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British Journal of Pharmacology Jun 2016Amylin is an important, but poorly understood, 37 amino acid glucoregulatory hormone with great potential to target metabolic diseases. A working example that the amylin... (Review)
Review
Amylin is an important, but poorly understood, 37 amino acid glucoregulatory hormone with great potential to target metabolic diseases. A working example that the amylin system is one worth developing is the FDA-approved drug used in insulin-requiring diabetic patients, pramlintide. However, certain characteristics of pramlintide pharmacokinetics and formulation leave considerable room for further development of amylin-mimetic compounds. Given that amylin-mimetic drug design and development is an active area of research, surprisingly little is known about the structure/function relationships of amylin. This is largely due to the unfavourable aggregative and solubility properties of the native peptide sequence, which are further complicated by the composition of amylin receptors. These are complexes of the calcitonin receptor with receptor activity-modifying proteins. This review explores what is known of the structure-function relationships of amylin and provides insights that can be drawn from the closely related peptide, CGRP. We also describe how this information is aiding the development of more potent and stable amylin mimetics, including peptide hybrids.
Topics: Amylin Receptor Agonists; Animals; Drug Design; Humans; Islet Amyloid Polypeptide; Receptors, Islet Amyloid Polypeptide; Structure-Activity Relationship
PubMed: 27061187
DOI: 10.1111/bph.13496 -
Frontiers in Bioscience (Landmark... Jun 2014Metabolic syndrome significantly increases the incidence of atherosclerosis-related diseases including coronary artery disease, stroke, and type 2 diabetes. Recent... (Review)
Review
Metabolic syndrome significantly increases the incidence of atherosclerosis-related diseases including coronary artery disease, stroke, and type 2 diabetes. Recent progress has demonstrated that amylin, or islet amyloid polypeptide, is circulating multifunctional hormone and neuropeptide, which is co-secreted with insulin into the bloodstream by pancreatic beta cells and plays a very important role in regulating feeding, energy homeostasis and inflammation. Recent FDA approval of amylin analog pramlintide as a new drug for treating type 1 and 2 diabetes positions amylin in the spotlight. In this analytical review, I summarize the recent progress on amylin studies in the following sections: 1) introduction to the molecular features of amylin; 2) amylin's amyloidogenic and proinflammatory effects; 3) a satiety hormone and new drug in increasing energy expenditure; and 4) a vasodilator inducing hypotension and tachycardia; and 5) a neuropeptide in depolarizing cholinergic neurons via closure of potassium channels. Continued improvement of our understanding on this multifunctional hormone would lead to future development of pramlintide as novel therapies for other inflammatory, hematological, metabolic, neurological and vascular diseases.
Topics: Brain; Cholinergic Neurons; Energy Metabolism; Humans; Hypoglycemic Agents; Inflammation; Islet Amyloid Polypeptide; Membrane Potentials; Vasodilation
PubMed: 24896327
DOI: 10.2741/4258 -
International Journal of Molecular... Jan 2024Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has... (Review)
Review
Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has emerged. The gut-brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from β-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.
Topics: Humans; Islet Amyloid Polypeptide; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Insulin; Obesity; Glucose; Amyloid
PubMed: 38338796
DOI: 10.3390/ijms25031517 -
Advances in Experimental Medicine and... 2015Amyloidosis is a biological event in which proteins undergo structural transitions from soluble monomers and oligomers to insoluble fibrillar aggregates that are often... (Review)
Review
Amyloidosis is a biological event in which proteins undergo structural transitions from soluble monomers and oligomers to insoluble fibrillar aggregates that are often toxic to cells. Exactly how amyloid proteins, such as the pancreatic hormone amylin, aggregate and kill cells is still unclear. Islet amyloid polypeptide, or amylin, is a recently discovered hormone that is stored and co-released with insulin from pancreatic islet β-cells. The pathology of type 2 diabetes mellitus (T2DM) is characterized by an excessive extracellular and intracellular accumulation of toxic amylin species, soluble oligomers and insoluble fibrils, in islets, eventually leading to β-cell loss. Obesity and elevated serum cholesterol levels are additional risk factors implicated in the development of T2DM. Because the homeostatic balance between cholesterol synthesis and uptake is lost in diabetics, and amylin aggregation is a hallmark of T2DM, this chapter focuses on the biophysical and cell biology studies exploring molecular mechanisms by which cholesterol and phospholipids modulate secondary structure, folding and aggregation of human amylin and other amyloid proteins on membranes and in cells. Amylin turnover and toxicity in pancreatic cells and the regulatory role of cholesterol in these processes are also discussed.
