BetaSys pp 363-386 | Cite as

Physiological and Pathophysiological Role of Islet Amyloid Polypeptide (IAPP, Amylin)

Part of the Systems Biology book series (SYSTBIOL, volume 2)


IAPP has a number of effects which may be of physiological relevance. Islet amyloid, which earlier was regarded as a non-important degenerative product, most likely plays a central role in the loss of β-cells in type 2 diabetes and probably in transplanted human islets. Taken together the results from human and animal studies show that amyloid develops before β-cell deficiency, and the occurrence of oligomers and amyloid intracellular induces β-cell death. Prevention of islet amyloid most likely will save β-cells and extend hormone secretion.


Islet amyloid Islet amyloid polypeptide IAPP ProIAPP ER-Stress Apoptosis Posttranslational processing 



I thank Per Westermark for valuable suggestions. Supported by The Swedish Research Council, the European Framework 6 Program to EURAMY, the Swedish Diabetes Association and Family Ernfors Fund.


  1. 1.
    Westermark P, Wernstedt C, Wilander E, Sletten K (1986) A novel peptide in the calcitonin gene related peptide family as an amyloid fibril protein in the endocrine pancreas. Biochem Biophys Res Commun 140:827–831PubMedGoogle Scholar
  2. 2.
    Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB et al (1987) Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci USA 84:8628–8632PubMedGoogle Scholar
  3. 3.
    Westermark P, Wernstedt C, Wilander E, Hayden DW, O’Brien TD et al (1987) 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. Proc Natl Acad Sci U S A 84:3881–3885PubMedGoogle Scholar
  4. 4.
    Goodman E, CIversen LL (1986) Calcitonin gene-related peptide: novel neuropeptide. Life Sci 38:2169–2178PubMedGoogle Scholar
  5. 5.
    Cooper GJ, Leighton B, Dimitriadis GD, Parry-Billings M, Kowalchuk JM et al (1988) Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle. Proc Natl Acad Sci USA 85:7763–7766PubMedGoogle Scholar
  6. 6.
    Cooper GJ, Willis AC, Reid KB, Clark A, Baker CA et al (1987) Diabetes-associated peptide. Lancet 2:966PubMedGoogle Scholar
  7. 7.
    Miyazato M, Nakazato M, Shiomi K, Aburaya J, Kangawa K et al (1992) Molecular forms of islet amyloid polypeptide (IAPP/amylin) in four mammals. Diabetes Res Clin Pract 15: 31–36PubMedGoogle Scholar
  8. 8.
    Christmanson L, Betsholtz C, Leckstrom A, Engstrom U, Cortie C et al (1993) Islet amyloid polypeptide in the rabbit and European hare: studies on its relationship to amyloidogenesis. Diabetologia 36:183–188PubMedGoogle Scholar
  9. 9.
    Nishi M, Chan SJ, Nagamatsu S, Bell GI, Steiner DF (1989) Conservation of the sequence of islet amyloid polypeptide in five mammals is consistent with its putative role as an islet hormone. Proc Natl Acad Sci USA 86:5738–5742PubMedGoogle Scholar
  10. 10.
    Betsholtz C, Christmanson L, Engstrom U, Rorsman F, Jordan K, et al (1990) Structure of cat islet amyloid polypeptide and identification of amino acid residues of potential significance for islet amyloid formation. Diabetes 39:118–122PubMedGoogle Scholar
  11. 11.
    Fan L, Westermark G, Chan SJ, Steiner DF (1994) Altered gene structure and tissue expression of islet amyloid polypeptide in the chicken. Mol Endocrinol 8:713–721PubMedGoogle Scholar
  12. 12.
    Westermark GT, Falkmer S, Steiner DF, Chan SJ, Engstrom U et al (2002) Islet amyloid polypeptide is expressed in the pancreatic islet parenchyma of the teleostean fish, Myoxocephalus (cottus) scorpius. Comp Biochem Physiol B Biochem Mol Biol 133: 119–125PubMedGoogle Scholar
  13. 13.
    Rindi G, Terenghi G, Westermark G, Westermark P, Moscoso G, et al (1991) Islet amyloid polypeptide in proliferating pancreatic B cells during development, hyperplasia, and neoplasia in humans and mice. Am J Pathol 138:1321–1334PubMedGoogle Scholar
  14. 14.
    Madsen OD, Jensen J, Blume N, Petersen HV, Lund K, et al (1996) Pancreatic development and maturation of the islet B cell. Studies of pluripotent islet cultures. Eur J Biochem 242:435–445PubMedGoogle Scholar
  15. 15.
    Wilson ME, Kalamaras JA, German MS (2002) Expression pattern of IAPP and prohormone convertase 1/3 reveals a distinctive set of endocrine cells in the embryonic pancreas. Mech Dev 115:171–176PubMedGoogle Scholar
  16. 16.
    Macfarlane WM, Campbell SC, Elrick LJ, Oates V, Bermano G et al (2000) Glucose regulates islet amyloid polypeptide gene transcription in a PDX1- and calcium-dependent manner. J Biol Chem 275:15330–15335PubMedGoogle Scholar
  17. 17.
    Hussain MA, Miller CP, Habener JF (2002) Brn-4 transcription factor expression targeted to the early developing mouse pancreas induces ectopic glucagon gene expression in insulin-producing beta cells. J Biol Chem 277:16028–16032PubMedGoogle Scholar
  18. 18.
    Johnson KH, Westermark P, Nilsson G, Sletten K, O’Brien TD et al (1985) Feline insular amyloid: immunohistochemical and immunochemical evidence that the amyloid is insulin-related. Vet Pathol 22:463–468PubMedGoogle Scholar
  19. 19.
    Kahn SE, D’Alessio DA, Schwartz MW, Fujimoto WY, Ensinck JW et al (1990) Evidence of cosecretion of islet amyloid polypeptide and insulin by beta-cells. Diabetes 39:634–638PubMedGoogle Scholar
  20. 20.
