| Discovery | AMY is a peptide hormone predominantly cosecreted withinsulin from pancreatic β cells. It aggregates to form an isletamyloid in type 2 diabetes. The deposition of an amyloid in the islets of Langerhans in type 2 diabetes has been observed, and wasdescribed as hyalinization in 1901. The genuine natureof the human pancreatic islet amyloid was described asAMY or IAPP by two independent groups in 1987. |
| Gene, mRNA, and precursor | The human AMY gene (IAPP), located on chromosome12 (12p12.1), consists of three exons and is regulated by atranscription factor, PDX-1. Human AMY mRNA has1992 bp. The gene structure and its mRNA size are wellconserved among vertebrates. Mammalian IAPP is expressed in islet β cells, δ cells,the gastrointestinal tract, and sensory neurons. In teleosts, iapp transcripts are detected and are found in theoptic tectum, hypothalamus, posterior brain, and testisof goldfish. |
| Receptors | The functional receptors for AMY are generated fromthe calcitonin receptor (CTR) in a complex with one of thethree receptor activity-modifying proteins (RAMP)-1, -2,or -3. The CTR/RAMP1 and CTR/RAMP3 complexesappear to be the dominant AMY receptors, judging bythe binding affinity. AMY also binds to CTR withoutRAMPs, but the affinity is low. CTR is a seventransmembrane-domain GPCR that is highly conservedamong vertebrates. It existed before the separation of thislineage, for it is identified in the invertebrate Ciona intestinalis. RAMP is a single-transmembrane accessory protein that regulates the activities of several GPCRs.Three types of RAMPs consisting of 148–175 aa residuesexist in mammals, and five types are identified inteleost fish. |
| Agonists and Antagonists | Salmon calcitonin. Salmon calcitonin8–32 and AMY8–37. |
| Biological functions | AMY reduces blood glucose levels. AMY is reported tosuppress glucagon release from pancreatic β cells and istherefore considered to play a role in glucose homeostasis. There have been contradictory reports regarding thein vitro effects of AMY on insulin secretion. AMY mayhave dual effects on insulin release, which stimulatesbasal insulin secretion and suppresses it when insulinsecretion is augmented. A number of studies have beencarried out on the autocrine/paracrine functions of pancreatic AMY, but the mechanisms are still largelyunknown. AMY is believed to inhibit food intake andgastric emptying in relation to satiety center stimulation.AMY has also been reported to inhibit insulin-stimulatedglucose uptake and the synthesis of glycogen in isolatedrat skeletal muscle. |
| Clinical implications | AMY aggregation forms the islet amyloid in the β cellsfound in type 2 diabetes. Aggregation occurs in a stepwise manner, with soluble monomeric AMY formingoligomeric structures, protofibrils, and eventually amyloid fibrils, which are toxic and lead to the cell death ofpancreatic β cells. The proposed mechanisms of AMY induced toxicity during amyloid formation start with cellmembrane disruption; then endoplasmic reticulum stresscauses unfolded protein release and mitochondrial dysfunction, which eventually leads to oxidative stress andapoptosis. The human AMY20–29 sequence is consideredto determine its ability to form amyloid fibrils. This isbecause AMY in other species such as rodents, whichhave variations within this region, does not form isletamyloids. AMY is cosecreted with insulin, and thus isnot produced in type 1 diabetes. |
| Description | Amylin is a 37-peptide that is structurally similar to CT. Amylin works together with insulin to regulate glucose concentrations after a meal. When in solution, amylin is viscous, unstable, and tends to aggregate; therefore it cannot be used parenterally and is not commercially available. |
| Uses | Amylin functions as part of the?endocrine?pancreas?and contributes to?glycemic control. It functions as a synergistic partner to insulin. The overall effect is to slow the rate of appearance (Ra) of glucose in the blood after eating. |
| Uses | Antidiabetic. |
| Biochem/physiol Actions | Islet amyloid polypeptide (IAPP) is a hormone coexpressed with insulin by pancreatic β-cells. IAPP is used to study the mechanisms of amyloid deposition and its role in molecular misfolding processes expecially in conditions such as diabetes type II. |
| Clinical Use | Pramlintide, whose sequence is based on rat AMY toavoid amyloid formation, is used for the treatment oftype 1 and type 2 diabetes to reduce blood glucose levels. |
| Clinical Use | Amylin normally is cosecreted with insulin from secretory granules in pancreatic β cells in response to meals and works withinsulin to provide postprandial glucose control. Native amylin is a single-chain peptide of 37 amino acids. Observeddeficiencies of amylin in both type 1 and type 2 patients treated with insulin have led to research and drug developmentrelated to amylin. |
| storage | Store at -20°C |
| Structure and conformation | Human AMY is derived after a 67-aa residue proAMY. The short C- and N-terminal flanking peptides are cleaved by the prohormone convertases PC2 and PC1/3 to form the 37-aa residues of mature AMY. Human AMY20–29 is considered to be the responsive region that forms the amyloid fibrils in type 2 diabetes, as synthesized 20–29 aa residues are extremely fibrillogenic. However, rat and mouse models of diabetes lack the islet amyloid. The AMY20–29 regions vary among humans and rodents, and rat/mouse AMY has three proline residues, known as β-sheet breakers, in this region. Because the amyloid is the aggregated protein in which molecules in a β-sheet structure are bound to each other, the lack of the islet amyloid in rodents appears to be due to the presence of proline residues in the AMY20–29 region. Therefore, the peptides in these species are saved from fibrillogenic conformation. The sequence of mature AMY is highly conserved across vertebrate lineages, but the sequence at the position 20–29 regions is variable, which also supports the theory that the islet amyloid is observed only in humans and cats.
|
| Description | DAP Human Recombinant produced in E.Coli is a single, non-glycosylated polypeptide chain containing 125 amino acids (1-102 a.a.) and having a molecular mass of 13.6kDa.
DAP is fused to a 23 amino acid His-tag at N-terminus & purified by proprietary chromatographic techniques. |
| Source | Escherichia Coli |
| Background | Death-Associated Protein (DAP) is a proline-rich protein. DAP, which is a negative regulator of autophagy, takes part in the mediation of IFN-gamma-induced cell death. |