Topics: Amino Acid Sequence; Amyloidosis; Animals; Cholesterol; Diabetes Mellitus, Type 2; Humans; Islet Amyloid Polypeptide; Islets of Langerhans; Molecular Sequence Data; Phospholipids; Protein Conformation; Protein Folding; Sequence Homology, Amino Acid
PubMed: 26149927
DOI: 10.1007/978-3-319-17344-3_4 -
American Journal of Physiology.... May 2021Amylin is a 37-amino acid endocrine hormone secreted from the pancreas in response to nutrient intake, acting centrally to promote meal-ending satiation. With many...
Amylin is a 37-amino acid endocrine hormone secreted from the pancreas in response to nutrient intake, acting centrally to promote meal-ending satiation. With many studies linking amylin action to the nervous system, determining the distribution or expression of amylin in the nervous system is critical. However, amylin shares sequence identity and structural homology to the related neuropeptide calcitonin gene-related peptide (CGRP). This creates challenges in identifying selective amylin antibodies that do not cross-react with CGRP, especially in neural tissues, where CGRP is densely packed into secretory vesicles. Here, we characterized eight amylin antibodies to determine their ability to detect amylin and cross-react with rat or human αCGRP, using immunoblots and preabsorption controls in rat pancreas. We observed that amylin antibodies frequently cross-reacted with αCGRP and are therefore not suitable for use in tissues that highly express CGRP. Earlier work using these antibodies should be revisited in light of our findings.
Topics: Amino Acid Sequence; Animals; Calcitonin; Calcitonin Gene-Related Peptide; Islet Amyloid Polypeptide; Male; Pancreas; Peptide Hormones
PubMed: 33565362
DOI: 10.1152/ajpregu.00338.2020 -
British Journal of Pharmacology May 2012The discoveries of the incretin hormone glucagon-like peptide-1 (GLP-1) and the β-cell hormone amylin have translated into hormone-based therapies for diabetes. Both... (Review)
Review
The discoveries of the incretin hormone glucagon-like peptide-1 (GLP-1) and the β-cell hormone amylin have translated into hormone-based therapies for diabetes. Both classes of molecules also exhibit weight-lowering effects and have been investigated for their anti-obesity potential. In the present review, we explore the mechanisms underlying the physiological and pharmacological actions of GLP-1 and amylin agonism. Despite their similarities (e.g. both molecular classes slow gastric emptying, decrease glucagon and inhibit food intake), there are important distinctions between the central and/or peripheral pathways that mediate their effects on glycaemia and energy balance. We suggest that understanding the similarities and differences between these molecules holds important implications for the development of novel, combination-based therapies, which are increasingly the norm for diabetes/metabolic disease. Finally, the future of GLP-1- and amylin agonist-based therapeutics is discussed.
Topics: Animals; Diabetes Mellitus; Eating; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Islet Amyloid Polypeptide; Metabolic Diseases; Obesity; Receptors, Glucagon
PubMed: 21671898
DOI: 10.1111/j.1476-5381.2011.01537.x -
Molecular Metabolism Apr 2021Therapies for metabolic diseases are numerous, yet improving insulin sensitivity beyond that induced by weight loss remains challenging. Therefore, search continues for... (Review)
Review
BACKGROUND
Therapies for metabolic diseases are numerous, yet improving insulin sensitivity beyond that induced by weight loss remains challenging. Therefore, search continues for novel treatment candidates that can stimulate insulin sensitivity and increase weight loss efficacy in combination with current treatment options. Calcitonin gene-related peptide (CGRP) and amylin belong to the same peptide family and have been explored as treatments for metabolic diseases. However, their full potential remains controversial.
SCOPE OF REVIEW
In this article, we introduce this rather complex peptide family and its corresponding receptors. We discuss the physiology of the peptides with a focus on metabolism and insulin sensitivity. We also thoroughly review the pharmacological potential of amylin, calcitonin, CGRP, and peptide derivatives as treatments for metabolic diseases, emphasizing their ability to increase insulin sensitivity based on preclinical and clinical studies.
MAJOR CONCLUSIONS
Amylin receptor agonists and dual amylin and calcitonin receptor agonists are relevant treatment candidates, especially because they increase insulin sensitivity while also assisting weight loss, and their unique mode of action complements incretin-based therapies. However, CGRP and its derivatives seem to have only modest if any metabolic effects and are no longer of interest as therapies for metabolic diseases.