    Nakazato M, Shiomi K, Miyazato M, Matsukura S (1992) Type I familial amyloidotic polyneuropathy in Japan. Intern Med 31:1335–1338PubMedGoogle Scholar
  21. 21.
    Betsholtz C, Svensson V, Rorsman F, Engstrom U, Westermark GT et al (1989) Islet amyloid polypeptide (IAPP):cDNA cloning and identification of an amyloidogenic region associated with the species-specific occurrence of age-related diabetes mellitus. Exp Cell Res 183: 484–493PubMedGoogle Scholar
  22. 22.
    Sanke T, Bell GI, Sample C, Rubenstein AH, Steiner DF (1988) An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing. J Biol Chem 263: 17243–17246PubMedGoogle Scholar
  23. 23.
    Marzban L, Trigo-Gonzalez G, Zhu X, Rhodes CJ, Halban PA et al (2004) Role of beta-cell prohormone convertase (PC)1/3 in processing of pro-islet amyloid polypeptide. Diabetes 53:141–148PubMedGoogle Scholar
  24. 24.
    Marzban L, Trigo-Gonzalez G, Verchere CB (2005) Processing of pro-islet amyloid polypeptide in the constitutive and regulated secretory pathways of beta cells. Mol Endocrinol 19:2154–2163PubMedGoogle Scholar
  25. 25.
    Wang J, Xu J, Finnerty J, Furuta M, Steiner DF et al (2001) The prohormone convertase enzyme 2 (PC2) is essential for processing pro-islet amyloid polypeptide at the NH2-terminal cleavage site. Diabetes 50:534–539PubMedGoogle Scholar
  26. 26.
    Marzban L, Soukhatcheva G, Verchere CB (2005) Role of carboxypeptidase E in processing of pro-islet amyloid polypeptide in {beta}-cells. Endocrinology 146:1808–1817PubMedGoogle Scholar
  27. 27.
    Roberts AN, Leighton B, Todd JA, Cockburn D, Schofield PN et al (1989) Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus. Proc Natl Acad Sci U S A 86:9662–9666PubMedGoogle Scholar
  28. 28.
    Halban PA, Irminger JC (2003) Mutant proinsulin that cannot be converted is secreted efficiently from primary rat beta-cells via the regulated pathway. Mol Biol Cell 14:1195–1203PubMedGoogle Scholar
  29. 29.
    Lukinius A, Wilander E, Westermark GT, Engstrom U, Westermark P (1989) Co-localization of islet amyloid polypeptide and insulin in the B cell secretory granules of the human pancreatic islets. Diabetologia 32:240–244PubMedGoogle Scholar
  30. 30.
    Clark A, Edwards CA, Ostle LR, Sutton R, Rothbard JB et al (1989) Localisation of islet amyloid peptide in lipofuscin bodies and secretory granules of human B-cells and in islets of type-2 diabetic subjects. Cell Tissue Res 257:179–185PubMedGoogle Scholar
  31. 31.
    Johnson KH, O’Brien TD, Hayden DW, Jordan K, Ghobrial HK et al (1988) Immunolocalization of islet amyloid polypeptide (IAPP) in pancreatic beta cells by means of peroxidase-antiperoxidase (PAP) and protein A-gold techniques. Am J Pathol 130:1–8PubMedGoogle Scholar
  32. 32.
    Westermark P, Li ZC, Westermark GT, Leckstrom A, Steiner DF (1996) Effects of beta cell granule components on human islet amyloid polypeptide fibril formation. FEBS Lett 379:203–206PubMedGoogle Scholar
  33. 33.
    Nishi M, Sanke T, Nagamatsu S, Bell GI, Steiner DF (1990) Islet amyloid polypeptide. A new beta cell secretory product related to islet amyloid deposits. J Biol Chem 265: 4173–4176PubMedGoogle Scholar
  34. 34.
    Jaikaran ET, Nilsson MR, Clark A (2004) Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation. Biochem J 377:709–716PubMedGoogle Scholar
  35. 35.
    Paulsson J, Westermark GT (2001) Differences in distribution of insulin and IAPP on the cellular level. In: Amyloid and Amyloidosis. The proceedings of the XIth international symposium on amyloidosis, edited by Bély M, Apáthy A. Budapest, Hungarian Academy of Science 424–426Google Scholar
  36. 36.
    van Hulst KL, Hackeng WH, Hoppener JW, van Jaarsveld BC, Nieuwenhuis MG et al (1994) An improved method for the determination of islet amyloid polypeptide levels in plasma. Ann Clin Biochem 31 ( Pt 2):165–170PubMedGoogle Scholar
  37. 37.
    Nakazato M, Asai J, Kangawa K, Matsukura S, Matsuo H (1989) Establishment of radioimmunoassay for human islet amyloid polypeptide and its tissue content and plasma concentration. Biochem Biophys Res Commun 164:394–399PubMedGoogle Scholar
  38. 38.
    Leckstrom A, Bjorklund K, Permert J, Larsson R, Westermark P (1997) Renal elimination of islet amyloid polypeptide. Biochem Biophys Res Commun 239:265–268PubMedGoogle Scholar
  39. 39.
    de Koning EJ, Fleming KA, Gray DW, Clark A (1995) High prevalence of pancreatic islet amyloid in patients with end-stage renal failure on dialysis treatment. J Pathol 175:253–258PubMedGoogle Scholar
  40. 40.
    Kautzky-Willer A, Thomaseth K, Pacini G, Clodi M, Ludvik B et al (1994) Role of islet amyloid polypeptide secretion in insulin-resistant humans. Diabetologia 37:188–194PubMedGoogle Scholar
  41. 41.
    Clodi M, Thomaseth K, Pacini G, Hermann K, Kautzky-Willer A et al (1998) Distribution and kinetics of amylin in humans. Am J Physiol 274:E903–908PubMedGoogle Scholar
  42. 42.
