Amylin

Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue is_associated_with::peptide hormone. It is cosecreted with is_associated_with::insulin from the pancreatic β-cells in the ratio of approximately 100:1. 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 is_associated_with::coding sequence. Proislet Amyloid Polypeptide (proIAPP,Proamylin, Proislet Protein) is produced in the pancreatic is_associated_with::beta cells (β-cells) as a 67 amino acid, 7404 Dalton pro-peptide and undergoes is_associated_with::post-translational modifications including protease cleavage to produce amylin.

Synthesis


ProIAPP consists of 67 is_associated_with::amino acids, which follow a 22 amino acid is_associated_with::signal peptide which is rapidly cleaved after translation of the 89 amino acid coding sequence. The human sequence (from is_associated_with::N-terminus to is_associated_with::C-terminus) is:

(MGILKLQVFLIVLSVALNHLKA) TPIESHQVEKR^ KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTYG^ KR^ NAVEVLKREPLNYLPL.

Once released from the signal peptide, it undergoes additional is_associated_with::proteolysis and is_associated_with::posttranslational modification (indicated by ^). 11 amino acids are removed from the N-terminus by the enzyme is_associated_with::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 is_associated_with::Carboxypeptidase E then removes the terminal is_associated_with::lysine and is_associated_with::arginine residues. The terminal is_associated_with::glycine amino acid that results from this cleavage allows the enzyme is_associated_with::peptidylglycine alpha-amidating monooxygenase (PAM) to add an is_associated_with::amine group. Finally, a is_associated_with::disulfide bond is formed between is_associated_with::cysteine residues numbers 2 and 7. After this the transformation from the precursor protein proIAPP to the biologically active IAPP is complete (IAPP sequence: KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY).

Regulation
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 is_associated_with::tumor necrosis factor alpha and is_associated_with::fatty acids. One of the defining features of is_associated_with::Type 2 diabetes is is_associated_with::insulin resistance. This is a condition wherein the body is unable to utilize insulin effectively, resulting in increased insulin production; since is_associated_with::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 is_associated_with::blood glucose levels play an important role in regulation of proIAPP synthesis.

Function
Amylin functions as part of the is_associated_with::endocrine is_associated_with::pancreas and contributes to is_associated_with::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 is_associated_with::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 is_associated_with::glucagon. These actions, which are mostly carried out via a glucose-sensitive part of the brain stem, the is_associated_with::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 is_associated_with::calcitonin and is_associated_with::calcitonin gene related peptide.

Rodent amylin knockouts are known to fail to achieve the normal anorexia following food consumption. Because it is an amidated peptide, like many is_associated_with::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. IAPP is capable of forming amyloid is_associated_with::fibrils in vitro. Within the fibrillization reaction, the early prefibrillar structures are extremely toxic to beta-cell and insuloma cell cultures. Later is_associated_with::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 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
IAPP was identified independently by two groups as the major component of is_associated_with::diabetes-associated islet is_associated_with::amyloid deposits in 1987.

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.

Clinical significance
ProIAPP has been linked to Type 2 diabetes and the loss of islet β-cells. Islet is_associated_with::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 is_associated_with::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 is_associated_with::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 granule 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 is_associated_with::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 is_associated_with::diabetes mellitus type 2, or containing an is_associated_with::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. Recent results suggest that amylin, like the related is_associated_with::beta-amyloid (Abeta) associated with is_associated_with::Alzheimer's disease, can induce apoptotic cell-death in is_associated_with::insulin-producing is_associated_with::beta cells, an effect that may be relevant to the development of type 2 diabetes.

A recent study reported a synergistic effect for weight loss with is_associated_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. Finally, a recent proteomics study showed that human amylin shares common toxicity targets with is_associated_with::beta-amyloid (Abeta), providing evidence 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 is_associated_with::diabetes mellitus type 1 and is_associated_with::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 is_associated_with::insulin-degrading enzyme.

Receptors
There appear to be at least three distinct receptor complexes that bind with high affinity to amylin. All three complexes contain the is_associated_with::calcitonin receptor at the core, plus one of three is_associated_with::receptor activity-modifying proteins, RAMP1, RAMP2, or RAMP3.