Amylin

Islet amyloid polypeptide
250px PDB Human amylin in SDS micelles:rendering based on 2kb8.
Available structures PDB 1KUW, 2G48, 2KB8, 3FPO, 3FR1, 3FTH, 3FTK, 3FTL, 3FTR, 3G7V, 3G7W, 3HGZ
Identifiers
Symbols	IAPP; DAP; IAP
External IDs	OMIM: 147940 MGI: 96382 HomoloGene: 36024 GeneCards: IAPP Gene
Gene Ontology Molecular function • receptor binding • hormone activity Cellular component • extracellular region • extracellular region • soluble fraction Biological process • apoptosis • signal transduction • cell-cell signaling • endocrine pancreas development Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3375	15874
Ensembl	ENSG00000121351	ENSMUSG00000041681
UniProt	P10997	P12968
RefSeq (mRNA)	NM_000415.2	NM_010491.2
RefSeq (protein)	NP_000406.1	NP_034621.1
Location (UCSC)	Chr 12: 21.51 – 21.53 Mb	Chr 6: 142.25 – 142.25 Mb
PubMed search	[1]	[2]

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. It is cosecreted with insulin from the pancreatic β-cells in a 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]

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.^{[citation needed]}

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] 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.^[25]

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.^[26]

Amylin is degraded in part by insulin-degrading enzyme.^[27]

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.^[28]

See also

• Proislet Amyloid Polypeptide
• Pramlintide
• Type II Diabetes
• islets of Langerhans
• proprotein convertase 2 (PC2)
• proprotein covertase 1/3 (PC1/3)
• carboxypeptidase E
• peptidylglycine alpha-amidating monooxygenase (PAM)

References

Further reading

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

External links

• MeSH amylin
• "Amylin Nucleation Site". PDB entry 1KUW. RCSB Protein Data Bank. http://www.pdb.org/pdb/explore.do?structureId=1KUW. Retrieved 2008-05-28.