    Stridsberg M, Sandler S, Wilander E (1993) Cosecretion of islet amyloid polypeptide (IAPP) and insulin from isolated rat pancreatic islets following stimulation or inhibition of beta-cell function. Regul Pept 45:363–370PubMedGoogle Scholar
  43. 43.
    Christmanson L, Rorsman F, Stenman G, Westermark P, Betsholtz C (1990) The human islet amyloid polypeptide (IAPP) gene. Organization, chromosomal localization and functional identification of a promoter region. FEBS Lett 267:160–166PubMedGoogle Scholar
  44. 44.
    Nishi M, Sanke T, Seino S, Eddy RL, Fan YS et al (1989) Human islet amyloid polypeptide gene: complete nucleotide sequence, chromosomal localization, and evolutionary history. Mol Endocrinol 3:1775–1781PubMedGoogle Scholar
  45. 45.
    Mosselman S, Hoppener JW, Lips CJ, Jansz HS (1989) The complete islet amyloid polypeptide precursor is encoded by two exons. FEBS Lett 247:154–158PubMedGoogle Scholar
  46. 46.
    Mosselman S, Hoppener JW, Zandberg J, van Mansfeld AD, Geurts van Kessel AH et al (1988) Islet amyloid polypeptide: identification and chromosomal localization of the human gene. FEBS Lett 239:227–232PubMedGoogle Scholar
  47. 47.
    Carty MD, Lillquist JS, Peshavaria M, Stein R, Soeller WC (1997) Identification of cis- and trans-active factors regulating human islet amyloid polypeptide gene expression in pancreatic beta-cells. J Biol Chem 272:11986–11993PubMedGoogle Scholar
  48. 48.
    German MS, Moss LG, Wang J, Rutter WJ (1992) The insulin and islet amyloid polypeptide genes contain similar cell-specific promoter elements that bind identical beta-cell nuclear complexes. Mol Cell Biol 12:1777–1788PubMedGoogle Scholar
  49. 49.
    Peshavaria M, Day IN (1993) Methylation patterns in the human muscle-specific enolase gene (ENO3). Biochem J 292 (Pt 3):701–704PubMedGoogle Scholar
  50. 50.
    Watada H, Kajimoto Y, Umayahara Y, Matsuoka T, Kaneto H et al (1996) The human glucokinase gene beta-cell-type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells. Diabetes 45:1478–1488PubMedGoogle Scholar
  51. 51.
    German M, Ashcroft S, Docherty K, Edlund H, Edlund T et al (1995) The insulin gene promoter. A simplified nomenclature. Diabetes 44:1002–1004PubMedGoogle Scholar
  52. 52.
    Ohlsson H, Karlsson K, Edlund T (1993) IPF1, a homeodomain-containing transactivator of the insulin gene. Embo J 12:4251–4259PubMedGoogle Scholar
  53. 53.
    Mulder H, Ahren B, Sundler F (1996) Islet amyloid polypeptide and insulin gene expression are regulated in parallel by glucose in vivo in rats. Am J Physiol 271:E1008–1014PubMedGoogle Scholar
  54. 54.
    Novials A, Sarri Y, Casamitjana R, Rivera F, Gomis R (1993) Regulation of islet amyloid polypeptide in human pancreatic islets. Diabetes 42:1514–1519PubMedGoogle Scholar
  55. 55.
    Gasa R, Gomis R, Casamitjana R, Novials A (1997) Signals related to glucose metabolism regulate islet amyloid polypeptide (IAPP) gene expression in human pancreatic islets. Regul Pept 68:99–104PubMedGoogle Scholar
  56. 56.
    Shepherd LM, Campbell SC, Macfarlane WM (2004) Transcriptional regulation of the IAPP gene in pancreatic beta-cells. Biochim Biophys Acta 1681:28–37PubMedGoogle Scholar
  57. 57.
    Copp DH (1963) Calcitonin – a New Hormone from the Parathyroid and Its Function in Regulating Blood Calcium. Rein Foie 6:23–30PubMedGoogle Scholar
  58. 58.
    Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298:240–244PubMedGoogle Scholar
  59. 59.
    Kitamura K, Sakata J, Kangawa K, Kojima M, Matsuo H et al (1993) Cloning and characterization of cDNA encoding a precursor for human adrenomedullin. Biochem Biophys Res Commun 194:720–725PubMedGoogle Scholar
  60. 60.
    Roh J, Chang CL, Bhalla A, Klein C, Hsu SY (2004) Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. J Biol Chem 279:7264–7274PubMedGoogle Scholar
  61. 61.
    Sexton PM, Albiston A, Morfis M, Tilakaratne N (2001) Receptor activity modifying proteins. Cell Signal 13:73–83PubMedGoogle Scholar
  62. 62.
    Udawela M, Hay DL, Sexton PM (2004) The receptor activity modifying protein family of G protein coupled receptor accessory proteins. Semin Cell Dev Biol 15:299–308PubMedGoogle Scholar
  63. 63.
    McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J et al (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–339PubMedGoogle Scholar
  64. 64.
    Tilakaratne N, Christopoulos G, Zumpe ET, Foord SM, Sexton PM (2000) Amylin receptor phenotypes derived from human calcitonin receptor/RAMP coexpression exhibit pharmacological differences dependent on receptor isoform and host cell environment. J Pharmacol Exp Ther 294:61–72PubMedGoogle Scholar
  65. 65.
    Ferrier GJ, Pierson AM, Jones PM, Bloom SR, Girgis SI et al (1989) Expression of the rat amylin (IAPP/DAP) gene. J Mol Endocrinol 3:R1–4PubMedGoogle Scholar
  66. 66.
    Mulder H, Lindh AC, Ekblad E, Westermark P, Sundler F (1994) Islet amyloid polypeptide is expressed in endocrine cells of the gastric mucosa in the rat and mouse. Gastroenterology 107:712–719PubMedGoogle Scholar
  67. 67.
