Amylin
![](https://upload.wikimedia.org/wikipedia/commons/thumb/f/fc/Amylin_primary_structure.png/250px-Amylin_primary_structure.png)
Amylin,orislet amyloid polypeptide(IAPP), is a 37-residuepeptide hormone.[5]It is co-secreted withinsulinfrom the pancreaticβ-cellsin the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role inglycemic regulationby slowing gastric emptying and promoting satiety, thereby preventingpost-prandialspikes in blood glucose levels.
IAPP is processed from an 89-residuecoding sequence.Proislet amyloid polypeptide(proIAPP, proamylin, proislet protein) is produced in the pancreaticbeta cells(β-cells) as a 67 amino acid, 7404 Dalton pro-peptide and undergoespost-translational modificationsincluding protease cleavage to produce amylin.[6]
Synthesis
[edit]ProIAPP consists of 67amino acids,which follow a 22 amino acidsignal peptidewhich is rapidly cleaved after translation of the 89 amino acid coding sequence. The human sequence (fromN-terminustoC-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, adisulfidebond is formed betweencysteineresidues numbers 2 and 7.[8]Later in the secretory pathway, the precursor undergoes additionalproteolysisandposttranslational modification(indicated by^).11 amino acids are removed from the N-terminus by the enzymeproprotein 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-terminusCarboxypeptidase Ethen removes the terminallysineandarginineresidues.[10]The terminalglycineamino acid that results from this cleavage allows the enzymepeptidylglycine Alpha -amidating monooxygenase(PAM) to add anaminegroup. After this the transformation from the precursor protein proIAPP to the biologically active IAPP is complete (IAPP sequence: KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY).[6]
Regulation
[edit]Insofar as both IAPP and insulin are produced by the pancreaticβ-cells,impaired β-cell function (due tolipotoxicityand glucotoxicity) will affect both insulin and IAPP production and release.[11]
Insulin and IAPP are regulated by similar factors since they share a common regulatorypromotermotif.[12]The IAPP promoter is also activated by stimuli which do not affect insulin, such astumor necrosis factor Alpha[13]andfatty acids.[14]One of the defining features ofType 2 diabetesisinsulin resistance.This is a condition wherein the body is unable to utilize insulin effectively, resulting in increased insulin production; sinceproinsulinand 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. Thusblood glucoselevels play an important role in regulation of proIAPP synthesis.
Function
[edit]Amylin functions as part of theendocrinepancreasand contributes toglycemic 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 toinsulin,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 hormoneglucagon.These actions, which are mostly carried out via a glucose-sensitive part of the brain stem, thearea 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 peptidescalcitoninandcalcitonin gene related peptide.[15]
Rodent amylinknockoutsdo not have a normalreduction of appetitefollowing food consumption.[citation needed]Because it is an amidated peptide, like manyneuropeptides,it is believed to be responsible for the effect on appetite.
Structure
[edit]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 amyloidfibrilsin vitro.Within the fibrillization reaction, the early prefibrillar structures are extremely toxic to beta-cell and insuloma cell cultures.[8]Lateramyloidfiber 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 fibrilsin vitro.[21][22]Rat IAPP is nontoxic to beta-cells when overexpressed in transgenic rodents.
History
[edit]Before amylin deposition was associated withdiabetes,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 aninsulin-producing tumorwas successful, a protein called IAP (InsulinomaAmyloidPeptide) was characterized, andamyloidswere 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
[edit]ProIAPP has been linked to Type 2 diabetes and the loss of islet β-cells.[28]Isletamyloidformation, 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-inducedapoptosisof 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 thesecretory 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 thenucleusupon 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.
![](https://upload.wikimedia.org/wikipedia/commons/thumb/e/ec/Amyloid_Formation.jpg/220px-Amyloid_Formation.jpg)
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 thepancreasin 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 inpancreatic isletsof patients sufferingdiabetes mellitus type 2,or containing aninsulinomacancer. 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 relatedbeta-amyloid(Abeta) associated withAlzheimer's disease,can induceapoptotic cell-deathininsulin-producingbeta 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 withleptinand 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 ofmetreleptinin 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 withbeta-amyloid(Abeta), suggesting that type 2 diabetes and Alzheimer's disease share common toxicity mechanisms.[34]
Pharmacology
[edit]A synthetic analog of human amylin with proline substitutions in positions 25, 26 and 29, or pramlintide (brand nameSymlin), was approved in 2005 for adult use in patients with bothdiabetes mellitus type 1anddiabetes 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 byinsulin-degrading enzyme.[36][37]Another long- acting analogue of Amylin isCagrilintidebeing developed by Novo Nordisk ( now in the Phase 3 trials with the proposed brand nameCagriSemaco- formulated with Semaglutide as a once weekly subcutaneous injection ) as a measure to treat type II DM and obesity.
