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Journal of Physiology and Pharmacology... Aug 2021Amylin or islet amyloid polypeptide (IAPP) is a peptide synthesized and secreted with insulin by the pancreatic β-cells. A role for amylin in the pathogenesis of type 2...
Amylin or islet amyloid polypeptide (IAPP) is a peptide synthesized and secreted with insulin by the pancreatic β-cells. A role for amylin in the pathogenesis of type 2 diabetes (T2D) by causing insulin resistance or inhibiting insulin synthesis and secretion has been suggested by in vitro and in vivo studies. These studies are consistent with the effect of endogenous amylin on pancreatic βcells to modulate and/or restrain insulin secretion. Here, we reported the correlation between amylin and insulin in rat insulinoma INS-1E cells by treating 2-deoxy-D-glucose (2-DG) and/or mannose. Cell viability was not affected by 24 h treatment with 2-DG and/or mannose, but it was significantly decreased by 48 h treatment with 5 and 10 mM 2-DG. in the 24 h treatment, the synthesis of insulin in the cells and the secretion of insulin into the media showed a significant inverse association. in the 48-h treatment, amylin synthesis vs. the secretion and insulin synthesis vs. the secretion showed a significant inverse relation. The synthesis of amylin vs. insulin and the secretion of amylin vs. insulin showed a significant inverse relationship. The p-ERK, antioxidant enzymes (Cu/Zn-superoxide dismutase (SOD), Mn-SOD, and catalase), and endoplasmic reticulum (ER) stress markers (cleaved caspase-12, CHOP, p-SAPK/JNK, and BiP/GRP78) were significantly increased or decreased by the 24 h and 48 h treatments. These data suggest the relative correlation to the synthesis of amylin by cells vs. the secretion into the media, the synthesis of amylin vs. insulin, and the secretion of amylin vs. insulin under 2-DG and/or mannose in rat insulinoma INS-1E cells. Therefore, these results can provide primary data for the hypothesis that the amylin-insulin relationships may be involved with the human amylin toxicity in pancreatic beta cells.
Topics: Animals; Deoxyglucose; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Chaperone BiP; Glucose; Insulin; Insulinoma; Islet Amyloid Polypeptide; Islets of Langerhans; Mannose; Pancreatic Neoplasms; Rats
PubMed: 34987125
DOI: 10.26402/jpp.2021.4.03 -
Physiology & Behavior Jul 2010Amylin is secreted by pancreatic beta-cells and is believed to be a physiological signal of satiation. Amylin's effect on eating has been shown to be mediated via a... (Review)
Review
Amylin is secreted by pancreatic beta-cells and is believed to be a physiological signal of satiation. Amylin's effect on eating has been shown to be mediated via a direct action at the area postrema (AP) via amylin receptors that are heterodimers of the calcitonin receptor core protein with a receptor activity modifying protein. Peripheral amylin leads to accumulation of cyclic guanosine monophosphate, phosphorylated extracellular-signal regulated kinase 1/2 and c-Fos protein in AP neurons. The particular amylin-activated AP neurons mediating its anorexigenic action seem to be noradrenergic. The central pathways mediating amylin's effects have been characterized by lesioning and tracing studies, identifying important connections from the AP to the nucleus of the solitary tract and lateral parabrachial nucleus. Amylin was shown to interact, probably at the brainstem, with other signals involved in the short term control of food intake, namely cholecystokinin, glucagon-like peptide 1 and peptide YY. Amylin also interacts with the adiposity signal leptin; this interaction, which is thought to involve the hypothalamus, may have important implications for the development of new and improved hormonal obesity treatments. In conclusion, amylin actions on food intake seem to reside primarily within the brainstem, and the associated mechanisms are starting to be unraveled. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.
Topics: Amyloid; Animals; Anorexia; Appetite Depressants; Brain Stem; Eating; Humans; Islet Amyloid Polypeptide; Neurons; Signal Transduction
PubMed: 20226802
DOI: 10.1016/j.physbeh.2010.03.001 -
Journal of Clinical Laboratory Analysis Mar 2016Insulin resistance is found in both psoriasis and Behçet's disease. No study has yet explored whether preptin and amylin, two hormones associated with insulin...