    Ahren B, Sundler F (1992) Localization of calcitonin gene-related peptide and islet amyloid polypeptide in the rat and mouse pancreas. Cell Tissue Res 269:315–322PubMedGoogle Scholar
  68. 68.
    Skofitsch G, Wimalawansa SJ, Jacobowitz DM, Gubisch W (1995) Comparative immunohistochemical distribution of amylin-like and calcitonin gene related peptide like immunoreactivity in the rat central nervous system. Can J Physiol Pharmacol 73:945–956PubMedGoogle Scholar
  69. 69.
    Silvestre RA, Peiro E, Degano P, Miralles P, Marco J (1990) Inhibitory effect of rat amylin on the insulin responses to glucose and arginine in the perfused rat pancreas. Regul Pept 31:23–31PubMedGoogle Scholar
  70. 70.
    Wang F, Adrian TE, Westermark GT, Ding X, Gasslander T et al (1999) Islet amyloid polypeptide tonally inhibits beta-, alpha-, and delta-cell secretion in isolated rat pancreatic islets. Am J Physiol 276:E19–24PubMedGoogle Scholar
  71. 71.
    Wang F, Permert J, Ostenson CG (2000) Islet amyloid polypeptide regulates multiple steps in stimulus-secretion coupling of beta cells in rat pancreatic islets. Pancreas 20:264–269PubMedGoogle Scholar
  72. 72.
    Silvestre RA, Rodriguez-Gallardo J, Gutierrez E, Marco J (1997) Influence of glucose concentration on the inhibitory effect of amylin on insulin secretion. Study in the perfused rat pancreas. Regul Pept 68:31–35PubMedGoogle Scholar
  73. 73.
    Salas M, Silvestre RA, Garcia-Hermida O, Fontela T, Rodriguez-Gallardo J et al (1995) Inhibitory effect of amylin (islet amyloid polypeptide) on insulin response to non-glucose stimuli. Study in perfused rat pancreas. Diabetes Metab 21:269–273Google Scholar
  74. 74.
    Furnsinn C, Leuvenink H, Roden M, Nowotny P, Schneider B et al (1994) Islet amyloid polypeptide inhibits insulin secretion in conscious rats. Am J Physiol 267:E300–305PubMedGoogle Scholar
  75. 75.
    Gebre-Medhin S, Mulder H, Pekny M, Westermark G, Tornell J et al (1998) Increased insulin secretion and glucose tolerance in mice lacking islet amyloid polypeptide (amylin). Biochem Biophys Res Commun 250:271–277PubMedGoogle Scholar
  76. 76.
    Leighton B, Cooper GJ (1988) Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro. Nature 335:632–635PubMedGoogle Scholar
  77. 77.
    Frontoni S, Choi SB, Banduch D, Rossetti L (1991) In vivo insulin resistance induced by amylin primarily through inhibition of insulin-stimulated glycogen synthesis in skeletal muscle. Diabetes 40:568–573PubMedGoogle Scholar
  78. 78.
    Young AA, Mott DM, Stone K, Cooper GJ (1991) Amylin activates glycogen phosphorylase in the isolated soleus muscle of the rat. FEBS Lett 281:149–151PubMedGoogle Scholar
  79. 79.
    Deems RO, Cardinaux F, Deacon RW, Young DA (1991) Amylin or CGRP (8–37) fragments reverse amylin-induced inhibition of 14C-glycogen accumulation. Biochem Biophys Res Commun 181:116–120PubMedGoogle Scholar
  80. 80.
    Johnson KH, O’Brien TD, Jordan K, Betsholtz C, Westermark P (1990) The putative hormone islet amyloid polypeptide (IAPP) induces impaired glucose tolerance in cats. Biochem Biophys Res Commun 167:507–513PubMedGoogle Scholar
  81. 81.
    Molina JM, Cooper GJ, Leighton B, Olefsky JM (1990) Induction of insulin resistance in vivo by amylin and calcitonin gene-related peptide. Diabetes 39:260–265PubMedGoogle Scholar
  82. 82.
    Sowa R, Sanke T, Hirayama J, Tabata H, Furuta H et al (1990) Islet amyloid polypeptide amide causes peripheral insulin resistance in vivo in dogs. Diabetologia 33:118–120PubMedGoogle Scholar
  83. 83.
    Kassir AA, Upadhyay AK, Lim TJ, Moossa AR, Olefsky JM (1991) Lack of effect of islet amyloid polypeptide in causing insulin resistance in conscious dogs during euglycemic clamp studies. Diabetes 40:998–1004PubMedGoogle Scholar
  84. 84.
    Panagiotidis G, Salehi AA, Westermark P, Lundquist I (1992) Homologous islet amyloid polypeptide: effects on plasma levels of glucagon, insulin and glucose in the mouse. Diabetes Res Clin Pract 18:167–171PubMedGoogle Scholar
  85. 85.
    Furrer D, Kaufmann K, Reusch CE, Lutz TA (2009) Amylin reduces plasma glucagon concentration in cats. Vet J 184:236–240Google Scholar
  86. 86.
    Brown K, Menius A, Sandefer E, Edwards J, James M (1994) The effects of amylin on changes in plasma glucose and gastric emptying following an oral Glucos load in conscious dags. Diabetes Care 43:172 (abstract)Google Scholar
  87. 87.
    Kolterman O, Gottlieb A, Moyses C (1994) Administration of triproamylin reduces postprandial hyperglycemia in subjects with juvenile onset diabetes. Diabetologia 37:A72:Google Scholar
  88. 88.
    Kolterman O, Kisicki J, Peltier l, Gottlieb A, Moyses C (1994) Infusion of amylin agonist AC-0137 reduces postprandial hyperglycemia in subjects with type I diabetes (IDDM). Clin Res 42:42:87AGoogle Scholar
  89. 89.
