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Amylin

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This article is about the polypeptide. For the defunct biotechnology company, see Amylin Pharmaceuticals.
IAPP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIAPP, DAP, IAP, islet amyloid polypeptide
External IDsOMIM: 147940; MGI: 96382; HomoloGene: 36024; GeneCards: IAPP; OMA:IAPP - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3375

15874

Ensembl

ENSG00000121351

ENSMUSG00000041681

UniProt

P10997

P12968

RefSeq (mRNA)

NM_000415
NM_001329201

NM_010491

RefSeq (protein)

NP_000406
NP_001316130

NP_034621

Location (UCSC)Chr 12: 21.35 – 21.38 MbChr 6: 142.24 – 142.25 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
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.[5] It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

IAPP is processed from an 89-residue coding sequence. Proislet amyloid polypeptide (proIAPP, proamylin, proislet protein) is produced in the pancreatic beta cells (β-cells) as a 67 amino acid, 7404 Dalton pro-peptide and undergoes post-translational modifications including protease cleavage to produce amylin.[6]

Synthesis

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ProIAPP consists of 67 amino acids, which follow a 22 amino acid signal peptide which is rapidly cleaved after translation of the 89 amino acid coding sequence. The human sequence (from N-terminus to C-terminus) is:

(MGILKLQVFLIVLSVALNHLKA) TPIESHQVEKR^ KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTYG^ KR^ NAVEVLKREPLNYLPL.[6][7] The signal peptide is removed during translation of the protein and transport into the endoplasmic reticulum. Once inside the endoplasmic reticulum, a disulfide bond is formed between cysteine residues numbers 2 and 7.[8] Later in the secretory pathway, the precursor undergoes additional proteolysis and posttranslational modification (indicated by ^). 11 amino acids are removed from the N-terminus by the enzyme proprotein convertase 2 (PC2) while 16 are removed from the C-terminus of the proIAPP molecule by proprotein convertase 1/3 (PC1/3).[9] At the C-terminus Carboxypeptidase E then removes the terminal lysine and arginine residues.[10] The terminal glycine amino acid that results from this cleavage allows the enzyme peptidylglycine alpha-amidating monooxygenase (PAM) to add an amine group. After this the transformation from the precursor protein proIAPP to the biologically active IAPP is complete (IAPP sequence: KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY).[6]

Regulation

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Insofar as both IAPP and insulin are produced by the pancreatic β-cells, impaired β-cell function (due to lipotoxicity and glucotoxicity) will affect both insulin and IAPP production and release.[11]

Insulin and IAPP are regulated by similar factors since they share a common regulatory promoter motif.[12] The IAPP promoter is also activated by stimuli which do not affect insulin, such as tumor necrosis factor alpha[13] and fatty acids.[14] One of the defining features of Type 2 diabetes is insulin resistance. This is a condition wherein the body is unable to utilize insulin effectively, resulting in increased insulin production; since proinsulin and proIAPP are cosecreted, this results in an increase in the production of proIAPP as well. Although little is known about IAPP regulation, its connection to insulin indicates that regulatory mechanisms that affect insulin also affect IAPP. Thus blood glucose levels play an important role in regulation of proIAPP synthesis.

Function

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Amylin functions as part of the endocrine pancreas and contributes to glycemic control. The peptide is secreted from the pancreatic islets into the blood circulation and is cleared by peptidases in the kidney. It is not found in the urine.

Amylin's metabolic function is well-characterized as an inhibitor of the appearance of nutrient [especially glucose] in the plasma.[15] 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 is to slow the rate of appearance (Ra) of glucose in the blood after eating; this is accomplished via coordinate slowing down gastric emptying, inhibition of digestive secretion [gastric acid, pancreatic enzymes, and bile ejection], and a resulting reduction in food intake. Appearance of new glucose in the blood is reduced by inhibiting secretion of the gluconeogenic hormone glucagon. These actions, which are mostly carried out 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.[16]

Amylin also acts in bone metabolism, along with the related peptides calcitonin and calcitonin gene related peptide.[15]

Rodent amylin knockouts do not have a normal reduction of appetite following food consumption.[citation needed] Because it is an amidated peptide, like many neuropeptides, it is believed to be responsible for the effect on appetite.

Structure

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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.[8] 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.[8] 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.[17][18][19] It was also demonstrated by solid-state NMR spectroscopy that the fragment 20-29 of the human-amylin fragments membranes.[20] Rats and mice have six substitutions (three of which are proline substitutions at positions 25, 28 and 29) that are believed to prevent the formation of amyloid fibrils, although not completely as seen by its propensity to form amyloid fibrils in vitro.[21][22] Rat IAPP is nontoxic to beta-cells when overexpressed in transgenic rodents.

