Amylin: Wikis

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Islet amyloid polypeptide

PDB Human amylin in SDS micelles:rendering based on 2kb8.
Available structures
2kb8,1kuw,3dgj,3dgl,2g48
Identifiers
Symbols IAPP; IAP; DAP; AMYLIN
External IDs OMIM147940 MGI96382 HomoloGene36024 GeneCards: IAPP Gene
RNA expression pattern
PBB GE IAPP 207062 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3375 15874
Ensembl ENSG00000121351 ENSMUSG00000041681
UniProt P10997 P12968
RefSeq (mRNA) NM_000415 NM_010491
RefSeq (protein) NP_000406 NP_034621
Location (UCSC) Chr 12:
21.42 - 21.42 Mb
Chr 6:
142.26 - 142.26 Mb
PubMed search [1] [2]
Amino acid sequence of amylin with disulfide bridge and cleavage sites of insulin degrading enzyme indicated with arrows

Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin (in a roughly 1:100 amylin:insulin ratio). [1]

Contents

Clinical significance

Islet, or insulinoma, amyloid polypeptide (IAPP, or amylin) is commonly found in pancreatic islets of patients suffering diabetes mellitus type 2, or harboring an insulinoma. While the association of amylin with the development of type 2 diabetes has been known for some time,[2] a direct causative role for amylin has been harder to establish. Recent results suggest that amylin, like the related beta-amyloid (Abeta) associated with Alzheimer's disease, can induce apoptotic cell-death in insulin-producing beta cells, an effect that may be relevant to the development of type 2 diabetes.[3]. Finally, a recent study reported a synergistic effect for weight loss with leptin and amylin coadministration in diet-induced obese rats by restoring hypothalamic sensitivity to leptin [4].

Function

Amylin functions as part of the endocrine pancreas and contributes to glycemic control. The peptide is secreted from the pancreas into the blood circulation and eventually excreted by the kidneys. Amylin's metabolic function is now somewhat well characterized as an inhibitor of the appearance of nutrient [especially glucose] in the plasma. [5] It thus functions as a synergistic partner to insulin, with which it is cosecreted from pancreatic beta cells in response to meals. The overall effect to slow the rate of appearance (Ra) from the meal is mediated via a coordinate reduction of food intake, slowing of gastric emptying, inhibition of digestive secretion [gastric acid, pancreatic enzymes, and bile ejection]. Appearance of new glucose is slowed by inhibiting secretion of the gluconeogenic hormone glucagon. These actions, which are mostly mediated via a glucose-sensitive part of the brain stem, the area postrema, may be over-ridden during hypoglycemia. They collectively reduce the total insulin demand.[6] Amylin also acts in bone metabolism, along with the related peptides calcitonin and calcitonin gene related peptide.. [5]

Rodent amylin knockouts are known to fail to achieve the normal anorexia following food consumption. Because it is an amidated peptide, like many neuropeptides, it is believed to be responsible for the anorectic effect.

Structure

The human form of IAPP has the amino acid sequence KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY, with a disulfide bridge between cysteine residues 2 and 7. Both the amidated C-terminus and the disulfide bridge are necessary for the full biological activity of amylin. [7] IAPP is capable of forming amyloid fibrils in vitro. Within the fibrillization reaction, the early prefibrillar structures are extremely toxic to beta-cell and insuloma cell cultures. [7] Later amyloid fiber structures also seem to have some cytotoxic effect on cell cultures. Studies have shown that fibrils are the end product and not necessarily the most toxic form of amyloid proteins/peptides in general. A non-fibril forming peptide (1-19 residues of human amylin) is toxic like the full-length peptide but the respective segment of rat amylin is not.[8][9][10]. It was also demonstrated by solid-state NMR spectroscopy that the fragment 20-29 of the human-amylin fragments membranes.[11] Rats and mice have six substitutions (three of which are proline substitions at positions 25, 28 and 29) that are believed to prevent the formation of amyloid fibrils. Rat IAPP is nontoxic to beta-cells, even when overexpressed.

History and Nomenclature

IAPP was identified independently by two groups as the major component of diabetes-associated islet amyloid deposits in 1987.[12][13]

The difference in nomenclature is largely geographical; European researchers tend to prefer IAPP whereas American researchers tend to prefer amylin. Some researchers discourage the use of "amylin" on the grounds that it may be confused with the pharmaceutical company.

