide a significant factor in pathogenesis or pathophysiology of diabetes? Steiner, D.F., Ohagi, S., Nagamatsu, S., Bell, G.I., Nishi, M. Diabetes (1991) [Pubmed]
  21. Identifying structural features of fibrillar islet amyloid polypeptide using site-directed spin labeling. Jayasinghe, S.A., Langen, R. J. Biol. Chem. (2004) [Pubmed]
  22. Two novel immortal pancreatic beta-cell lines expressing and secreting human islet amyloid polypeptide do not spontaneously develop islet amyloid. Andrikopoulos, S., Verchere, C.B., Teague, J.C., Howell, W.M., Fujimoto, W.Y., Wight, T.N., Kahn, S.E. Diabetes (1999) [Pubmed]
  23. Identification of cis- and trans-active factors regulating human islet amyloid polypeptide gene expression in pancreatic beta-cells. Carty, M.D., Lillquist, J.S., Peshavaria, M., Stein, R., Soeller, W.C. J. Biol. Chem. (1997) [Pubmed]
  24. Altered gene structure and tissue expression of islet amyloid polypeptide in the chicken. Fan, L., Westermark, G., Chan, S.J., Steiner, D.F. Mol. Endocrinol. (1994) [Pubmed]
  25. Identification of a heparin binding domain in the N-terminal cleavage site of pro-islet amyloid polypeptide. Implications for islet amyloid formation. Park, K., Verchere, C.B. J. Biol. Chem. (2001) [Pubmed]
  26. The mechanism of insulin action on islet amyloid polypeptide fiber formation. Larson, J.L., Miranker, A.D. J. Mol. Biol. (2004) [Pubmed]
  27. Destabilization of human IAPP amyloid fibrils by proline mutations outside of the putative amyloidogenic domain: is there a critical amyloidogenic domain in human IAPP? Abedini, A., Raleigh, D.P. J. Mol. Biol. (2006) [Pubmed]
  28. Insulin upstream factor 1 and a novel ubiquitous factor bind to the human islet amyloid polypeptide/amylin gene promoter. Bretherton-Watt, D., Gore, N., Boam, D.S. Biochem. J. (1996) [Pubmed]
  29. Amylin receptor phenotypes derived from human calcitonin receptor/RAMP coexpression exhibit pharmacological differences dependent on receptor isoform and host cell environment. Tilakaratne, N., Christopoulos, G., Zumpe, E.T., Foord, S.M., Sexton, P.M. J. Pharmacol. Exp. Ther. (2000) [Pubmed]
  30. Investigation and characterization of binding sites for islet amyloid polypeptide in rat membranes. Bhogal, R., Smith, D.M., Bloom, S.R. Endocrinology (1992) [Pubmed]
  31. Expression of islet amyloid polypeptide in fetal and adult porcine and human pancreatic islet cells. Lukinius, A., Korsgren, O., Grimelius, L., Wilander, E. Endocrinology (1997) [Pubmed]
  32. Whole-body autoradiography of 123I-labelled islet amyloid polypeptide (IAPP). Accumulation in the lung parenchyma and in the villi of the intestinal mucosa in rats. Stridsberg, M., Tjälve, H., Wilander, E. Acta oncologica (Stockholm, Sweden) (1993) [Pubmed]
  33. Islet amyloid polypeptide stimulates cyclic AMP accumulation via the porcine calcitonin receptor. Christmanson, L., Westermark, P., Betsholtz, C. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
  34. Effect of pH and insulin on fibrillogenesis of islet amyloid polypeptide in vitro. Chargé, S.B., de Koning, E.J., Clark, A. Biochemistry (1995) [Pubmed]
  35. Vasodilator responses to calcitonin gene-related peptide (CGRP) and amylin in the rat isolated perfused kidney are mediated via CGRP1 receptors. Chin, S.Y., Hall, J.M., Brain, S.D., Morton, I.K. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  36. Hypocalcemic actions of amylin amide in humans. Wimalawansa, S.J., Gunasekera, R.D., Datta, H.K. J. Bone Miner. Res. (1992) [Pubmed]
  37. Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product. Christopoulos, G., Perry, K.J., Morfis, M., Tilakaratne, N., Gao, Y., Fraser, N.J., Main, M.J., Foord, S.M., Sexton, P.M. Mol. Pharmacol. (1999) [Pubmed]
  38. Processing of pro-islet amyloid polypeptide (proIAPP) by the prohormone convertase PC2. Badman, M.K., Shennan, K.I., Jermany, J.L., Docherty, K., Clark, A. FEBS Lett. (1996) [Pubmed]
  39. Phospholipid catalysis of diabetic amyloid assembly. Knight, J.D., Miranker, A.D. J. Mol. Biol. (2004) [Pubmed]
  40. Islet amyloid polypeptide-like immunoreactivity in human tissue and endocrine tumors. Bretherton-Watt, D., Ghatei, M.A., Bloom, S.E., Williams, S., Bloom, S.R. J. Clin. Endocrinol. Metab. (1993) [Pubmed]
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