    Nowak TV, Johnson CP, Kalbfleisch JH, Roza AM, Wood CM et al (1995) Highly variable gastric emptying in patients with insulin dependent diabetes mellitus. Gut 37:23–29PubMedGoogle Scholar
  90. 90.
    Heptulla RA, Rodriguez LM, Mason KJ, Haymond MW (2008) Gastric emptying and postprandial glucose excursions in adolescents with type 1 diabetes. Pediatr Diabetes 9:561–566PubMedGoogle Scholar
  91. 91.
    Beaumont K, Kenney MA, Young AA, Rink TJ (1993) High affinity amylin binding sites in rat brain. Mol Pharmacol 44:493–497PubMedGoogle Scholar
  92. 92.
    Paxinos G, Chai SY, Christopoulos G, Huang XF, Toga AW et al (2004) In vitro autoradiographic localization of calcitonin and amylin binding sites in monkey brain. J Chem Neuroanat 27:217–236PubMedGoogle Scholar
  93. 93.
    Balasubramaniam A, Renugopalakrishnan V, Stein M, Fischer JE, Chance WT (1991) Syntheses, structures and anorectic effects of human and rat amylin. Peptides 12: 919–924PubMedGoogle Scholar
  94. 94.
    Chance WT, Balasubramaniam A, Zhang FS, Wimalawansa SJ, Fischer JE (1991) Anorexia following the intrahypothalamic administration of amylin. Brain Res 539:352–354PubMedGoogle Scholar
  95. 95.
    Mollet A, Gilg S, Riediger T, Lutz TA (2004) Infusion of the amylin antagonist AC 187 into the area postrema increases food intake in rats. Physiol Behav 81:149–155PubMedGoogle Scholar
  96. 96.
    Morley JE, Flood JF (1991) Amylin decreases food intake in mice. Peptides 12:865–869PubMedGoogle Scholar
  97. 97.
    Chance WT, Balasubramaniam A, Stallion A, Fischer JE (1993) Anorexia following the systemic injection of amylin. Brain Res 607:185–188PubMedGoogle Scholar
  98. 98.
    Lutz TA, Del Prete E, Scharrer E (1994) Reduction of food intake in rats by intraperitoneal injection of low doses of amylin. Physiol Behav 55:891–895PubMedGoogle Scholar
  99. 99.
    Arnelo U, Permert J, Adrian TE, Larsson J, Westermark P et al (1996) Chronic infusion of islet amyloid polypeptide causes anorexia in rats. Am J Physiol 271:R1654–1659PubMedGoogle Scholar
  100. 100.
    Lutz TA, Mollet A, Rushing PA, Riediger T, Scharrer E (2001) The anorectic effect of a chronic peripheral infusion of amylin is abolished in area postrema/nucleus of the solitary tract (AP/NTS) lesioned rats. Int J Obes Relat Metab Disord 25:1005–1011PubMedGoogle Scholar
  101. 101.
    Banks WA, Kastin AJ, Maness LM, Huang W, Jaspan JB (1995) Permeability of the blood-brain barrier to amylin. Life Sci 57:1993–2001PubMedGoogle Scholar
  102. 102.
    D’Este L, Casini A, Wimalawansa SJ, Renda TG (2000) Immunohistochemical localization of amylin in rat brainstem. Peptides 21:1743–1749PubMedGoogle Scholar
  103. 103.
    Dobolyi A (2009) Central amylin expression and its induction in rat dams. J Neurochem 111:1490–1500PubMedGoogle Scholar
  104. 104.
    Cornish J, Callon KE, Cooper GJ, Reid IR (1995) Amylin stimulates osteoblast proliferation and increases mineralized bone volume in adult mice. Biochem Biophys Res Commun 207:133–139PubMedGoogle Scholar
  105. 105.
    Villa I, Melzi R, Pagani F, Ravasi F, Rubinacci A et al (2000) Effects of calcitonin gene-related peptide and amylin on human osteoblast-like cells proliferation. Eur J Pharmacol 409:273–278PubMedGoogle Scholar
  106. 106.
    Zaidi M, Datta HK, Bevis PJ, Wimalawansa SJ, MacIntyre I (1990) Amylin-amide: a new bone-conserving peptide from the pancreas. Exp Physiol 75:529–536PubMedGoogle Scholar
  107. 107.
    Datta HK, MacIntyre I, Zaidi M (1989) The effect of extracellular calcium elevation on morphology and function of isolated rat osteoclasts. Biosci Rep 9:747–751PubMedGoogle Scholar
  108. 108.
    Alam AS, Moonga BS, Bevis PJ, Huang CL, Zaidi M (1993) Amylin inhibits bone resorption by a direct effect on the motility of rat osteoclasts. Exp Physiol 78:183–196PubMedGoogle Scholar
  109. 109.
    Tamura T, Miyaura C, Owan I, Suda T (1992) Mechanism of action of amylin in bone. J Cell Physiol 153:6–14PubMedGoogle Scholar
  110. 110.
    Dacquin R, Davey RA, Laplace C, Levasseur R, Morris HA et al (2004) Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo. J Cell Biol 164:509–514PubMedGoogle Scholar
  111. 111.
    Wojcik MH, Meenaghan E, Lawson EA, Misra M, Klibanski A et al (2009) Reduced amylin levels are associated with low bone mineral density in women with anorexia nervosa. Bone 46:796–800Google Scholar
  112. 112.
    McQueen J (2005) Pramlintide acetate. Am J Health Syst Pharm 62:2363–2372PubMedGoogle Scholar
  113. 113.
    Chan JL, Roth JD, Weyer C (2009) It takes two to tango: combined amylin/leptin agonism as a potential approach to obesity drug development. J Investig Med 57:777–783PubMedGoogle Scholar
  114. 114.
    Westermark P, Benson MD, Buxbaum JN, Cohen AS, Frangione B et al (2007) A primer of amyloid nomenclature. Amyloid 14:179–183PubMedGoogle Scholar
  115. 115.