Pharmacology

Synthetic amylin, or pramlintide (brand name Symlin), was recently approved for adult use in patients with both diabetes mellitus type 1 and diabetes mellitus type 2. Insulin and pramlintide, injected separately but both before a meal, work together to control the post-prandial glucose excursion.[14]

Amylin is degraded in part by insulin-degrading enzyme.[15]

Receptors

There appears to be at least three distinct receptor complexes that bind with high affinity to amylin. All three complexes contain the calcitonin receptor at the core, plus one of three receptor activity-modifying proteins, RAMP1, RAMP2, or RAMP3.[16]

See also

References

  1. ^ "Entrez Gene: IAPP islet amyloid polypeptide". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3375.  
  2. ^ Hayden MR (2002). "Islet amyloid, metabolic syndrome, and the natural progressive history of type 2 diabetes mellitus". JOP 3 (5): 126–38. PMID 12221327.  
  3. ^ Lorenzo A, Razzaboni B, Weir GC, Yankner BA (1994). "Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus". Nature 368 (6473): 756–60. doi:10.1038/368756a0. PMID 8152488.  
  4. ^ Roth JD and al. (2008). "Leptin responsiveness restored by amylin agonism in diet-induced obesity - evidence from nonclinical and clinical studies". PNAS 105 (20): 7257–7262. doi:10.1073/pnas.0706473105. PMID 18458326.  
  5. ^ a b Pittner RA, Albrandt K, Beaumont K, et al. (1994). "Molecular physiology of amylin". J. Cell. Biochem. 55 Suppl: 19–28. doi:10.1002/jcb.240550004. PMID 7929615.  
  6. ^ Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, Weyer C, Kolterman OG (2004). "Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial". Diabet Med 21 (11): 1204–12. doi:10.1111/j.1464-5491.2004.01319.x. PMID 15498087.  
  7. ^ a b Roberts AN, Leighton B, Todd JA, et al. (1990). "Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus". Proc. Natl. Acad. Sci. U.S.A. 86 (24): 9662–6. doi:10.1073/pnas.86.24.9662. PMID 2690069.  
  8. ^ Brender JR, Lee EL, Cavitt MA, Gafni A, Steel DG, Ramamoorthy A (May 2008). "Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide". J. Am. Chem. Soc. 130 (20): 6424–9. doi:10.1021/ja710484d. PMID 18444645.  
  9. ^ Brender JR, Hartman K, Reid KR, Kennedy RT, Ramamoorthy A (November 2008). "A Single Mutation in the Nonamyloidogenic Region of Islet Amyloid Polypeptide Greatly Reduces Toxicity". Biochemistry 47: 12680. doi:10.1021/bi801427c. PMID 18989933.  
  10. ^ Nanga RP, Brender JR, Xu J, Veglia G, Ramamoorthy A (November 2008). "Structures of Rat and Human Islet Amyloid Polypeptide IAPP1-19 in Micelles by NMR Spectroscopy". Biochemistry 47: 12689. doi:10.1021/bi8014357. PMID 18989932.  
  11. ^ Brender JR, Dürr UH, Heyl D, Budarapu MB, Ramamoorthy A (September 2007). "Membrane fragmentation by an amyloidogenic fragment of human Islet Amyloid Polypeptide detected by solid-state NMR spectroscopy of membrane nanotubes". Biochim. Biophys. Acta 1768 (9): 2026–9. doi:10.1016/j.bbamem.2007.07.001. PMID 17662957.  
  12. ^ Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB (1987). "Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients". Proc Natl Acad Sci USA 84 (23): 8628–32. doi:10.1073/pnas.84.23.8628. PMID 3317417.  
  13. ^ Westermark P, Wernstedt C, Wilander E, Hayden DW, O'Brien TD, Johnson KH (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 USA 84 (11): 3881–3885. doi:10.1073/pnas.84.11.3881. PMID 3035556.  
  14. ^ "SYMLIN (pramlintide acetate)". Amylin Pharmaceuticals, Inc.. 2006. http://www.amylin.com/pipeline/symlin.cfm/. Retrieved 2008-05-28.  
  15. ^ Shen Y, Joachimiak A, Rosner MR, Tang WJ (October 2006). "Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism". Nature 443 (7113): 870–4. doi:10.1038/nature05143. PMID 17051221.  
  16. ^ Hay DL, Christopoulos G, Christopoulos A, Sexton PM (2004). "Amylin receptors: molecular composition and pharmacology". Biochem Soc Trans 32 (5): 865–7. doi:10.1042/BST0320865. PMID 15494035.  

