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Pharmacological Reviews Jul 2015Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. Here, we review the literature in rodents and in humans on amylin... (Review)
Review
Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. Here, we review the literature in rodents and in humans on amylin research since its discovery as a hormone about 25 years ago. Amylin is a 37-amino-acid peptide that activates its specific receptors, which are multisubunit G protein-coupled receptors resulting from the coexpression of a core receptor protein with receptor activity-modifying proteins, resulting in multiple receptor subtypes. Amylin's major role is as a glucoregulatory hormone, and it is an important regulator of energy metabolism in health and disease. Other amylin actions have also been reported, such as on the cardiovascular system or on bone. Amylin acts principally in the circumventricular organs of the central nervous system and functionally interacts with other metabolically active hormones such as cholecystokinin, leptin, and estradiol. The amylin-based peptide, pramlintide, is used clinically to treat type 1 and type 2 diabetes. Clinical studies in obesity have shown that amylin agonists could also be useful for weight loss, especially in combination with other agents.
Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Weight Loss
PubMed: 26071095
DOI: 10.1124/pr.115.010629 -
Headache May 2017Amylin is a 37 amino acid peptide hormone that is closely related to calcitonin gene-related peptide (CGRP). Amylin and CGRP share a receptor and are reported to have... (Review)
Review
Amylin is a 37 amino acid peptide hormone that is closely related to calcitonin gene-related peptide (CGRP). Amylin and CGRP share a receptor and are reported to have several similar biological actions. Given the important role of CGRP in migraine and intense efforts to develop drugs against this target, it is important to consider potential areas of overlap between the amylin and CGRP systems. This short review provides a brief introduction to amylin biology, the use of an amylin analog to treat diabetes, and consideration of whether amylin could have any role in headache disorders. Finally, this review informs readers about the AMY (amylin subtype 1) receptor, which is a dual receptor for amylin and CGRP and potentially plays a role in the bioactivity of both of these peptides.
Topics: Animals; Humans; Islet Amyloid Polypeptide; Receptors, Islet Amyloid Polypeptide
PubMed: 28485843
DOI: 10.1111/head.13077 -
Peptides Oct 2020Amylin is a peptide hormone that is mainly known to be produced by pancreatic β-cells in response to a meal but amylin is also produced by brain cells in discrete brain... (Review)
Review
Amylin is a peptide hormone that is mainly known to be produced by pancreatic β-cells in response to a meal but amylin is also produced by brain cells in discrete brain areas albeit in a lesser amount. Amylin receptor (AMY) is composed of the calcitonin core-receptor (CTR) and one of the 3 receptor activity modifying protein (RAMP), thus forming AMY1-3; RAMP enhances amylin binding properties to the CTR. However, amylin receptor agonist such as salmon calcitonin is able to bind CTR alone. Peripheral amylin's main binding site is located in the area postrema (AP) which then propagate the signal to the nucleus of the solitary tract and lateral parabrachial nucleus (LPBN) and it is then transmitted to the forebrain areas such as central amygdala and bed nucleus of the stria terminalis. Amylin's activation of these different brain areas mediates eating and other metabolic pathways controlling energy expenditure and glucose homeostasis. Peripheral amylin can also bind in the arcuate nucleus of the hypothalamus where it acts independently of the AP to activate POMC and NPY neurons. Amylin activation of NPY neurons has been shown to be transmitted to LPBN neurons to act on eating while amylin POMC signaling affects energy expenditure and locomotor activity. While a large amount of experiments have already been conducted, future studies will have to further investigate how amylin is taken up by forebrain areas and deepen our understanding of amylin action on peripheral metabolism.
Topics: Animals; Appetite Depressants; Brain; Eating; Humans; Islet Amyloid Polypeptide; Pancreatic Hormones; Signal Transduction
PubMed: 32634450
DOI: 10.1016/j.peptides.2020.170366 -
Appetite May 2022This paper is based on a presentation given at the Annual Meeting of the Society for the Study of Ingestive Behavior in July 2021 and provides a personal view on some of... (Review)
Review
This paper is based on a presentation given at the Annual Meeting of the Society for the Study of Ingestive Behavior in July 2021 and provides a personal view on some of the milestones in the discovery of amylin as a constituent of pancreatic islet amyloid deposits, as a pancreatic beta-cell hormone, and on its role in physiology and pathophysiology. Only selected effects of amylin are discussed here because we recently published extensive reviews on the physiology and pathophysiology of amylin. Amylin was discovered as the main constituent of islet amyloid that is predominantly found in pancreatic islets in type 2 diabetics. These deposits, and in particular small oligomer aggregates of amylin seem to contribute to the progressive beta-cell damage seen in type 2 diabetics. Amylin is also a physiologically relevant circulating hormone with diverse metabolic functions, e.g. inhibition of eating, of pancreatic glucagon secretion and of gastric emptying. Knowledge of these types of functions and amylin's mechanisms of action lead to the development of amylin analogues that are now among the most promising anti-obesity targets in clinical testing. With this review, I want to give a short overview of 35 exciting years of amylin research.