    Jarrett JT, Lansbury PT, Jr. (1993) Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 73:1055–1058PubMedGoogle Scholar
  116. 116.
    Rochet JC, Lansbury PT Jr (2000) Amyloid fibrillogenesis: themes and variations. Curr Opin Struct Biol 10:60–68PubMedGoogle Scholar
  117. 117.
    Opie EL (1901) The Relation Of diabetes mellitus to lesions of the pancreas. hyaline degeneration of the Islands Of Langerhans. J Exp Med 5:527–540PubMedGoogle Scholar
  118. 118.
    Westermark P (1972) Quantitative studies on amyloid in the islets of Langerhans. Ups J Med Sci 77:91–94PubMedGoogle Scholar
  119. 119.
    Maloy AL, Longnecker DS, Greenberg ER (1981) The relation of islet amyloid to the clinical type of diabetes. Hum Pathol 12:917–922PubMedGoogle Scholar
  120. 120.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA et al (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110PubMedGoogle Scholar
  121. 121.
    Sempoux C, Guiot Y, Dubois D, Moulin P, Rahier J (2001) Human type 2 diabetes: morphological evidence for abnormal beta-cell function. Diabetes 50 Suppl 1:S172–177Google Scholar
  122. 122.
    Rocken C, Linke RP, Saeger W (1992) Immunohistology of islet amyloid polypeptide in diabetes mellitus: semi-quantitative studies in a post-mortem series. Virchows Arch A Pathol Anat Histopathol 421:339–344PubMedGoogle Scholar
  123. 123.
    Guardado-Mendoza R, Davalli AM, Chavez AO, Hubbard GB, Dick EJ et al (2009) Pancreatic islet amyloidosis, beta-cell apoptosis, and alpha-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons. Proc Natl Acad Sci USA 106: 13992–13997PubMedGoogle Scholar
  124. 124.
    Howard CF Jr (1978) Insular amyloidosis and diabetes mellitus in Macaca nigra. Diabetes 27:357–364PubMedGoogle Scholar
  125. 125.
    de Koning EJ, Bodkin NL, Hansen BC, Clark A (1993) Diabetes mellitus in Macaca mulatta monkeys is characterised by islet amyloidosis and reduction in beta-cell population. Diabetologia 36:378–384PubMedGoogle Scholar
  126. 126.
    Johnson KH, Hayden DW, O’Brien TD, Westermark P (1986) Spontaneous diabetes mellitus-islet amyloid complex in adult cats. Am J Pathol 125:416–419PubMedGoogle Scholar
  127. 127.
    Howard CF, Jr. (1986) Longitudinal studies on the development of diabetes in individual Macaca nigra. Diabetologia 29:301–306PubMedGoogle Scholar
  128. 128.
    Zhao HL, Lai FM, Tong PC, Zhong DR, Yang D et al (2003) Prevalence and clinicopathological characteristics of islet amyloid in Chinese patients with type 2 diabetes. Diabetes 52:2759–2766PubMedGoogle Scholar
  129. 129.
    Westermark P, Engstrom U, Johnson KH, Westermark GT, Betsholtz C (1990) Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc Natl Acad Sci USA 87:5036–5040PubMedGoogle Scholar
  130. 130.
    Jaikaran ET, Clark A (2001) Islet amyloid and type 2 diabetes: from molecular misfolding to islet pathophysiology. Biochim Biophys Acta 1537:179–203PubMedGoogle Scholar
  131. 131.
    Higham CE, Jaikaran ET, Fraser PE, Gross M, Clark A (2000) Preparation of synthetic human islet amyloid polypeptide (IAPP) in a stable conformation to enable study of conversion to amyloid-like fibrils. FEBS Lett 470:55–60PubMedGoogle Scholar
  132. 132.
    Goldsbury C, Goldie K, Pellaud J, Seelig J, Frey P et al (2000) Amyloid fibril formation from full-length and fragments of amylin. J Struct Biol 130:352–362PubMedGoogle Scholar
  133. 133.
    Nanga RP, Brender JR, Xu J, Veglia G, Ramamoorthy A (2008) Structures of rat and human islet amyloid polypeptide IAPP(1-19) in micelles by NMR spectroscopy. Biochemistry 47:12689–12697PubMedGoogle Scholar
  134. 134.
    Nishi M, Steiner DF (1990) Cloning of complementary DNAs encoding islet amyloid polypeptide, insulin, and glucagon precursors from a New World rodent, the degu, Octodon degus. Mol Endocrinol 4:1192–1198PubMedGoogle Scholar
  135. 135.
    Hellman U, Wernstedt C, Westermark P, O’Brien TD, Rathbun WB et al (1990) Amino acid sequence from degu islet amyloid-derived insulin shows unique sequence characteristics. Biochem Biophys Res Commun 169:571–577PubMedGoogle Scholar
  136. 136.
    Fox N, Schrementi J, Nishi M, Ohagi S, Chan SJ et al (1993) Human islet amyloid polypeptide transgenic mice as a model of non-insulin-dependent diabetes mellitus (NIDDM). FEBS Lett 323:40–44PubMedGoogle Scholar
  137. 137.
    D’Alessio DA, Verchere CB, Kahn SE, Hoagland V, Baskin DG et al (1994) Pancreatic expression and secretion of human islet amyloid polypeptide in a transgenic mouse. Diabetes 43:1457–1461PubMedGoogle Scholar
  138. 138.
    Yagui K, Yamaguchi T, Kanatsuka A, Shimada F, Huang CI et al (1995) Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin. Eur J Endocrinol 132:487–496PubMedGoogle Scholar
  139. 139.
    Butler AE, Jang J, Gurlo T, Carty MD, Soeller WC et al (2004) Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat): a new model for type 2 diabetes. Diabetes 53:1509–1516PubMedGoogle Scholar
  140. 140.