Further reading

  • Westermark P, Andersson A, Westermark GT (2005). "Is aggregated IAPP a cause of beta-cell failure in transplanted human pancreatic islets?". Curr. Diab. Rep. 5 (3): 184–8. doi:10.1007/s11892-005-0007-2. PMID 15929864.  
  • Höppener JW, Oosterwijk C, Visser-Vernooy HJ, et al. (1993). "Characterization of the human islet amyloid polypeptide/amylin gene transcripts: identification of a new polyadenylation site". Biochem. Biophys. Res. Commun. 189 (3): 1569–77. doi:10.1016/0006-291X(92)90255-J. PMID 1282806.  
  • Hubbard JA, Martin SR, Chaplin LC, et al. (1991). "Solution structures of calcitonin-gene-related-peptide analogues of calcitonin-gene-related peptide and amylin". Biochem. J. 275 ( Pt 3): 785–8. PMID 2039456.  
  • Butler PC, Chou J, Carter WB, et al. (1990). "Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans". Diabetes 39 (6): 752–6. doi:10.2337/diabetes.39.6.752. PMID 2189768.  
  • van Mansfeld AD, Mosselman S, Höppener JW, et al. (1990). "Islet amyloid polypeptide: structure and upstream sequences of the IAPP gene in rat and man". Biochim. Biophys. Acta 1087 (2): 235–40. PMID 2223885.  
  • Christmanson L, Rorsman F, Stenman G, et al. (1990). "The human islet amyloid polypeptide (IAPP) gene. Organization, chromosomal localization and functional identification of a promoter region". FEBS Lett. 267 (1): 160–6. doi:10.1016/0014-5793(90)80314-9. PMID 2365085.  
  • Clark A, Edwards CA, Ostle LR, 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 (1): 179–85. doi:10.1007/BF00221649. PMID 2546670.  
  • Nishi M, Sanke T, Seino S, et al. (1990). "Human islet amyloid polypeptide gene: complete nucleotide sequence, chromosomal localization, and evolutionary history". Mol. Endocrinol. 3 (11): 1775–81. doi:10.1210/mend-3-11-1775. PMID 2608057.  
  • Mosselman S, Höppener JW, Lips CJ, Jansz HS (1989). "The complete islet amyloid polypeptide precursor is encoded by two exons". FEBS Lett. 247 (1): 154–8. doi:10.1016/0014-5793(89)81260-8. PMID 2651160.  
  • Westermark P, Wernstedt C, Wilander E, 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 (11): 3881–5. doi:10.1073/pnas.84.11.3881. PMID 3035556.  
  • Sanke T, Bell GI, Sample C, et al. (1988). "An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing". J. Biol. Chem. 263 (33): 17243–6. PMID 3053705.  
  • Mosselman S, Höppener JW, Zandberg J, et al. (1988). "Islet amyloid polypeptide: identification and chromosomal localization of the human gene". FEBS Lett. 239 (2): 227–32. doi:10.1016/0014-5793(88)80922-0. PMID 3181427.  
  • Cooper GJ, Willis AC, Clark A, et al. (1988). "Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients". Proc. Natl. Acad. Sci. U.S.A. 84 (23): 8628–32. doi:10.1073/pnas.84.23.8628. PMID 3317417.  
  • 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 (3): 827–31. doi:10.1016/0006-291X(86)90708-4. PMID 3535798.  
  • Höppener JW, Verbeek JS, de Koning EJ, et al. (1994). "Chronic overproduction of islet amyloid polypeptide/amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia". Diabetologia 36 (12): 1258–65. doi:10.1007/BF00400803. PMID 8307253.  
  • Lim YA, Ittner LM, Lim YL, Götz J. (2008). "Human but not rat amylin shares neurotoxic properties with Abeta42 in long-term hippocampal and cortical cultures.". FEBS Lett 582 (15): 2188–2194. doi:10.1016/j.febslet.2008.05.006. PMID 18486611.  

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