BACKGROUND
Insulin resistance is found in both psoriasis and Behçet's disease. No study has yet explored whether preptin and amylin, two hormones associated with insulin resistance, are involved in the insulin resistance observed in patients with psoriasis and Behçet's disease.
OBJECTIVES
We aimed to explore how the amounts of preptin and amylin change in psoriasis and Behçet's disease and whether they are involved in the etiopathology of these two diseases, by comparing hormone levels in patients and healthy controls.
METHODS
The study registered 30 patients with psoriasis, 30 patients with Behçet's disease, and 30 healthy volunteers (as a control group). Fasting blood sugar, triglyceride, LDL, VLDL, HDL, total cholesterol, HbA1c, C-peptide, insulin, and serum preptin and amylin levels were measured in all subjects.
RESULTS
Serum preptin and amylin levels were significantly lower in the patients with psoriasis and Behçet's disease than in the control group (P < 0.001, P = 0.004, and P = 0.008, respectively). A comparison of the serum preptin and amylin levels between the patients with psoriasis and Behçet's disease did not reveal a statistically significant difference. Serum insulin level and The homeostasis model assessment of insulin resistance (HOMA-IR) index were significantly lower in the psoriasis patient group relative to the control group (P = 0.02 and P = 0.03, respectively), while the values for the Behçet's disease group did not differ significantly from those for the control group
CONCLUSIONS
Serum levels of preptin and amylin were significantly lower in patients with psoriasis and Behçet's disease, indicating that these hormones may be a factor for development of metabolic syndrome in these two diseases.
Topics: Adult; Behcet Syndrome; Case-Control Studies; Humans; Insulin-Like Growth Factor II; Islet Amyloid Polypeptide; Peptide Fragments; Psoriasis
PubMed: 25545917
DOI: 10.1002/jcla.21831 -
Expert Review of Proteomics 2015Type II diabetes increases the risk for cognitive decline via multiple traits. Amylin is a pancreatic hormone that has amyloidogenic and cytotoxic properties similar to... (Review)
Review
Type II diabetes increases the risk for cognitive decline via multiple traits. Amylin is a pancreatic hormone that has amyloidogenic and cytotoxic properties similar to the amyloid-β peptide. The amylin hormone is overexpressed in individuals with pre-diabetic insulin resistance or obesity leading to amylin oligomerization and deposition in pancreatic islets. Amylin oligomerization was implicated in the apoptosis of the insulin-producing β-cells. Recent studies showed that brain tissue from diabetic patients with cerebrovascular dementia or Alzheimer's disease contains significant deposits of oligomerized amylin. It has also been reported that the brain amylin deposition reduced exploratory drive, recognition memory and vestibulomotor function in a rat model that overexpresses human amylin in the pancreas. These novel findings are reviewed here and the hypothesis that type II diabetes is linked with cognitive decline by amylin accumulation in the brain is proposed. Deciphering the impact of hyperamylinemia on the brain is critical for both etiology and treatment of dementia.