    Soeller WC, Janson J, Hart SE, Parker JC, Carty MD et al (1998) Islet amyloid-associated diabetes in obese A(vy)/a mice expressing human islet amyloid polypeptide. Diabetes 47:743–750PubMedGoogle Scholar
  141. 141.
    Verchere CB, D’Alessio DA, Palmiter RD, Weir GC, Bonner-Weir S et al (1996) Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide. Proc Natl Acad Sci U S A 93:3492–3496PubMedGoogle Scholar
  142. 142.
    Westermark GT, Gebre-Medhin S, Steiner DF, Westermark P (2000) Islet amyloid development in a mouse strain lacking endogenous islet amyloid polypeptide (IAPP) but expressing human IAPP. Mol Med 6:998–1007PubMedGoogle Scholar
  143. 143.
    Couce M, Kane LA, O’Brien TD, Charlesworth J, Soeller W et al (1996) Treatment with growth hormone and dexamethasone in mice transgenic for human islet amyloid polypeptide causes islet amyloidosis and beta-cell dysfunction. Diabetes 45:1094–1101PubMedGoogle Scholar
  144. 144.
    Hoppener JW, Oosterwijk C, Nieuwenhuis MG, Posthuma G, Thijssen JH et al (1999) Extensive islet amyloid formation is induced by development of Type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model. Diabetologia 42:427–434PubMedGoogle Scholar
  145. 145.
    O’Brien TD, Butler AE, Roche PC, Johnson KH, Butler PC (1994) Islet amyloid polypeptide in human insulinomas. Evidence for intracellular amyloidogenesis. Diabetes 43:329–336PubMedGoogle Scholar
  146. 146.
    Westermark P, Eizirik DL, Pipeleers DG, Hellerstrom C, Andersson A (1995) Rapid deposition of amyloid in human islets transplanted into nude mice. Diabetologia 38:543–549PubMedGoogle Scholar
  147. 147.
    de Koning EJ, Morris ER, Hofhuis FM, Posthuma G, Hoppener JW et al (1994) Intra- and extracellular amyloid fibrils are formed in cultured pancreatic islets of transgenic mice expressing human islet amyloid polypeptide. Proc Natl Acad Sci USA 91:8467–8471PubMedGoogle Scholar
  148. 148.
    Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S et al (1999) Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19:8876–8884PubMedGoogle Scholar
  149. 149.
    Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L et al (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416: 507–511PubMedGoogle Scholar
  150. 150.
    Lorenzo A, Razzaboni B, Weir GC, Yankner BA (1994) Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature 368:756–760PubMedGoogle Scholar
  151. 151.
    Kayed R, Head E, Sarsoza F, Saing T, Cotman CW et al (2007) Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener 2:18PubMedGoogle Scholar
  152. 152.
    Arispe N, Pollard HB, Rojas E (1993) Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1-40)] in bilayer membranes. Proc Natl Acad Sci U S A 90:10573–10577PubMedGoogle Scholar
  153. 153.
    Pollard HB, Rojas E, Arispe N (1993) A new hypothesis for the mechanism of amyloid toxicity, based on the calcium channel activity of amyloid beta protein (A beta P) in phospholipid bilayer membranes. Ann N Y Acad Sci 695:165–168PubMedGoogle Scholar
  154. 154.
    Mirzabekov TA, Lin MC, Kagan BL (1996) Pore formation by the cytotoxic islet amyloid peptide amylin. J Biol Chem 271:1988–1992PubMedGoogle Scholar
  155. 155.
    Quist A, Doudevski I, Lin H, Azimova R, Ng D et al (2005) Amyloid ion channels: a common structural link for protein-misfolding disease. Proc Natl Acad Sci U S A 102:10427–10432PubMedGoogle Scholar
  156. 156.
    Engel MF, Khemtemourian L, Kleijer CC, Meeldijk HJ, Jacobs J et al (2008) Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane. Proc Natl Acad Sci USA 105:6033–6038PubMedGoogle Scholar
  157. 157.
    Engel MF, Yigittop H, Elgersma RC, Rijkers DT, Liskamp RM et al (2006) Islet amyloid polypeptide inserts into phospholipid monolayers as monomer. J Mol Biol 356:783–789PubMedGoogle Scholar
  158. 158.
    Huang CJ, Haataja L, Gurlo T, Butler AE, Wu X et al (2007) Induction of endoplasmic reticulum stress-induced beta-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide. Am J Physiol Endocrinol Metab 293:E1656–1662PubMedGoogle Scholar
  159. 159.
    Huang CJ, Lin CY, Haataja L, Gurlo T, Butler AE et al (2007) High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated beta-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes 56: 2016–2027PubMedGoogle Scholar
  160. 160.
    Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK et al (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50:752–763PubMedGoogle Scholar
  161. 161.
    Hull RL, Zraika S, Udayasankar J, Aston-Mourney K, Subramanian SL et al (2009) Amyloid formation in human IAPP transgenic mouse islets and pancreas, and human pancreas, is not associated with endoplasmic reticulum stress. Diabetologia 52:1102–1111PubMedGoogle Scholar
  162. 162.
    Gurlo T, Ryazantsev S, Huang CJ, Yeh MW, Reber HA et al (2009) Evidence for Proteotoxicity in {beta} Cells in Type 2 Diabetes, Toxic Islet Amyloid Polypeptide Oligomers form Intracellularly in the Secretory Pathway. Am J Pathol 176:861–869Google Scholar
  163. 163.
    Westermark GT, Steiner DF, Gebre-Medhin S, Engstrom U, Westermark P (2000) Pro islet amyloid polypeptide (ProIAPP) immunoreactivity in the islets of Langerhans. Ups J Med Sci 105:97–106PubMedGoogle Scholar
  164. 164.