History

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Before amylin deposition was associated with diabetes, already in 1901, scientists described the phenomenon of "islet hyalinization", which could be found in some cases of diabetes.[23][24] A thorough study of this phenomenon was possible much later. In 1986, the isolation of an aggregate from an insulin-producing tumor was successful, a protein called IAP (Insulinoma Amyloid Peptide) was characterized, and amyloids were isolated from the pancreas of a diabetic patient, but the isolated material was not sufficient for full characterization.[25] This was achieved only a year later by two research teams whose research was a continuation of the work from 1986.[26][27]

Clinical significance

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ProIAPP has been linked to Type 2 diabetes and the loss of islet β-cells.[28] Islet amyloid formation, initiated by the aggregation of proIAPP, may contribute to this progressive loss of islet β-cells. It is thought that proIAPP forms the first granules that allow for IAPP to aggregate and form amyloid which may lead to amyloid-induced apoptosis of β-cells.

IAPP is cosecreted with insulin. Insulin resistance in Type 2 diabetes produces a greater demand for insulin production which results in the secretion of proinsulin.[29] ProIAPP is secreted simultaneously, however, the enzymes that convert these precursor molecules into insulin and IAPP, respectively, are not able to keep up with the high levels of secretion, ultimately leading to the accumulation of proIAPP.

In particular, the impaired processing of proIAPP that occurs at the N-terminal cleavage site is a key factor in the initiation of amyloid.[29] Post-translational modification of proIAPP occurs at both the carboxy terminus and the amino terminus, however, the processing of the amino terminus occurs later in the secretory pathway. This might be one reason why it is more susceptible to impaired processing under conditions where secretion is in high demand.[10] Thus, the conditions of Type 2 diabetes—high glucose concentrations and increased secretory demand for insulin and IAPP—could lead to the impaired N-terminal processing of proIAPP. The unprocessed proIAPP can then serve as the nucleus upon which IAPP can accumulate and form amyloid.[30]

The amyloid formation might be a major mediator of apoptosis, or programmed cell death, in the islet β-cells.[30] Initially, the proIAPP aggregates within secretory vesicles inside the cell. The proIAPP acts as a seed, collecting matured IAPP within the vesicles, forming intracellular amyloid. When the vesicles are released, the amyloid grows as it collects even more IAPP outside the cell. The overall effect is an apoptosis cascade initiated by the influx of ions into the β-cells.

General Scheme for Amyloid Formation

In summary, impaired N-terminal processing of proIAPP is an important factor initiating amyloid formation and β-cell death. These amyloid deposits are pathological characteristics of the pancreas in Type 2 diabetes. However, it is still unclear as to whether amyloid formation is involved in or merely a consequence of type 2 diabetes.[29] Nevertheless, it is clear that amyloid formation reduces working β-cells in patients with Type 2 diabetes. This suggests that repairing proIAPP processing may help to prevent β-cell death, thereby offering hope as a potential therapeutic approach for Type 2 diabetes.

Amyloid deposits deriving from islet amyloid polypeptide (IAPP, or amylin) are commonly found in pancreatic islets of patients suffering diabetes mellitus type 2, or containing an insulinoma cancer. While the association of amylin with the development of type 2 diabetes has been known for some time,[citation needed] its direct role as the cause has been harder to establish. Some studies 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.[31]

A 2008 study reported a synergistic effect for weight loss with leptin and amylin coadministration in diet-induced obese rats by restoring hypothalamic sensitivity to leptin.[32] However, in clinical trials, the study was halted at Phase 2 in 2011 when a problem involving antibody activity that might have neutralized the weight-loss effect of metreleptin in two patients who took the drug in a previously completed clinical study. The study combined metreleptin, a version of the human hormone leptin, and pramlintide, which is Amylin's diabetes drug Symlin, into a single obesity therapy.[33] A proteomics study showed that human amylin shares common toxicity targets with beta-amyloid (Abeta), suggesting that type 2 diabetes and Alzheimer's disease share common toxicity mechanisms.[34]

Pharmacology

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A synthetic analog of human amylin with proline substitutions in positions 25, 26 and 29, or pramlintide (brand name Symlin), was approved in 2005 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.[35]

Amylin is degraded in part by insulin-degrading enzyme.[36][37] Another long- acting analogue of Amylin is Cagrilintide being developed by Novo Nordisk ( now in the Phase 3 trials with the proposed brand name CagriSema co- formulated with Semaglutide as a once weekly subcutaneous injection ) as a measure to treat type II DM and obesity.