Topics: Animals; Dementia; Diabetes Mellitus, Type 2; Humans; Islet Amyloid Polypeptide
PubMed: 26503000
DOI: 10.1586/14789450.2015.1104251 -
Current Pharmaceutical Design 2020Type II Diabetes (T2D) is a major risk factor for Alzheimer's Disease (AD). These two diseases share several pathological features, including amyloid accumulation,... (Review)
Review
Type II Diabetes (T2D) is a major risk factor for Alzheimer's Disease (AD). These two diseases share several pathological features, including amyloid accumulation, inflammation, oxidative stress, cell death and cognitive decline. The metabolic hormone amylin and amyloid-beta are both amyloids known to self-aggregate in T2D and AD, respectively, and are thought to be the main pathogenic entities in their respective diseases. Furthermore, studies suggest amylin's ability to seed amyloid-beta aggregation, the activation of common signaling cascades in the pancreas and the brain, and the ability of amyloid beta to signal through amylin receptors (AMYR), at least in vitro. However, paradoxically, non-aggregating forms of amylin such as pramlintide are given to treat T2D and functional and neuroprotective benefits of amylin and pramlintide administration have been reported in AD transgenic mice. These paradoxical results beget a deeper study of the complex nature of amylin's signaling through the several AMYR subtypes and other receptors associated with amylin effects to be able to fully understand its potential role in mediating AD development and/or prevention. The goal of this review is to provide such critical insight to begin to elucidate how the complex nature of this hormone's signaling may explain its equally complex relationship with T2D and mechanisms of AD pathogenesis.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Diabetes Mellitus, Type 2; Islet Amyloid Polypeptide; Mice; Mice, Transgenic
PubMed: 32188374
DOI: 10.2174/1381612826666200318151146 -
Inorganic Chemistry Feb 2020Protein aggregation has attracted substantial interest because of its role in causing many serious illnesses, such as neurodegenerative diseases and type II diabetes....
Protein aggregation has attracted substantial interest because of its role in causing many serious illnesses, such as neurodegenerative diseases and type II diabetes. Recent studies have shown that protein aggregation can be prevented by forming metal ion complexes with a target protein, which affects their conformation in solution and their physical properties, such as aggregation. Thus, understanding the interactions between aggregating molecules and bioactive metal ions such as Cu is beneficial for new drug discovery. Pramlintide, a synthetic peptide drug, and its natural counterpart rat amylin are known to be resistant to aggregation because of the presence of proline residues, which are usually β-sheet "breakers" within their amino acid sequence. Here, we investigate the Cu coordination properties of pramlintide and rat amylin using nuclear magnetic resonance, circular dichroism, electron paramagnetic resonance, ultraviolet-visible spectroscopy, potentiometry, and mass spectrometry. We test the influence of Cu on the aggregation properties of these amylin analogues with thioflavin T assays. We find that both peptides form stable complexes with Cu with similar affinities at a 1:1 ratio. The N-termini of both peptides are involved in Cu binding; His18 imidazole is an equally attractive binding site in the case of pramlintide. Our results show that Cu ions influence the aggregation of pramlintide, but not that of rat amylin.
Topics: Amino Acid Sequence; Animals; Binding Sites; Coordination Complexes; Copper; Islet Amyloid Polypeptide; Protein Binding; Protein Multimerization; Rats
PubMed: 32027132
DOI: 10.1021/acs.inorgchem.9b03498 -
Basic & Clinical Pharmacology &... Sep 2020The prevalence of obesity and associated comorbidities such as type 2 diabetes and cardiovascular disease is increasing globally. Body-weight loss reduces the risk of... (Review)
Review
The prevalence of obesity and associated comorbidities such as type 2 diabetes and cardiovascular disease is increasing globally. Body-weight loss reduces the risk of morbidity and mortality in obese individuals, and thus, pharmacotherapies that induce weight loss can be of great value in improving the health and well-being of people living with obesity. Treatment with amylin and calcitonin receptor agonists reduces food intake and induces weight loss in several animal models, and a number of companies have started clinical testing for peptide analogues in the treatment of obesity and/or type 2 diabetes. Studies predominantly performed in rodent models show that amylin and the dual amylin/calcitonin receptor agonist salmon calcitonin achieve their metabolic effects by engaging areas in the brain associated with regulating homeostatic energy balance. In particular, signalling via neuronal circuits in the caudal hindbrain and the hypothalamus is implicated in mediating effects on food intake and energy expenditure. We review the current literature investigating the interaction of amylin/calcitonin receptor agonists with neurocircuits that induce the observed metabolic effects. Moreover, the status of drug development of amylin and calcitonin receptor agonists for the treatment of metabolic diseases is summarized.