Receptors
[edit]There appear to be at least three distinct receptor complexes thatamylinbinds to with high affinity. All three complexes contain thecalcitonin receptorat the core, plus one of threereceptor activity-modifying proteins,RAMP1,RAMP2,orRAMP3.[38]
See also
[edit]- carboxypeptidase E
- Pancreatic islets
- peptidylglycine Alpha -amidating monooxygenase (PAM)
- Pramlintide
- proprotein convertase 1/3 (PC1/3)
- proprotein convertase 2(PC2)
- Type II Diabetes
References
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- ^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.PMID20186753.S2CID33077667.
- ^"SYMLIN (pramlintide acetate)".Amylin Pharmaceuticals, Inc. 2006.Archivedfrom the original on 13 June 2008.Retrieved2008-05-28.
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Further reading
[edit]- Westermark P, Andersson A, Westermark GT (June 2005). "Is aggregated IAPP a cause of beta-cell failure in transplanted human pancreatic islets?".Current Diabetes Reports.5(3): 184–188.doi:10.1007/s11892-005-0007-2.PMID15929864.S2CID24682226.
- Höppener JW, Oosterwijk C, Visser-Vernooy HJ, Lips CJ, Jansz HS (December 1992). "Characterization of the human islet amyloid polypeptide/amylin gene transcripts: identification of a new polyadenylation site".Biochemical and Biophysical Research Communications.189(3): 1569–1577.doi:10.1016/0006-291X(92)90255-J.PMID1282806.
- Hubbard JA, Martin SR, Chaplin LC, Bose C, Kelly SM, Price NC (May 1991)."Solution structures of calcitonin-gene-related-peptide analogues of calcitonin-gene-related peptide and amylin".The Biochemical Journal.275 ( Pt 3) (Pt 3): 785–788.doi:10.1042/bj2750785.PMC1150122.PMID2039456.
- Butler PC, Chou J, Carter WB, Wang YN, Bu BH, Chang D, et al. (June 1990). "Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans".Diabetes.39(6): 752–756.doi:10.2337/diabetes.39.6.752.PMID2189768.
- van Mansfeld AD, Mosselman S, Höppener JW, Zandberg J, van Teeffelen HA, Baas PD, et al. (October 1990). "Islet amyloid polypeptide: structure and upstream sequences of the IAPP gene in rat and man".Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression.1087(2): 235–240.doi:10.1016/0167-4781(90)90210-S.PMID2223885.
- Christmanson L, Rorsman F, Stenman G, Westermark P, Betsholtz C (July 1990)."The human islet amyloid polypeptide (IAPP) gene. Organization, chromosomal localization and functional identification of a promoter region".FEBS Letters.267(1): 160–166.doi:10.1016/0014-5793(90)80314-9.PMID2365085.S2CID41096586.
- Clark A, Edwards CA, Ostle LR, Sutton R, Rothbard JB, Morris JF, Turner RC (July 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 and Tissue Research.257(1): 179–185.doi:10.1007/BF00221649.PMID2546670.S2CID22046812.
- Nishi M, Sanke T, Seino S, Eddy RL, Fan YS, Byers MG, et al. (November 1989)."Human islet amyloid polypeptide gene: complete nucleotide sequence, chromosomal localization, and evolutionary history".Molecular Endocrinology.3(11): 1775–1781.doi:10.1210/mend-3-11-1775.PMID2608057.
- Mosselman S, Höppener JW, Lips CJ, Jansz HS (April 1989)."The complete islet amyloid polypeptide precursor is encoded by two exons".FEBS Letters.247(1): 154–158.doi:10.1016/0014-5793(89)81260-8.PMID2651160.S2CID45121588.
- 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.PMC304980.PMID3035556.
- Mosselman S, Höppener JW, Zandberg J, van Mansfeld AD, Geurts van Kessel AH, Lips CJ, Jansz HS (November 1988)."Islet amyloid polypeptide: identification and chromosomal localization of the human gene".FEBS Letters.239(2): 227–232.doi:10.1016/0014-5793(88)80922-0.hdl:1874/23977.PMID3181427.S2CID26985644.
- 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.PMC299599.PMID3317417.
- 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.PMID3535798.
- Höppener JW, Verbeek JS, de Koning EJ, Oosterwijk C, van Hulst KL, Visser-Vernooy HJ, et al. (December 1993)."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): 1258–1265.doi:10.1007/BF00400803.PMID8307253.
- Lim YA, Ittner LM, Lim YL, Götz J (June 2008). "Human but not rat amylin shares neurotoxic properties with Abeta42 in long-term hippocampal and cortical cultures".FEBS Letters.582(15): 2188–2194.doi:10.1016/j.febslet.2008.05.006.PMID18486611.S2CID6201956.
External links
[edit]- amylinat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- "Amylin Nucleation Site".PDB Entry 1KUW.RCSB Protein Data Bank.doi:10.2210/pdb1kuw/pdb.Archivedfrom the original on 16 April 2008.Retrieved2008-05-28.
- HumanDAPgenome location andDAPgene details page in theUCSC Genome Browser.
- HumanIAPPgenome location andIAPPgene details page in theUCSC Genome Browser.