Biology:Amylin

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Short description: Peptide hormone that plays a role in glycemic regulation


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
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.[1] 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.[2]

Synthesis

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.[2][3] 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.[4] 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).[5] At the C-terminus Carboxypeptidase E then removes the terminal lysine and arginine residues.[6] 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).[2]

Regulation

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.[7]

Insulin and IAPP are regulated by similar factors since they share a common regulatory promoter motif.[8] The IAPP promoter is also activated by stimuli which do not affect insulin, such as tumor necrosis factor alpha[9] and fatty acids.[10] 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

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.[11] 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.[12]

Amylin also acts in bone metabolism, along with the related peptides calcitonin and calcitonin gene related peptide.[11]

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

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.[4] 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.[4] 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.[13][14][15] It was also demonstrated by solid-state NMR spectroscopy that the fragment 20-29 of the human-amylin fragments membranes.[16] 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.[17][18] Rat IAPP is nontoxic to beta-cells when overexpressed in transgenic rodents.

History

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.[19][20] 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.[21] This was achieved only a year later by two research teams whose research was a continuation of the work from 1986.[22][23]

Clinical significance

ProIAPP has been linked to Type 2 diabetes and the loss of islet β-cells.[24] 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.[25] 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.[25] 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.[6] 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.[26]

The amyloid formation might be a major mediator of apoptosis, or programmed cell death, in the islet β-cells.[26] 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.[25] 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.[27]

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.[28] 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.[29] 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.[30]

Pharmacology

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.[31]

Amylin is degraded in part by insulin-degrading enzyme.[32][33] Another long- acting analogue of Amylin is Cagrilintide being developed by Novo Nordisk ( now in the Phase 2 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

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.[34]

