Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. 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.
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. 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. 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). At the C-terminus Carboxypeptidase E then removes the terminal lysine and arginine residues. 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).
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.
Insulin and IAPP are regulated by similar factors since they share a common regulatory promoter motif. The IAPP promoter is also activated by stimuli which do not affect insulin, such as tumor necrosis factor alpha and fatty acids. 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. 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.
Amylin also acts in bone metabolism, along with the related peptides calcitonin and calcitonin gene related peptide.
Rodent amylin knockouts do not have a normal reduction of appetite following food consumption. 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. 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 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. It was also demonstrated by solid-state NMR spectroscopy that the fragment 20-29 of the human-amylin fragments membranes. 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. Rat IAPP is nontoxic to beta-cells when overexpressed in transgenic rodents.
History
IAPP was identified independently by two groups as the major component of diabetes-associated islet amyloid deposits in 1987.
Clinical significance
ProIAPP has been linked to Type 2 diabetes and the loss of islet β-cells. 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. 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. 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. 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.
The amyloid formation might be a major mediator of apoptosis, or programmed cell death, in the islet β-cells. 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.
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. 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, 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.
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. 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. 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.
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.
Amylin is degraded in part by insulin-degrading enzyme. 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.
See also
- carboxypeptidase E
- Pancreatic islets
- peptidylglycine alpha-amidating monooxygenase (PAM)
- Pramlintide
- proprotein convertase 1/3 (PC1/3)
- proprotein convertase 2 (PC2)
- Type II Diabetes
Further reading
- 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. doi:10.1007/s11892-005-0007-2. PMID 15929864. S2CID 24682226.
- 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. doi:10.1016/0006-291X(92)90255-J. 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. doi:10.1042/bj2750785. PMC 1150122. 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. doi:10.2337/diabetes.39.6.752. 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. doi:10.1016/0167-4781(90)90210-S. 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. doi:10.1016/0014-5793(90)80314-9. PMID 2365085. S2CID 41096586.
- 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. doi:10.1007/BF00221649. PMID 2546670. S2CID 22046812.
- 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. doi:10.1210/mend-3-11-1775. 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. doi:10.1016/0014-5793(89)81260-8. PMID 2651160. S2CID 45121588.
- 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. Bibcode:1987PNAS...84.3881W. doi:10.1073/pnas.84.11.3881. PMC 304980. PMID 3035556.
- Mosselman S, Höppener JW, Zandberg J, et al. (1988). "Islet amyloid polypeptide: identification and chromosomal localization of the human gene" (PDF). FEBS Lett. 239 (2): 227–32. doi:10.1016/0014-5793(88)80922-0. hdl:1874/23977. PMID 3181427. S2CID 26985644.
- 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. Bibcode:1987PNAS...84.8628C. doi:10.1073/pnas.84.23.8628. PMC 299599. 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. doi:10.1016/0006-291X(86)90708-4. PMID 3535798.
- 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. doi:10.1007/BF00400803. 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. doi:10.1016/j.febslet.2008.05.006. PMID 18486611. S2CID 6201956.
External links
- amylin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- "Amylin Nucleation Site". PDB Entry 1KUW. RCSB Protein Data Bank. doi:10.2210/pdb1kuw/pdb. Archived from the original on 16 April 2008. Retrieved 2008-05-28.
- Human DAP genome location and DAP gene details page in the UCSC Genome Browser.
- Human IAPP genome location and IAPP gene details page in the UCSC Genome Browser.
|
PDB gallery
| |
|---|---|
|