Topics: Amyloid; Feeding Behavior; Gastric Emptying; Humans; Islet Amyloid Polypeptide; Obesity
PubMed: 35183619
DOI: 10.1016/j.appet.2022.105965 -
Journal of Medicinal Chemistry Aug 2021A hallmark of the pancreatic hormone amylin is its high propensity toward the formation of amyloid fibrils, which makes it a challenging drug design effort. The amylin...
A hallmark of the pancreatic hormone amylin is its high propensity toward the formation of amyloid fibrils, which makes it a challenging drug design effort. The amylin analogue pramlintide is commercially available for diabetes treatment as an adjunct to insulin therapy but requires three daily injections due to its short half-life. We report here the development of the stable, lipidated long-acting amylin analogue cagrilintide () and some of the structure-activity efforts that led to the selection of this analogue for clinical development with obesity as an indication. Cagrilintide is currently in clinical trial and has induced significant weight loss when dosed alone or in combination with the GLP-1 analogue semaglutide.
Topics: Dose-Response Relationship, Drug; Drug Development; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Models, Molecular; Molecular Structure; Structure-Activity Relationship
PubMed: 34288673
DOI: 10.1021/acs.jmedchem.1c00565 -
Current Neuropharmacology 2022The metabolic peptide hormone amylin, in concert with other metabolic peptides like insulin and leptin, has an important role in metabolic homeostasis and has been... (Review)
Review
The metabolic peptide hormone amylin, in concert with other metabolic peptides like insulin and leptin, has an important role in metabolic homeostasis and has been intimately linked to Alzheimer's disease (AD). Interestingly, this pancreatic amyloid peptide is known to self-aggregate much like amyloid-beta and has been reported to be a source of pathogenesis in both Type II diabetes mellitus (T2DM) and Alzheimer's disease. The traditional "gain of toxic function" properties assigned to amyloid proteins are, however, contrasted by several reports highlighting neuroprotective effects of amylin and a recombinant analog, pramlintide, in the context of these two diseases. This suggests that pharmacological therapies aimed at modulating the amylin receptor may be therapeutically beneficial for AD development, as they already are for T2DMM. However, the nature of amylin receptor signaling is highly complex and not well studied in the context of CNS function. Therefore, to begin to address this pharmacological paradox in amylin research, the goal of this review is to summarize the current research on amylin signaling and CNS functions and critically address the paradoxical nature of this hormone's signaling in the context of AD pathogenesis.
Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Diabetes Mellitus, Type 2; Humans; Islet Amyloid Polypeptide; Receptors, Islet Amyloid Polypeptide
PubMed: 34852745
DOI: 10.2174/1570159X19666211201093147 -
Current Opinion in Endocrinology,... Apr 2022To summarize recent developments of long-acting amylin analogues for the treatment of obesity and to outline their mode of action. (Review)
Review
PURPOSE OF REVIEW
To summarize recent developments of long-acting amylin analogues for the treatment of obesity and to outline their mode of action.
RECENT FINDINGS
Amylin is a pancreatic hormone acting to control energy homeostasis and body weight. Activity at the calcitonin and amylin receptors in the area postrema seems to - at least partly - be responsible for these effects of amylin. Both preclinical and early-stage clinical studies investigating long-acting amylin receptor analogues demonstrate beneficial effects on body weight in obesity. Cagrilintide, a novel amylin analogue suitable for once-weekly administration, is in phase II clinical development and has shown promising body weight reducing effects alone and in combination with the glucagon-like peptide 1 receptor agonist semaglutide.
SUMMARY
Long-acting amylin analogues have emerged as a possible pharmacotherapy against obesity, but more studies are needed to support the utility and long-term effects of this strategy in relevant populations.
