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Canadian Journal of Physiology and... Jul 1995Amylin has been demonstrated to decrease food intake in mice and rats. Amylin is effective when delivered both peripherally and directly into the central nervous system.... (Review)
Review
Amylin has been demonstrated to decrease food intake in mice and rats. Amylin is effective when delivered both peripherally and directly into the central nervous system. Amylin's effect on food intake is not aversive. Amylin may produce its effect on food intake by modulating nitric oxide synthesis. Calcitonin gene related peptide also decreases food intake after peripheral and central administration. In addition, amylin has been demonstrated to modulate memory at both peripheral and central sites.
Topics: Amyloid; Animals; Anorexia; Appetite; Calcitonin Gene-Related Peptide; Humans; Islet Amyloid Polypeptide; Memory
PubMed: 8846398
DOI: 10.1139/y95-147 -
Molecular Metabolism Feb 2018Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. One of its best-characterized effects is the reduction in eating and... (Review)
Review
BACKGROUND
Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. One of its best-characterized effects is the reduction in eating and body weight seen in preclinical and clinical studies. Amylin activates specific receptors, a portion of which it shares with calcitonin gene-related peptide (CGRP). Amylin's role in the control of energy metabolism relates to its satiating effect, but recent data indicate that amylin may also affect hedonic aspects in the control of eating, including a reduction of the rewarding value of food. Recently, several amylin-based peptides have been characterized. Pramlintide (Symlin) is currently the only one being used clinically to treat type 1 and type 2 diabetes. However other amylin analogs with improved pharmacokinetic properties are being considered as anti-obesity treatment strategies. Several other studies in obesity have shown that amylin agonists could also be useful for weight loss, especially in combination with other agents.
SCOPE OF REVIEW
This review will briefly summarize amylin physiology and pharmacology and then focus on amylin's role in food reward and the effects of amylin analogs in pre-clinical testing for anti-obesity drugs.
CONCLUSION
We propose here that the effects of amylin may be homeostatic and hedonic in nature.
Topics: Animals; Anti-Obesity Agents; Brain Stem; Humans; Hyperphagia; Islet Amyloid Polypeptide; Obesity; Peptide Fragments; Reward
PubMed: 29203236
DOI: 10.1016/j.molmet.2017.11.009 -
International Journal of Biological... Jul 2019Apart from its relevance to pathology, protein misfolding disease like Type-II Diabetes Mellitus, caused by amyloids of amylin protein has attracted more attention due...
Apart from its relevance to pathology, protein misfolding disease like Type-II Diabetes Mellitus, caused by amyloids of amylin protein has attracted more attention due to structural changes occurring during the aggregation process. We report extensive spectroscopy data of amylin during fibril formation through Raman, FTIR, CD, UV-vis absorption and photoluminescence (PL) spectroscopy. UV-vis and PL spectrum showed the sigmoidal growth of fibril with a lag time of ~2 days, which is consistent with earlier reported work using dynamic light scattering (DLS). Raman spectra revealed the formation of parallel and anti-parallel β-sheet from 0% to 20% with ageing (1st day to 21st day) at pH 6.5 ± 0.1. The results are corroborated by CD and FTIR data. These show the change in β-sheet by 23% at pH 6.5 ± 0.1, 26% at pH = 1.0 ± 0.1 and 30% at pH = 12 ± 0.1. It is also shown that the formation and conversion of other secondary structures into β-sheet is very sensitive towards the pH and ageing. The study may be used for the development of therapeutic strategies that could inhibit or even reverse the process of aggregation.
Topics: Aging; Humans; Hydrogen-Ion Concentration; Islet Amyloid Polypeptide; Protein Aggregates; Spectrum Analysis
PubMed: 31028814
DOI: 10.1016/j.ijbiomac.2019.04.167 -
Biophysical Chemistry Jul 2024Amylin is a systemic neuroendocrine hormone co-expressed and co-secreted with insulin by pancreatic β-cells. In persons with thype-2 diabetes, amylin forms pancreatic... (Review)
Review
Amylin is a systemic neuroendocrine hormone co-expressed and co-secreted with insulin by pancreatic β-cells. In persons with thype-2 diabetes, amylin forms pancreatic amyloid triggering inflammasome and interleukin-1β signaling and inducing β-cell apoptosis. Here, we summarize recent progress in understanding the potential link between amyloid-forming pancreatic amylin and Alzheimer's disease (AD). Clinical data describing amylin pathology in AD alongside mechanistic studies in animals are reviewed. Data from multiple research teams indicate higher amylin concentrations are associated with increased frequency of cognitive impairment and amylin co-aggregates with β-amyloid in AD-type dementia. Evidence from rodent models further suggests cerebrovascular amylin accumulation as a causative factor underlying neurological deficits. Analysis of relevant literature suggests that modulating the amylin-interleukin-1β pathway may provide an approach for counteracting neuroinflammation in AD.