See also

References

  1. ↑ "Entrez Gene: IAPP islet amyloid polypeptide". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3375. 
  2. ↑ 2.0 2.1 2.2 "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. August 2000. doi:10.1046/j.1432-1327.2000.01548.x. PMID 10931181. 
  3. ↑ "islet amyloid polypeptide precursor [Homo sapiens"]. NCBI. https://www.ncbi.nlm.nih.gov/protein/NP_000406.1.  (the current NCBI RefSeq)
  4. ↑ 4.0 4.1 4.2 "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. December 1989. doi:10.1073/pnas.86.24.9662. PMID 2690069. Bibcode: 1989PNAS...86.9662R. 
  5. ↑ "An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing". The Journal of Biological Chemistry 263 (33): 17243–17246. November 1988. doi:10.1016/S0021-9258(19)77825-9. PMID 3053705. 
  6. ↑ 6.0 6.1 "Role of carboxypeptidase E in processing of pro-islet amyloid polypeptide in {beta}-cells". Endocrinology 146 (4): 1808–1817. April 2005. doi:10.1210/en.2004-1175. PMID 15618358. 
  7. ↑ "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. April 2009. doi:10.2337/db09-9028. PMID 19336687. 
  8. ↑ "Islet amyloid and type 2 diabetes mellitus". The New England Journal of Medicine 343 (6): 411–419. August 2000. doi:10.1056/NEJM200008103430607. PMID 10933741. 
  9. ↑ "TNF-α acutely upregulates amylin expression in murine pancreatic beta cells". Diabetologia 54 (3): 617–626. March 2011. doi:10.1007/s00125-010-1972-9. PMID 21116608. 
  10. ↑ "Fatty acids induce amylin expression and secretion by pancreatic beta-cells". American Journal of Physiology. Endocrinology and Metabolism 298 (1): E99–E107. January 2010. doi:10.1152/ajpendo.00242.2009. PMID 19843871. 
  11. ↑ 11.0 11.1 "Molecular physiology of amylin". Journal of Cellular Biochemistry 55 (Suppl): 19–28. 1994. doi:10.1002/jcb.240550004. PMID 7929615. 
  12. ↑ "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. November 2004. doi:10.1111/j.1464-5491.2004.01319.x. PMID 15498087. 
  13. ↑ "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. May 2008. doi:10.1021/ja710484d. PMID 18444645. 
  14. ↑ "A single mutation in the nonamyloidogenic region of islet amyloid polypeptide greatly reduces toxicity". Biochemistry 47 (48): 12680–12688. December 2008. doi:10.1021/bi801427c. PMID 18989933. 
  15. ↑ "Structures of rat and human islet amyloid polypeptide IAPP(1-19) in micelles by NMR spectroscopy". Biochemistry 47 (48): 12689–12697. December 2008. doi:10.1021/bi8014357. PMID 18989932. 
  16. ↑ "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. September 2007. doi:10.1016/j.bbamem.2007.07.001. PMID 17662957. 
  17. ↑ "Stepwise oligomerization of murine amylin and assembly of amyloid fibrils". Biophysical Chemistry 180-181: 135–144. 2013. doi:10.1016/j.bpc.2013.07.013. PMID 23974296. 
  18. ↑ "Regulation of the assembly and amyloid aggregation of murine amylin by zinc". Biophysical Chemistry 218: 58–70. November 2016. doi:10.1016/j.bpc.2016.09.008. PMID 27693831. 
  19. ↑ "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. January 1901. doi:10.1084/jem.5.4.397. PMID 19866952. 
  20. ↑ "Beiträge zur Kenntnis des Feineren Baues der Schilddrüse der Neunaugenlarven". Zeitschrift für Zellforschung und Mikroskopische Anatomie 15 (1): 1–35. March 1932. doi:10.1007/978-3-662-29315-7. ISBN 978-3-662-27815-4. 
  21. ↑ "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. November 1986. doi:10.1016/0006-291x(86)90708-4. PMID 3535798. 
  22. ↑ "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. December 1987. doi:10.1073/pnas.84.23.8628. PMID 3317417. Bibcode: 1987PNAS...84.8628C. 
  23. ↑ "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. June 1987. doi:10.1073/pnas.84.11.3881. PMID 3035556. Bibcode: 1987PNAS...84.3881W. 
  24. ↑ "Aberrant processing of human proislet amyloid polypeptide results in increased amyloid formation". Diabetes 54 (7): 2117–2125. July 2005. doi:10.2337/diabetes.54.7.2117. PMID 15983213. 
  25. ↑ 25.0 25.1 25.2 "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. August 2006. doi:10.2337/db05-1566. PMID 16873681. 
  26. ↑ 26.0 26.1 "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. June 2006. doi:10.1007/s00125-006-0206-7. PMID 16570161. 
  27. ↑ "Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus". Nature 368 (6473): 756–760. April 1994. doi:10.1038/368756a0. PMID 8152488. Bibcode: 1994Natur.368..756L. 
  28. ↑ "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. May 2008. doi:10.1073/pnas.0706473105. PMID 18458326. Bibcode: 2008PNAS..105.7257R. 
  29. ↑ {{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}}
  30. ↑ "Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction". Proteomics 10 (8): 1621–1633. April 2010. doi:10.1002/pmic.200900651. PMID 20186753. 
  31. ↑ "SYMLIN (pramlintide acetate)". Amylin Pharmaceuticals, Inc.. 2006. http://www.amylin.com/pipeline/symlin.cfm/. 
  32. ↑ "Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism". Nature 443 (7113): 870–874. October 2006. doi:10.1038/nature05143. PMID 17051221. Bibcode: 2006Natur.443..870S. 
  33. ↑ "Role of Amylin in Obesity". Journal of PharmaSciTech 5: 5–10. July 2015. http://www.pharmascitech.in/abstract.php?article_id=93. 
  34. ↑ "Amylin receptors: molecular composition and pharmacology". Biochemical Society Transactions 32 (Pt 5): 865–867. November 2004. doi:10.1042/BST0320865. PMID 15494035. 

Further reading

External links



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