Topics: Body Weight; Humans; Islet Amyloid Polypeptide; Obesity; Weight Loss
PubMed: 35066542
DOI: 10.1097/MED.0000000000000716 -
Current Protein & Peptide Science 2019The histopathological hallmark of type 2 diabetes is islet amyloid implicated in the developing treatment options. The major component of human islet amyloid is 37 amino... (Review)
Review
The histopathological hallmark of type 2 diabetes is islet amyloid implicated in the developing treatment options. The major component of human islet amyloid is 37 amino acid peptide known as amylin or islet amyloid polypeptide (IAPP). Amylin is an important hormone that is co-localized, copackaged, and co-secreted with insulin from islet β cells. Physiologically, amylin regulates glucose homeostasis by inhibiting insulin and glucagon secretion. Furthermore, amylin modulates satiety and inhibits gastric emptying via the central nervous system. Normally, human IAPP is soluble and natively unfolded in its monomeric state. Pathologically, human IAPP has a propensity to form oligomers and aggregate. The oligomers show misfolded α-helix conformation and can further convert themselves to β-sheet-rich fibrils as amyloid deposits. The pathological findings and physiological functions of amylin have led to the introduction of pramlintide, an amylin analog, for the treatment of diabetes. The history of amylin's discovery is a representative example of how a pathological finding can translate into physiological exploration and lead to pharmacological intervention. Understanding the importance of transitioning from pathology to physiology and pharmacology can provide novel insight into diabetes mellitus and Alzheimer's disease.
Topics: Amyloid; Amyloidosis; Animals; Disease Susceptibility; Gene Expression Regulation; Humans; Islet Amyloid Polypeptide; Protein Aggregation, Pathological; Signal Transduction
PubMed: 30919775
DOI: 10.2174/1389203720666190328111833 -
Neuropharmacology Jul 2018Alzheimer's disease (AD) is a neurodegenerative disease for which we currently lack effective treatments or a cure. The pancreatic peptide hormone amylin has recently... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disease for which we currently lack effective treatments or a cure. The pancreatic peptide hormone amylin has recently garnered interest as a potential pharmacological target for the treatment of AD. A number of studies have demonstrated that amylin and amylin analogs like the FDA-approved diabetes drug pramlintide can reduce amyloid burden in the brain and improve cognitive symptoms of AD. However, other data suggest that amylin may have pathological effects in AD due to its propensity to misfold and aggregate under certain conditions. Here, the literature supporting a beneficial versus harmful role of amylin in AD is reviewed. Additionally, several critical gaps in the literature are discussed, such as our limited understanding of the amylin system during aging and in disease states, as well as complexities of amylin receptor signaling and of changing pathophysiology during AD progression that might underlie the seemingly conflicting or contradictory results in the amylin/AD literature. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'
Topics: Alzheimer Disease; Animals; Central Nervous System Agents; Humans; Islet Amyloid Polypeptide
PubMed: 29233636
DOI: 10.1016/j.neuropharm.2017.12.016 -
Journal of Inorganic Biochemistry Feb 2019Islet Amyloid Polypeptide (IAPP), also known as amylin, is a 37-amino-acid peptide hormone that is secreted by pancreatic islet β-cells. Amylin is complementary to... (Review)
Review
Islet Amyloid Polypeptide (IAPP), also known as amylin, is a 37-amino-acid peptide hormone that is secreted by pancreatic islet β-cells. Amylin is complementary to insulin in regulating and maintaining blood glucose levels in the human body. The misfolding and aggregation of amylin is primarily associated with type 2 diabetes mellitus, which is classified as an amyloid disease. Recently, the interactions between amylin and specific metal ions, e.g., copper(II), zinc(II), and iron(II), were found to impact its performance and aggregation processes. Therefore, the focus in this review will be on how the chemistry and structural properties of amylin are affected by these interactions. In addition, the impact of amylin and other amyloidogenic peptides interacting with metal ions on the cell membranes is discussed. In particular, recent studies on the interactions of amylin with copper, zinc, iron, nickel, gold, ruthenium, and vanadium are discussed.
Topics: Animals; Cell Membrane; Humans; Islet Amyloid Polypeptide; Transition Elements
PubMed: 30468944
DOI: 10.1016/j.jinorgbio.2018.11.004