    Paulsson JF, Andersson A, Westermark P, Westermark GT (2006) Intracellular amyloid-like deposits contain unprocessed pro-islet amyloid polypeptide (proIAPP) in beta cells of transgenic mice overexpressing the gene for human IAPP and transplanted human islets. Diabetologia 49:1237–1246PubMedGoogle Scholar
  165. 165.
    Kahn SE, Halban PA (1997) Release of incompletely processed proinsulin is the cause of the disproportionate proinsulinemia of NIDDM. Diabetes 46:1725–1732PubMedGoogle Scholar
  166. 166.
    Porte D, Kahn SE Jr (1989) Hyperproinsulinemia and amyloid in NIDDM. Clues to etiology of islet beta-cell dysfunction? Diabetes 38:1333–1336PubMedGoogle Scholar
  167. 167.
    Hou X, Ling Z, Quartier E, Foriers A, Schuit F et al (1999) Prolonged exposure of pancreatic beta cells to raised glucose concentrations results in increased cellular content of islet amyloid polypeptide precursors. Diabetologia 42:188–194PubMedGoogle Scholar
  168. 168.
    Paulsson JF, Westermark GT (2005) Aberrant processing of human proislet amyloid polypeptide results in increased amyloid formation. Diabetes 54:2117–2125PubMedGoogle Scholar
  169. 169.
    Janciauskiene S, Eriksson S, Carlemalm E, Ahren B (1997) B cell granule peptides affect human islet amyloid polypeptide (IAPP) fibril formation in vitro. Biochem Biophys Res Commun 236:580–585PubMedGoogle Scholar
  170. 170.
    Hickey AJ, Bradley JW, Skea GL, Middleditch MJ, Buchanan CM et al (2009) Proteins associated with immunopurified granules from a model pancreatic islet beta-cell system: proteomic snapshot of an endocrine secretory granule. J Proteome Res 8:178–186PubMedGoogle Scholar
  171. 171.
    Sakagashira S, Sanke T, Hanabusa T, Shimomura H, Ohagi S et al (1996) Missense mutation of amylin gene (S20G) in Japanese NIDDM patients. Diabetes 45:1279–1281PubMedGoogle Scholar
  172. 172.
    Seino S (2001) S20G mutation of the amylin gene is associated with Type II diabetes in Japanese. Study Group of Comprehensive Analysis of Genetic Factors in Diabetes Mellitus. Diabetologia 44:906–909PubMedGoogle Scholar
  173. 173.
    Garcia-Gonzalez CL, Montoya-Fuentes H, Padilla-Rosas M, Sanchez-Corona J (2007) Amylin S20G mutation in Mexican population. Diabetes Res Clin Pract 76:146–148PubMedGoogle Scholar
  174. 174.
    Ma Z, Westermark GT, Sakagashira S, Sanke T, Gustavsson A et al (2001) Enhanced in vitro production of amyloid-like fibrils from mutant (S20G) islet amyloid polypeptide. Amyloid 8:242–249PubMedGoogle Scholar
  175. 175.
    Sakagashira S, Hiddinga HJ, Tateishi K, Sanke T, Hanabusa T et al (2000) S20G mutant amylin exhibits increased in vitro amyloidogenicity and increased intracellular cytotoxicity compared to wild-type amylin. Am J Pathol 157:2101–2109PubMedGoogle Scholar
  176. 176.
    Novials A, Rojas I, Casamitjana R, Usac EF, Gomis R (2001) A novel mutation in islet amyloid polypeptide (IAPP) gene promoter is associated with Type II diabetes mellitus. Diabetologia 44:1064–1065PubMedGoogle Scholar
  177. 177.
    Novials A, Mato E, Lucas M, Franco C, Rivas M et al (2004) Mutation at position -132 in the islet amyloid polypeptide ( IAPP) gene promoter enhances basal transcriptional activity through a new CRE-like binding site. Diabetologia 47:1167–1174PubMedGoogle Scholar
  178. 178.
    Esapa C, Moffitt JH, Novials A, McNamara CM, Levy JC et al (2005) Islet amyloid polypeptide gene promoter polymorphisms are not associated with Type 2 diabetes or with the severity of islet amyloidosis. Biochim Biophys Acta 1740:74–78PubMedGoogle Scholar
  179. 179.
    Prokopenko I, McCarthy MI, Lindgren CM (2008) Type 2 diabetes: new genes, new understanding. Trends Genet 24:613–621PubMedGoogle Scholar
  180. 180.
    Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638–645PubMedGoogle Scholar
  181. 181.
    Tsai FJ, Yang CF, Chen CC, Chuang LM, Lu CH et al (2010) A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet 6:e1000847Google Scholar
  182. 182.
    Najarian JS, Sutherland DE, Matas AJ, Steffes MW, Simmons RL et al (1977) Human islet transplantation: a preliminary report. Transplant Proc 9:233–236PubMedGoogle Scholar
  183. 183.
    Westermark GT, Westermark P, Nordin A, Tornelius E, Andersson A (2003) Formation of amyloid in human pancreatic islets transplanted to the liver and spleen of nude mice. Ups J Med Sci 108:193–203PubMedGoogle Scholar
  184. 184.
    Udayasankar J, Kodama K, Hull RL, Zraika S, Aston-Mourney K et al (2009) Amyloid formation results in recurrence of hyperglycaemia following transplantation of human IAPP transgenic mouse islets. Diabetologia 52:145–153PubMedGoogle Scholar
  185. 185.
    Westermark GT, Westermark P, Berne C, Korsgren O (2008) Widespread amyloid deposition in transplanted human pancreatic islets. N Engl J Med 359:977–979PubMedGoogle Scholar
  186. 186.
    Marzban L, Tomas A, Becker TC, Rosenberg L, Oberholzer J et al (2008) Small interfering RNA-mediated suppression of proislet amyloid polypeptide expression inhibits islet amyloid formation and enhances survival of human islets in culture. Diabetes 57:3045–3055PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Medical Cell BiologyUppsala UniversityUppsalaSweden

Personalised recommendations