Topics: Islet Amyloid Polypeptide; Humans; Animals; Neuroinflammatory Diseases; Alzheimer Disease; Inflammasomes
PubMed: 38663120
DOI: 10.1016/j.bpc.2024.107252 -
Physiology & Behavior Aug 2021The ability of amylin to inhibit gastric emptying and glucagon secretion in rats is reduced under hypoglycemic conditions. These effects are considered part of a...
The ability of amylin to inhibit gastric emptying and glucagon secretion in rats is reduced under hypoglycemic conditions. These effects are considered part of a fail-safe mechanism that prevents amylin from further decreasing nutrient supply when blood glucose levels are low. Because these actions and amylin-induced satiation are mediated by the area postrema (AP), it is plausible that these phenomena are based on the co-sensitivity of AP neurons to amylin and glucose. Using hyperinsulinemic glucose clamps in unrestrained and freely-feeding rats, we investigated whether amylin's ability to inhibit food intake is also reduced by hypoglycemia (HYPO). Following an 18 h fast, rats were infused with insulin and glucose for 45 min to clamp blood glucose at baseline levels (between 90 and 100 mg/dL). HYPO (approximately 55 mg/dL) was induced between 45 and 60 min and then maintained for the remainder of the clamp. Rats were injected with amylin (20 µg/kg) or saline and offered normal chow at 85 min. Food intake was measured at 30 and 60 min after amylin. Control hyperinsulinemic/euglycemic (EU) rats were maintained at approximately 150 mg/dL (which is a physiological periprandial glucose level) before and after amylin injection. Terminal experiments tested the effect of amylin to induce the phosphorylation of ERK, a marker of amylin action in the AP, in EU and HYPO conditions. Amylin significantly reduced 30- and 60-min food intake in EU rats, but the effect at 60-min was attenuated in HYPO rats. Interestingly, glucose infusion rate had to be dramatically reduced at meal onset in saline-treated, but not in amylin-treated, EU or HYPO rats; this suggests that meal-related glucose appearance in the blood was inhibited by amylin under both EU and HYPO. Finally, amylin induced a similar pERK response in the AP in EU and HYPO rats. We conclude that amylin's action to decrease eating is blunted in hypoglycemia, and this effect seems to be downstream from amylin-induced pERK in AP neurons. These data allow us to extend the idea of a hypoglycemic brake on amylin's actions to its food intake-reducing effect, but also demonstrate that amylin can buffer meal-induced glucose appearance at EU and HYPO levels.
Topics: Amyloid; Animals; Area Postrema; Eating; Hypoglycemia; Islet Amyloid Polypeptide; Male; Rats
PubMed: 33933418
DOI: 10.1016/j.physbeh.2021.113435 -
Biological Psychiatry May 2024
Topics: Prefrontal Cortex; Impulsive Behavior; Humans; Islet Amyloid Polypeptide; Animals; Feeding Behavior
PubMed: 38692798
DOI: 10.1016/j.biopsych.2024.02.1008 -
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 -
The Journal of Infectious Diseases Apr 2021Varicella zoster virus (VZV) vasculopathy is characterized by persistent arterial inflammation leading to stroke. Studies show that VZV induces amyloid formation that...
BACKGROUND
Varicella zoster virus (VZV) vasculopathy is characterized by persistent arterial inflammation leading to stroke. Studies show that VZV induces amyloid formation that may aggravate vasculitis. Thus, we determined if VZV central nervous system infection produces amyloid.
METHODS
Aβ peptides, amylin, and amyloid were measured in cerebrospinal fluid (CSF) from 16 VZV vasculopathy subjects and 36 stroke controls. To determine if infection induced amyloid deposition, mock- and VZV-infected quiescent primary human perineurial cells (qHPNCs), present in vasculature, were analyzed for intracellular amyloidogenic transcripts/proteins and amyloid. Supernatants were assayed for amyloidogenic peptides and ability to induce amyloid formation. To determine amylin's function during infection, amylin was knocked down with small interfering RNA and viral complementary DNA (cDNA) was quantitated.
RESULTS
Compared to controls, VZV vasculopathy CSF had increased amyloid that positively correlated with amylin and anti-VZV antibody levels; Aβ40 was reduced and Aβ42 unchanged. Intracellular amylin, Aβ42, and amyloid were seen only in VZV-infected qHPNCs. VZV-infected supernatant formed amyloid fibrils following addition of amyloidogenic peptides. Amylin knockdown decreased viral cDNA.
CONCLUSIONS
VZV infection increased levels of amyloidogenic peptides and amyloid in CSF and qHPNCs, indicating that VZV-induced amyloid deposition may contribute to persistent arterial inflammation in VZV vasculopathy. In addition, we identified a novel proviral function of amylin.