Receptors

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There appear to be at least three distinct receptor complexes that amylin binds to with high affinity. All three complexes contain the calcitonin receptor at the core, plus one of three receptor activity-modifying proteins, RAMP1, RAMP2, or RAMP3.[38]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000121351 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000041681 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: IAPP islet amyloid polypeptide".
  6. ^ a b c Higham CE, Hull RL, Lawrie L, Shennan KI, Morris JF, Birch NP, et al. (August 2000). "Processing of synthetic pro-islet amyloid polypeptide (proIAPP) 'amylin' by recombinant prohormone convertase enzymes, PC2 and PC3, in vitro". European Journal of Biochemistry. 267 (16): 4998–5004. doi:10.1046/j.1432-1327.2000.01548.x. PMID 10931181.
  7. ^ "islet amyloid polypeptide precursor [Homo sapiens]". NCBI. (the current NCBI RefSeq)
  8. ^ a b c Roberts AN, Leighton B, Todd JA, Cockburn D, Schofield PN, Sutton R, et al. (December 1989). "Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus". Proceedings of the National Academy of Sciences of the United States of America. 86 (24): 9662–9666. Bibcode:1989PNAS...86.9662R. doi:10.1073/pnas.86.24.9662. PMC 298561. PMID 2690069.
  9. ^ Sanke T, Bell GI, Sample C, Rubenstein AH, Steiner DF (November 1988). "An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing". The Journal of Biological Chemistry. 263 (33): 17243–17246. doi:10.1016/S0021-9258(19)77825-9. PMID 3053705.
  10. ^ a b Marzban L, Soukhatcheva G, Verchere CB (April 2005). "Role of carboxypeptidase E in processing of pro-islet amyloid polypeptide in {beta}-cells". Endocrinology. 146 (4): 1808–1817. doi:10.1210/en.2004-1175. PMID 15618358.
  11. ^ Defronzo RA (April 2009). "Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus". Diabetes. 58 (4): 773–795. doi:10.2337/db09-9028. PMC 2661582. PMID 19336687.
  12. ^ Höppener JW, Ahrén B, Lips CJ (August 2000). "Islet amyloid and type 2 diabetes mellitus". The New England Journal of Medicine. 343 (6): 411–419. doi:10.1056/NEJM200008103430607. PMID 10933741.
  13. ^ Cai K, Qi D, Wang O, Chen J, Liu X, Deng B, et al. (March 2011). "TNF-α acutely upregulates amylin expression in murine pancreatic beta cells". Diabetologia. 54 (3): 617–626. doi:10.1007/s00125-010-1972-9. PMID 21116608.
  14. ^ Qi D, Cai K, Wang O, Li Z, Chen J, Deng B, et al. (January 2010). "Fatty acids induce amylin expression and secretion by pancreatic beta-cells". American Journal of Physiology. Endocrinology and Metabolism. 298 (1): E99–E107. doi:10.1152/ajpendo.00242.2009. PMID 19843871.
  15. ^ a b Pittner RA, Albrandt K, Beaumont K, Gaeta LS, Koda JE, Moore CX, et al. (1994). "Molecular physiology of amylin". Journal of Cellular Biochemistry. 55 (Suppl): 19–28. doi:10.1002/jcb.240550004. PMID 7929615. S2CID 35842871.
  16. ^ Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, et al. (November 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". Diabetic Medicine. 21 (11): 1204–1212. doi:10.1111/j.1464-5491.2004.01319.x. PMID 15498087. S2CID 23236294.
  17. ^ 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". Journal of the American Chemical Society. 130 (20): 6424–6429. doi:10.1021/ja710484d. PMC 4163023. PMID 18444645.
  18. ^ Brender JR, Hartman K, Reid KR, Kennedy RT, Ramamoorthy A (December 2008). "A single mutation in the nonamyloidogenic region of islet amyloid polypeptide greatly reduces toxicity". Biochemistry. 47 (48): 12680–12688. doi:10.1021/bi801427c. PMC 2645932. PMID 18989933.
  19. ^ Nanga RP, Brender JR, Xu J, Veglia G, Ramamoorthy A (December 2008). "Structures of rat and human islet amyloid polypeptide IAPP(1-19) in micelles by NMR spectroscopy". Biochemistry. 47 (48): 12689–12697. doi:10.1021/bi8014357. PMC 2953382. PMID 18989932.
  20. ^ 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". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1768 (9): 2026–2029. doi:10.1016/j.bbamem.2007.07.001. PMC 2042489. PMID 17662957.
  21. ^ Palmieri LC, Melo-Ferreira B, Braga CA, Fontes GN, Mattos LJ, Lima LM (2013). "Stepwise oligomerization of murine amylin and assembly of amyloid fibrils". Biophysical Chemistry. 180–181: 135–144. doi:10.1016/j.bpc.2013.07.013. PMID 23974296.
