Amylin
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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.[1]
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.[2]
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.[3]. It was also demonstrated by solid-state NMR spectroscopy that the fragment 20-29 of the humar-amylin fragments membranes.[4]
History and Nomenclature
IAPP was identified independently by two groups as the major component of diabetes-associated islet amyloid deposits in 1987.[5][6]
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.[citation needed]
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.[7]
Amylin is degraded in part by insulin-degrading enzyme.[8]
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.[9]
References
- ↑ "Entrez Gene: IAPP islet amyloid polypeptide".
- ↑ 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.
- ↑ Brender JR, Lee EL, Cavitt MA, Gafni A, Steel DG, Ramamoorthy A (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. Unknown parameter
|month=ignored (help) - ↑ Brender JR, Dürr UH, Heyl D, Budarapu MB, Ramamoorthy A (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. PMC 2042489. PMID 17662957. Unknown parameter
|month=ignored (help) - ↑ 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.
- ↑ 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.
- ↑ "SYMLIN (pramlintide acetate)". Amylin Pharmaceuticals, Inc. 2006. Retrieved 2008-05-28.
- ↑ Shen Y, Joachimiak A, Rosner MR, Tang WJ (2006). "Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism". Nature. 443 (7113): 870–4. doi:10.1038/nature05143. PMID 17051221. Unknown parameter
|month=ignored (help) - ↑ 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
- Pittner RA, Albrandt K, Beaumont K; et al. (1994). "Molecular physiology of amylin". J. Cell. Biochem. 55 Suppl: 19–28. PMID 7929615.
- 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.
- 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.
- 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. 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. 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. 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. 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. PMID 2651160.
- 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.
- 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.
- 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. 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. 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. PMID 3535798.
- 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.
- 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.
- 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.
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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