Topics: Animals; Calcitonin; Calcitonin Gene-Related Peptide; Humans; Insulin Resistance; Islet Amyloid Polypeptide; Metabolic Diseases; Obesity; Receptors, Calcitonin; Receptors, Calcitonin Gene-Related Peptide; Receptors, Cell Surface; Weight Loss
PubMed: 33166741
DOI: 10.1016/j.molmet.2020.101109 -
Obesity Research Oct 2002Amylin, also known as islet amyloid polypeptide, identified in 1987, is a naturally occurring hormone, released by the beta cells of the pancreas and consists of 37... (Review)
Review
Amylin, also known as islet amyloid polypeptide, identified in 1987, is a naturally occurring hormone, released by the beta cells of the pancreas and consists of 37 amino acids. Amylin seems to decrease food intake through both central and peripheral mechanisms and indirectly by slowing gastric emptying. The mean basal amylin concentration is higher in obese than in lean human subjects. The amylin response to oral glucose is also greater in obese subjects, whether or not they have impaired glucose tolerance. The elevated amylin levels in obesity may lead to down-regulation of amylin receptors and lessen the impact of postprandial amylin secretion on satiety and gastric emptying. Amylin administration may overcome resistance at target tissues, delay gastric emptying, and have potential for inducing weight loss in obese individuals.
Topics: Amyloid; Eating; Female; Gastric Emptying; Humans; Islet Amyloid Polypeptide; Male; Obesity; Satiety Response
PubMed: 12376591
DOI: 10.1038/oby.2002.147 -
Handbook of Experimental Pharmacology 2018Human islet amyloid polypeptide or amylin (hA) is a 37-amino acid peptide hormone produced and co-secreted with insulin by pancreatic β-cells. Under physiological... (Review)
Review
Human islet amyloid polypeptide or amylin (hA) is a 37-amino acid peptide hormone produced and co-secreted with insulin by pancreatic β-cells. Under physiological conditions, hA regulates a broad range of biological processes including insulin release and slowing of gastric emptying, thereby maintaining glucose homeostasis. However, under the pathological conditions associated with type 2 diabetes mellitus (T2DM), hA undergoes a conformational transition from soluble random coil monomers to alpha-helical oligomers and insoluble β-sheet amyloid fibrils or amyloid plaques. There is a positive correlation between hA oligomerization/aggregation, hA toxicity, and diabetes progression. Because the homeostatic balance between hA synthesis, release, and uptake is lost in diabetics and hA aggregation is a hallmark of T2DM, this chapter focuses on the biophysical and cell biology studies investigating molecular mechanisms of hA uptake, trafficking, and degradation in pancreatic cells and its relevance to h's toxicity. We will also discuss the regulatory role of endocytosis and proteolytic pathways in clearance of toxic hA species. Finally, we will discuss potential pharmacological approaches for specific targeting of hA trafficking pathways and toxicity in islet β-cells as potential new avenues toward treatments of T2DM patients.
Topics: Amyloidosis; Animals; Diabetes Mellitus, Type 2; Endocytosis; Humans; Islet Amyloid Polypeptide; Islets of Langerhans; Proteasome Endopeptidase Complex; Protein Aggregates
PubMed: 29043504
DOI: 10.1007/164_2017_62 -
Physiology & Behavior Aug 2016Amylin, a peptide hormone produced in the pancreas and in the brain, has well-established physiological roles in glycemic regulation and energy balance control. It... (Review)
Review
Amylin, a peptide hormone produced in the pancreas and in the brain, has well-established physiological roles in glycemic regulation and energy balance control. It improves postprandial blood glucose levels by suppressing gastric emptying and glucagon secretion; these beneficial effects have led to the FDA-approved use of the amylin analog pramlintide in the treatment of diabetes mellitus. Amylin also acts centrally as a satiation signal, reducing food intake and body weight. The ability of amylin to promote negative energy balance, along with its unique capacity to cooperatively facilitate or enhance the intake- and body weight-suppressive effects of other neuroendocrine signals like leptin, have made amylin a leading target for the development of novel pharmacotherapies for the treatment of obesity. In addition to these more widely studied effects, a growing body of literature suggests that amylin may play a role in processes related to cognition, including the neurodegeneration and cognitive deficits associated with Alzheimer's disease (AD). Although the function of amylin in AD is still unclear, intriguing recent reports indicate that amylin may improve cognitive ability and reduce hallmarks of neurodegeneration in the brain. The frequent comorbidity of diabetes mellitus and obesity, as well as the increased risk for and occurrence of AD associated with these metabolic diseases, suggests that amylin-based pharmaceutical strategies may provide multiple therapeutic benefits. This review will discuss the known effects of amylin on glycemic regulation, energy balance control, and cognitive/motivational processes. Particular focus will be devoted to the current and/or potential future clinical use of amylin pharmacotherapies for the treatment of diseases in each of these realms.
Topics: Animals; Appetite Depressants; Blood Glucose; Cognition; Energy Metabolism; Humans; Islet Amyloid Polypeptide
PubMed: 26922873
DOI: 10.1016/j.physbeh.2016.02.034