  22. ^ Erthal LC, Marques AF, Almeida FC, Melo GL, Carvalho CM, Palmieri LC, et al. (November 2016). "Regulation of the assembly and amyloid aggregation of murine amylin by zinc". Biophysical Chemistry. 218: 58–70. doi:10.1016/j.bpc.2016.09.008. PMID 27693831.
  23. ^ Opie EL (January 1901). "On the Relation of Chronic Interstitial Pancreatitis to the Islands of Langerhans and to Diabetes Melutus". The Journal of Experimental Medicine. 5 (4): 397–428. doi:10.1084/jem.5.4.397. PMC 2118050. PMID 19866952.
  24. ^ Hensel H (March 1932). "Beiträge zur Kenntnis des Feineren Baues der Schilddrüse der Neunaugenlarven". Zeitschrift für Zellforschung und Mikroskopische Anatomie. 15 (1): 1–35. doi:10.1007/978-3-662-29315-7. ISBN 978-3-662-27815-4.
  25. ^ Westermark P, Wernstedt C, Wilander E, Sletten K (November 1986). "A novel peptide in the calcitonin gene related peptide family as an amyloid fibril protein in the endocrine pancreas". Biochemical and Biophysical Research Communications. 140 (3): 827–831. doi:10.1016/0006-291x(86)90708-4. PMID 3535798.
  26. ^ Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB (December 1987). "Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients". Proceedings of the National Academy of Sciences of the United States of America. 84 (23): 8628–8632. Bibcode:1987PNAS...84.8628C. doi:10.1073/pnas.84.23.8628. PMC 299599. PMID 3317417.
  27. ^ Westermark P, Wernstedt C, Wilander E, Hayden DW, O'Brien TD, Johnson KH (June 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". Proceedings of the National Academy of Sciences of the United States of America. 84 (11): 3881–3885. Bibcode:1987PNAS...84.3881W. doi:10.1073/pnas.84.11.3881. PMC 304980. PMID 3035556.
  28. ^ Paulsson JF, Westermark GT (July 2005). "Aberrant processing of human proislet amyloid polypeptide results in increased amyloid formation". Diabetes. 54 (7): 2117–2125. doi:10.2337/diabetes.54.7.2117. PMID 15983213.
  29. ^ a b c Marzban L, Rhodes CJ, Steiner DF, Haataja L, Halban PA, Verchere CB (August 2006). "Impaired NH2-terminal processing of human proislet amyloid polypeptide by the prohormone convertase PC2 leads to amyloid formation and cell death". Diabetes. 55 (8): 2192–2201. doi:10.2337/db05-1566. PMID 16873681.
  30. ^ a b Paulsson JF, Andersson A, Westermark P, Westermark GT (June 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 (6): 1237–1246. doi:10.1007/s00125-006-0206-7. PMID 16570161.
  31. ^ Lorenzo A, Razzaboni B, Weir GC, Yankner BA (April 1994). "Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus". Nature. 368 (6473): 756–760. Bibcode:1994Natur.368..756L. doi:10.1038/368756a0. PMID 8152488. S2CID 4244347.
  32. ^ Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, et al. (May 2008). "Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies". Proceedings of the National Academy of Sciences of the United States of America. 105 (20): 7257–7262. Bibcode:2008PNAS..105.7257R. doi:10.1073/pnas.0706473105. PMC 2438237. PMID 18458326.
  33. ^ {{cite web] |title=Amylin and Takeda halt obesity drug study |url= https://www.pmlive.com/pharma_news/amylin_and_takeda_halt_obesity_drug_study_266050 | work = PMLive |date=17 March 2011}}
  34. ^ Lim YA, Rhein V, Baysang G, Meier F, Poljak A, Raftery MJ, et al. (April 2010). "Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction". Proteomics. 10 (8): 1621–1633. doi:10.1002/pmic.200900651. PMID 20186753. S2CID 33077667.
  35. ^ "SYMLIN (pramlintide acetate)". Amylin Pharmaceuticals, Inc. 2006. Archived from the original on 13 June 2008. Retrieved 2008-05-28.
  36. ^ 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): 870–874. Bibcode:2006Natur.443..870S. doi:10.1038/nature05143. PMC 3366509. PMID 17051221.
  37. ^ Suva MA, Patel AM, Sharma N (July 2015). "Role of Amylin in Obesity". Journal of PharmaSciTech. 5: 5–10 – via Google scholar.
  38. ^ Hay DL, Christopoulos G, Christopoulos A, Sexton PM (November 2004). "Amylin receptors: molecular composition and pharmacology". Biochemical Society Transactions. 32 (Pt 5): 865–867. doi:10.1042/BST0320865. PMID 15494035.

Further reading

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