Topics: Amyloid; Amyloid beta-Peptides; Arteritis; DNA, Complementary; DNA, Viral; Herpes Zoster; Herpesvirus 3, Human; Humans; Islet Amyloid Polypeptide; Peptide Fragments; Stroke
PubMed: 32809013
DOI: 10.1093/infdis/jiaa513 -
Journal of Alzheimer's Disease : JAD 2019Recent studies demonstrate that peripheral amylin treatment reduces pathology in mouse models of Alzheimer's disease (AD). However, soluble and aggregated amylin are...
Recent studies demonstrate that peripheral amylin treatment reduces pathology in mouse models of Alzheimer's disease (AD). However, soluble and aggregated amylin are distinct species; while amylin is a physiological neuropeptide, amylin aggregation is a pathological factor for diabetes. We thus hypothesized that because of their similarity in secondary structures, amylin antagonizes amyloid-β peptide (Aβ)-induced AD pathology in neurons with a dose-dependent pattern. To test the hypothesis, we conducted both in vitro and in vivo experiments with different doses of amylin and with its analog, pramlintide. Here we report that a high concentration of either Aβ or amylin alone induced tau phosphorylation (pTau) in primary neurons. Interestingly, with a low concentration, amylin had direct effects to reverse the Aβ-induced pTau, as well as damaged neuronal synapses and neurite disorganization. However, when the concentration was high (10.24 μM), amylin lost the effects against the Aβ-induced cellular AD pathology and, together with Aβ, worsened tauopathy in neurons. In the 5XFAD AD mouse model, daily peripheral amylin treatment with a low dose (200 μg/kg) more effectively reduced amyloid burden, and increased synapse, but with a high dose (800 μg/kg), it more effectively reduced tauopathy. Correspondingly, amylin treatment improved learning and memory in these mice. It demonstrates that amylin has a dose-dependent U-shape effect against AD pathogenesis. Within a physiological range, amylin is a neuroprotective hormone against AD in neurons; but when both Aβ and amylin concentrations are elevated, imbalance of Aβ and amylin may contribute to brain AD pathogenesis.
Topics: Amino Acid Sequence; Amyloid beta-Peptides; Animals; Animals, Newborn; Cells, Cultured; Dose-Response Relationship, Drug; Female; Humans; Islet Amyloid Polypeptide; Mice; Mice, Transgenic; Neurons; Peptide Fragments; Pregnancy; Rats; Rats, Wistar; Synapses; Tauopathies
PubMed: 31306122
DOI: 10.3233/JAD-190161 -
European Journal of Pain (London,... Nov 2016Amylin is a peptide from the calcitonin gene-related peptides (CGRP) family that is expressed by nociceptors. Amylin may modulate pain via a spinal action.
BACKGROUND
Amylin is a peptide from the calcitonin gene-related peptides (CGRP) family that is expressed by nociceptors. Amylin may modulate pain via a spinal action.
METHODS
The effect of amylin's administration on the formalin test of acute and tonic pain was evaluated. Amylin's ability to modulate neuronal activity was analysed by c-Fos expression at the spinal cord lumbar 4-5 region (L4-5) and brain.
RESULTS
Amylin subcutaneous administration 20 min prior, but not immediately before formalin, shortened the interphase and anticipated the beginning of the tonic pain phase. Amylin reduced the number of activated spinal cord neurons. Blockade of spinal amylin-receptors by prior L4-5 intrathecal administration of an amylin-receptor antagonist (AC187) attenuated these effects, whereas intrathecal BIBN4096 (CGRP-receptor antagonist) did not, proving that part of amylin's effects were spinally mediated via amylin-receptors. The locus coeruleus and other areas involved in descending modulation and affective responses to pain showed an increased number of activated neurons upon amylin subcutaneous administration, suggesting a role for supraspinal areas in some observed effects. L4-5 intrathecal injection of amylin or AC187 showed that both ligands attenuated tonic pain, but blockade of the amylin-receptor action by AC187 decreased further the number of paw jerks in this period.
CONCLUSIONS
Overall, data suggested that amylin modulates pain with an inflammatory component and the autoanalgesic/inhibitory mechanisms occurring in the interphase of the formalin test. Amylin might have affected the nociceptive system at different levels (spinal cord and brain), explaining the different effects observed according to the time of amylin injection. WHAT DOES THIS STUDY ADD?: Amylin modulated formalin interphase and tonic pain behaviours probably by targeting spinal neurons and affecting supraspinal areas involved in affective and modulatory components of pain. Activation of spinal amylin-receptors may contribute to the initiation of inflammatory pain mechanisms.
Topics: Amylin Receptor Agonists; Animals; Brain; Disease Models, Animal; Formaldehyde; Injections, Spinal; Islet Amyloid Polypeptide; Male; Pain; Pain Measurement; Peptide Fragments; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, Calcitonin Gene-Related Peptide; Spinal Cord
PubMed: 27264026
DOI: 10.1002/ejp.898