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Amylin Information

Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue peptide hormone. It is cosecreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1.[1] 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, Amyloid Polypeptide Precursor, 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]

Contents

Structure and Synthesis

Post-translational Modification of proIAPP to form IAPP

ProIAPP consists of 67 amino acids, which follow a 22 amino acid signal peptide (parentheses) 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]

Once released from the signal peptide, it 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).[4] At the C-terminus Carboxypeptidase E then removes the terminal lysine and arginine residues.[5] The terminal glycine amino acid that results from this cleavage allows the enzyme peptidylglycine alpha-amidating monooxygenase (PAM) to add an amine group. Finally, a disulfide bond is formed between cysteine residues numbers 2 and 7.[6] After this the transformation from the precursor protein proIAPP to the biologically active IAPP is complete (IAPP sequence: KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY).[2]

Regulation

Insulin and IAPP are regulated by similar factors since they share a common regulatory promoter motif.[7] The IAPP promoter is also activated by stimuli which do not affect insulin, such as tumor necrosis factor alpha[8] and fatty acids.[9] 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 mechanism 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 now somewhat well characterized as an inhibitor of the appearance of nutrient [especially glucose] in the plasma.[10] 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) of glucose from the meal 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 is slowed down 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.[11]

Amylin also acts in bone metabolism, along with the related peptides calcitonin and calcitonin gene related peptide.[10]

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. Both the amidated C-terminus and the disulfide bridge are necessary for the full biological activity of amylin.[12] 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.[12] 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 substitions at positions 25, 28 and 29) that are believed to prevent the formation of amyloid fibrils. Rat IAPP is nontoxic to beta-cells, even when overexpressed.

History and Nomenclature

IAPP was identified independently by two groups as the major component of diabetes-associated islet amyloid deposits in 1987.[17][18]

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.

Role in Disease

ProIAPP has been linked to Type 2 diabetes and the loss of islet β-cells.[19] 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.[20] 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.[20] 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.[5] 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 granule upon which IAPP can accumulate and form amyloid.[21]

The amyloid formation might be a major mediator of apoptosis, or programmed cell death, in the islet β-cells.[21] Initially, the proIAPP aggregates inside the cell. The proIAPP acts as a seed, collecting IAPP from neighboring cells and forming an intracellular amyloid. As the amyloid grows, it spreads outside of the cell. The extracellular amyloid begins to excrete IAPP to other cells, inducing similar amyloid formation in other β-cells. 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.[20] 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.

Clinical significance

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,[22] its direct role as the cause has been harder to establish. Recent results 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.[23]

A recent study reported a synergistic effect for weight loss with leptin and amylin coadministration in diet-induced obese rats by restoring hypothalamic sensitivity to leptin.[24] 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.[25] Finally, a recent proteomics study showed that human amylin shares common toxicity targets with beta-amyloid (Abeta), providing evidence that type 2 diabetes and Alzheimer's disease share common toxicity mechanisms.[26]

Pharmacology

A synthetic analog of human amylin with proline substitutions in positions 25, 26 and 29, 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.[27]

Amylin is degraded in part by insulin-degrading enzyme.[28]

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.[29]

