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07-SEPTEMBER-2008 03:17:44 - Amylin This article is about the polypeptide. For the biotechnology company, see Amylin Pharmaceuticals. Islet amyloid polypeptide PDB Human IAPP in complex with insulin-degrading enzyme: rendering based on 2g48. Available structures: 2g48 Identifiers Symbols IAPP; IAP; DAP; AMYLIN External IDs OMIM: 147940 MGI: 96382 HomoloGene: 36024 Gene ontology Molecular function: hormone activity Cellular component: extracellular region soluble fraction Biological process: apoptosis signal transduction cell-cell signaling RNA expression pattern More reference expression data Orthologs Human Mouse Entrez 3375 15874 Ensembl ENSG00000121351 ENSMUSG00000041681 Uniprot P10997 P12968 Refseq NM_000415 mRNA NP_000406 protein NM_010491 mRNA NP_034621 protein Location 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 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.1 Contents 1 Function 2 Structure 3 History and Nomenclature 4 Pharmacology 5 Receptors 6 References 7 Further reading 8 External links 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 1987.56 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 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. ^ 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. ^ 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 on 2008-05-28. ^ 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. ^ 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 MeSH amylin Amylin Nucleation Site. PDB entry 1KUW. RCSB Protein Data Bank. Retrieved on 2008-05-28. v d e Metabolic disease: amyloidosis E85, 277.3 Forms of amyloid Serum amyloid P component - Serum amyloid A - Transthyretin - Beta-2 microglobulin - Bence Jones protein/Multiple myeloma - Amyloid precursor protein/Beta amyloid - Amylin Systemic amyloidosis AL amyloidosis - AA amyloidosis - Haemodialysis-associated amyloidosis - Senile systemic amyloidosis - Finnish type amyloidosis - Familial Merranean fever Organ-limited amyloidosis heart: Cardiac amyloidosis brain: Familial amyloid neuropathy - Cerebral amyloid angiopathy - Alzheimer's disease kidney: Familial renal amyloidosis cutaneous: Primary cutaneous amyloidosis Retrieved from http://en..org/wiki/Amylin Categories: Genes on chromosome 12 | Human proteins | Metabolic disorders | Peptide hormones | Diabetes | Endocrine system | Anti-diabetic drugsHidden categories: All articles with statements | Articles with statements since August 2008 Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Italiano Polski Português This page was last modified on 27 August 2008, at 05:3
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