Amylin

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File:Amylin primary structure.png

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 100:1 ratio).

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, a direct causative role for amylin has been harder to establish. Recent results suggest that amylin, like the related beta-amyloid (Abeta) assosciated with Alzheimer's disease, can induce apoptotic cell-death in particular cultured cells, an effect that may be relevant to the development of type 2 diabetes.

Function

Amylin functions as part of the endocrine pancreas and contributes to glycemic control. Amylin's metabolic function is now somewhat well characterized as an inhibitor of the appearance of nutrient [especially glucose] in the plasma. 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.

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. The peptide is secreted from the pancreas into the blood circulation and eventually excreted by the kidneys. 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. Later amyloid fibril structures also seem to have some cytotoxic effect on cell cultures. 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 unique since it is the only non fibril forming IAPP form. 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.. It was also demonstrated by solid-state NMR spectroscopy that the fragment 20-29 of the humar-amylin fragments membranes.

History and Nomenclature

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

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.

Amylin is degraded in part by insulin-degrading enzyme.

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.

Further reading

• Pittner RA, Albrandt K, Beaumont K; et al. (1994). "Molecular physiology of amylin". J. Cell. Biochem. 55 Suppl: 19–28. PMID 7929615.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Hayden MR (2002). "Islet amyloid, metabolic syndrome, and the natural progressive history of type 2 diabetes mellitus". JOP. 3 (5): 126–38. PMID 12221327.
• 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. PMID 15929864.CS1 maint: Multiple names: authors list (link)
• 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. PMID 1282806.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 2189768.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 2365085.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 2546670.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 2608057.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 2651160.CS1 maint: Multiple names: authors list (link)
• 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. PMID 2690069.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 3035556.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 3181427.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 3317417.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 3535798.CS1 maint: Multiple names: authors list (link)
• 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.CS1 maint: Multiple names: authors list (link)
• 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. PMID 8307253.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMID 18486611.CS1 maint: Multiple names: authors list (link)

External links

• amylin at the US National Library of Medicine Medical Subject Headings (MeSH)
• "Amylin Nucleation Site". PDB entry 1KUW. RCSB Protein Data Bank. Retrieved 2008-05-28.

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