See also

References

  1. ^ "Entrez Gene: IAPP islet amyloid polypeptide". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3375.
  2. ^ a b c Higham, C. E., Hull, R. L., Lawrie, L., Shennan, K. I. H., Morris, J. F., Birch, N. P., Dochery, K., & Clark, A. (2000). "Processing of synthetic pro-islet amyloid polypeptide (proIAPP) `amylin' by recombinant prohormone convertase enzymes, PC2 and PC3, in vitro.". European Journal of Biochemistry. pp. 4998–5004. http://content.febsjournal.org/cgi/content/full/267/16/4998.
  3. ^ "islet amyloid polypeptide precursor [Homo sapiens"]. NCBI. http://www.ncbi.nlm.nih.gov/protein/NP_000406.1. (the current NCBI RefSeq)
  4. ^ Sanke,T., Bell, G. I., Sample, C., Rubenstein, A. H., & Steiner, D. F. (1988). "An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing". Journal of Biological Chemistry 263 (33): 17243–17246. http://www.jbc.org/cgi/content/abstract/263/33/17243.
  5. ^ a b Marzban, L., Soukhatcheva, G., & Verchere, C. (2005). "Role of carboxypeptidase E in processing of pro-islet amyloid polypeptide in beta-cells". Endocrinology 146 (4): 1808–1817. http://endo.endojournals.org/cgi/content/full/146/4/1808.
  6. ^ Roberts A. N., Leighton B., Todd J. A., et al. (1989). "Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus". Proceedings of the National Academy of Sciences 86: 9662–9666. doi:10.1073/pnas.86.24.9662. PMC 298561. PMID 2690069. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=298561.
  7. ^ Höppener, Jo, Ahrén, Bo, Lips, Cornelius (2000). "Islet Amyloid and Type 2 Diabetes Mellitus". NEJM 343: 411–419. http://content.nejm.org/cgi/content/full/343/6/411.
  8. ^ Cai K, Qi D, Wang O, et al. (March 2011). "TNF-α acutely upregulates amylin expression in murine pancreatic beta cells". Diabetologia 54 (3): 617–26. doi:10.1007/s00125-010-1972-9. PMID 21116608.
  9. ^ Qi et al. (2010-01). Fatty acids induce amylin expression and secretion by pancreatic β-cells. 298. Am J Physiol Endocrinol Metab.. pp. E99-E107. http://ajpendo.physiology.org/content/298/1/E99.long.
  10. ^ a b Pittner RA, Albrandt K, Beaumont K, et al. (1994). "Molecular physiology of amylin". J. Cell. Biochem. 55 Suppl: 19–28. doi:10.1002/jcb.240550004. PMID 7929615.
  11. ^ 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.
  12. ^ a b 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. doi:10.1073/pnas.86.24.9662. PMC 298561. PMID 2690069. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=298561.
  13. ^ 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.
  14. ^ Brender JR, Hartman K, Reid KR, Kennedy RT, Ramamoorthy A (November 2008). "A Single Mutation in the Non-Amyloidogenic Region of IAPP (Amylin) Greatly Reduces Toxicity". Biochemistry 47 (48): 12680–8. doi:10.1021/bi801427c. PMC 2645932. PMID 18989933. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2645932.
  15. ^ Nanga RP, Brender JR, Xu J, Veglia G, Ramamoorthy A (November 2008). "Structures of Rat and Human Islet Amyloid Polypeptide IAPP1–19 in Micelles by NMR Spectroscopy". Biochemistry 47 (48): 12689–97. doi:10.1021/bi8014357. PMC 2953382. PMID 18989932. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2953382.
  16. ^ 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. PMC 2042489. PMID 17662957. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2042489.
  17. ^ 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. PMC 299599. PMID 3317417. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=299599.
  18. ^ 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. PMC 304980. PMID 3035556. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=304980.
  19. ^ Paulsson, J.R., Westermark, P. (2005). "Aberrant Processing of Human Proislet Amyloid Polypeptide Results in Increased Amyloid Formation". Diabetes 54 (7): 2117–2125. http://diabetes.diabetesjournals.org/cgi/content/full/54/7/2117.
  20. ^ a b c Marzban, L., Rhodes, C., Haataja, L., Halban, P., Verchere, C. (2006). [*"Impaired NH2-Terminal Processing of Human Proislet Amyloid Polypeptide by the Prohormone Covertase PC2 Leads to Amyloid Formation and Cell Death". Diabetes 55 (8): 2192–2201.
  21. ^ a b Paulsson, J. R., Andersson, A., Westermark, P., & Westermark, G. T. (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: 1237–1248. http://www.springerlink.com/content/w824704516157312/fulltext.html.
  22. ^ Hayden MR (2002). "Islet amyloid, metabolic syndrome, and the natural progressive history of type 2 diabetes mellitus". JOP 3 (5): 126–38. PMID 12221327.
  23. ^ 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.
  24. ^ Roth JD and al. (2008). "Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies". PNAS 105 (20): 7257–7262. doi:10.1073/pnas.0706473105. PMC 2438237. PMID 18458326. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2438237.
  25. ^ Darce, Keith. "Amylin halts trial of weight-loss therapy". http://www.utsandiego.com/news/2011/mar/16/amlyn-halts-trial-weight-loss-therapy/.
  26. ^ Lim YA, Rhein V, Baysang G, Meier F, Poljak A, Raftery MJ, Guilhaus M, Ittner LM, Eckert A, Götz J. (2010). "Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction". Proteomics 10 (8): 1621–33. doi:10.1002/pmic.200900651. PMID 20186753.
  27. ^ "SYMLIN (pramlintide acetate)". Amylin Pharmaceuticals, Inc.. 2006. http://www.amylin.com/pipeline/symlin.cfm/. Retrieved 2008-05-28.
  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.
  29. ^ 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

PDB gallery
2g48: crystal structure of human insulin-degrading enzyme in complex with amylin

External links

Metabolic disease: amyloidosis (E85, 277.3)
Common amyloid forming proteins
Systemic amyloidosis
Organ-limited amyloidosis
Heart AANF/Isolated atrial amyloidosis
Brain
Kidney
Cutaneous
Endocrine
Thyroid
ACal/Medullary thyroid cancer
Pituitary
APro/Prolactinoma
Pancreas
AIAPP/Insulinoma
AIAPP/Diabetes mellitus type 2
Endocrine system: hormones (Peptide hormones · Steroid hormones)
Endocrine glands
Hypothalamic- pituitary
Hypothalamus GnRH · TRH · Dopamine · CRH · GHRH/Somatostatin · Melanin concentrating hormone
Posterior pituitary Vasopressin · Oxytocin
Anterior pituitary α (FSH FSHB, LH LHB, TSH TSHB, CGA) · Prolactin · POMC (CLIP, ACTH, MSH, Endorphins, Lipotropin) · GH
Adrenal axis Adrenal cortex: aldosterone · cortisol · DHEA Adrenal medulla: epinephrine · norepinephrine
Thyroid axis Thyroid: thyroid hormone (T3 and T4) · calcitonin Parathyroid: PTH
Gonadal axis

Testis: testosterone · AMH · inhibin

Ovary: estradiol · progesterone · activin and inhibin · relaxin (pregnancy)

Placenta: hCG · HPL · estrogen · progesterone
Islet-Acinar Axis Pancreas: glucagon · insulin · amylin · somatostatin · pancreatic polypeptide
Pineal gland Pineal gland: melatonin
Non-end. glands

Thymus: Thymosin (Thymosin α1, Thymosin beta) · Thymopoietin · Thymulin

Digestive system: Stomach: gastrin · ghrelin · Duodenum: CCK · Incretins (GIP, GLP-1) · secretin · motilin · VIP · Ileum: enteroglucagon · peptide YY · Liver/other: Insulin-like growth factor (IGF-1, IGF-2)

Adipose tissue: leptin · adiponectin · resistin

Skeleton: Osteocalcin

Kidney: JGA (renin) · peritubular cells (EPO) · calcitriol · prostaglandin

Heart: Natriuretic peptide (ANP, BNP)

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Noun

Amylin Wikipedia amylin (uncountable)
  1. (biochemistry) The dextrin of starch
  2. (biochemistry) An amyloid polypeptide
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from: Wiktionary: amylin,
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