AMYLIN, HUMAN

AMY is a peptide hormone predominantly cosecreted with insulin from pancreatic β cells. It aggregates to form an islet amyloid in type 2 diabetes. The deposition of an amyloid in the islets of Langerhans in type 2 diabetes has been observed, and was described as hyalinization in 1901. The genuine nature of the human pancreatic islet amyloid was described as AMY or IAPP by two independent groups in 1987.

The human AMY gene (IAPP), located on chromosome 12 (12p12.1), consists of three exons and is regulated by a transcription factor, PDX-1. Human AMY mRNA has 1992 bp. The gene structure and its mRNA size are well conserved 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 the optic tectum, hypothalamus, posterior brain, and testis of goldfish.

The functional receptors for AMY are generated from the calcitonin receptor (CTR) in a complex with one of the three receptor activity-modifying proteins (RAMP)-1, -2, or -3. The CTR/RAMP1 and CTR/RAMP3 complexes appear to be the dominant AMY receptors, judging by the binding affinity. AMY also binds to CTR without RAMPs, but the affinity is low. CTR is a seventransmembrane-domain GPCR that is highly conserved among vertebrates. It existed before the separation of this lineage, 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 residues exist in mammals, and five types are identified in teleost fish.

Salmon calcitonin. Salmon calcitonin8–32 and AMY8–37.

AMY reduces blood glucose levels. AMY is reported to suppress glucagon release from pancreatic β cells and is therefore considered to play a role in glucose homeostasis. There have been contradictory reports regarding the in vitro effects of AMY on insulin secretion. AMY may have dual effects on insulin release, which stimulates basal insulin secretion and suppresses it when insulin secretion is augmented. A number of studies have been carried out on the autocrine/paracrine functions of pancreatic AMY, but the mechanisms are still largely unknown. AMY is believed to inhibit food intake and gastric emptying in relation to satiety center stimulation. AMY has also been reported to inhibit insulin-stimulated glucose uptake and the synthesis of glycogen in isolated rat skeletal muscle.

AMY aggregation forms the islet amyloid in the β cells found in type 2 diabetes. Aggregation occurs in a stepwise manner, with soluble monomeric AMY forming oligomeric structures, protofibrils, and eventually amyloid fibrils, which are toxic and lead to the cell death of pancreatic β cells. The proposed mechanisms of AMY induced toxicity during amyloid formation start with cell membrane disruption; then endoplasmic reticulum stress causes unfolded protein release and mitochondrial dysfunction, which eventually leads to oxidative stress and apoptosis. The human AMY20–29 sequence is considered to determine its ability to form amyloid fibrils. This is because AMY in other species such as rodents, which have variations within this region, does not form islet amyloids. AMY is cosecreted with insulin, and thus is not produced in type 1 diabetes.

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.

Antidiabetic.

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.

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.

Pramlintide, whose sequence is based on rat AMY to avoid amyloid formation, is used for the treatment of type 1 and type 2 diabetes to reduce blood glucose levels.

Amylin normally is cosecreted with insulin from secretory granules in pancreatic β cells in response to meals and works with insulin to provide postprandial glucose control. Native amylin is a single-chain peptide of 37 amino acids. Observed deficiencies of amylin in both type 1 and type 2 patients treated with insulin have led to research and drug development related to amylin.

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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.