Topics: Amylin Receptor Agonists; Animals; Energy Metabolism; Humans; Hypothalamus; Islet Amyloid Polypeptide; Leptin; Metabolic Diseases; Mice; Rats; Receptors, Calcitonin; Rhombencephalon
PubMed: 32363722
DOI: 10.1111/bcpt.13427 -
Journal of Molecular Biology Jan 2022Human amylin forms structurally heterogeneous amyloids that have been linked to type-2 diabetes. Thus, understanding the molecular interactions governing amylin...
Human amylin forms structurally heterogeneous amyloids that have been linked to type-2 diabetes. Thus, understanding the molecular interactions governing amylin aggregation can provide mechanistic insights in its pathogenic formation. Here, we demonstrate that fibril formation of amylin is altered by synthetic amphipathic copolymer derivatives of the styrene-maleic-acid (SMAQA and SMAEA). High-speed AFM is used to follow the real-time aggregation of amylin by observing the rapid formation of de novo globular oligomers and arrestment of fibrillation by the positively-charged SMAQA. We also observed an accelerated fibril formation in the presence of the negatively-charged SMAEA. These findings were further validated by fluorescence, SOFAST-HMQC, DOSY and STD NMR experiments. Conformational analysis by CD and FT-IR revealed that the SMA copolymers modulate the conformation of amylin aggregates. While the species formed with SMAQA are α-helical, the ones formed with SMAEA are rich in β-sheet structure. The interacting interfaces between SMAEA or SMAQA and amylin are mapped by NMR and microseconds all-atom MD simulation. SMAEA displayed π-π interaction with Phe23, electrostatic π-cation interaction with His18 and hydrophobic packing with Ala13 and Val17; whereas SMAQA showed a selective interaction with amylin's C terminus (residues 31-37) that belongs to one of the two β-sheet regions (residues 14-19 and 31-36) involved in amylin fibrillation. Toxicity analysis showed both SMA copolymers to be non-toxic in vitro and the amylin species formed with the copolymers showed minimal deformity to zebrafish embryos. Together, this study demonstrates that chemical tools, such as copolymers, can be used to modulate amylin aggregation, alter the conformation of species.
Topics: Amyloid; Animals; Computer Simulation; Diabetes Mellitus, Type 2; Fluorescence; Humans; Hydrophobic and Hydrophilic Interactions; Islet Amyloid Polypeptide; Maleates; Molecular Conformation; Protein Aggregates; Spectroscopy, Fourier Transform Infrared; Styrene; Styrenes; Zebrafish
PubMed: 34883118
DOI: 10.1016/j.jmb.2021.167385 -
Domestic Animal Endocrinology Jan 2021Amylin is a pancreatic hormone cosecreted along with insulin and involved in pancreatic amyloidosis and β-cell apoptosis in diabetic cats and humans. Amylin is usually...
Amylin is a pancreatic hormone cosecreted along with insulin and involved in pancreatic amyloidosis and β-cell apoptosis in diabetic cats and humans. Amylin is usually elevated in early stages of type 2 diabetes but recently was found to be increased in acute and chronic pancreatitis in humans. Currently, there are little data about feline amylin propensity to fibrillate and no information on circulating levels of this hormone during feline pancreatitis. We compared 4 amylin analogues and found cat amylin to be more prone to amyloid fibrillation than human amylin, the triple-proline analogue pramlintide and rat amylin. We also measured plasma amylin levels in healthy lean cats, diabetic cats, and cats with pancreatitis. Plasma amylin was higher in diabetic cats compared with healthy lean cats (P < 0.001). Interestingly, amylin levels during pancreatitis were higher than those of both lean cats (P < 0.0001) and diabetic cats without pancreatitis (P < 0.005). These data support evidence of feline amylin being more prone to aggregation than human amylin in vitro, which may influence diabetes mellitus progression and β-cell failure in vivo. Furthermore, our data show an increase in amylin levels during feline pancreatitis and the need for future research on the role of this hormone in the pathogenesis of pancreatic inflammation associated to feline diabetes mellitus.
Topics: Animals; Case-Control Studies; Cat Diseases; Cats; Diabetes Mellitus; Female; Islet Amyloid Polypeptide; Male; Pancreatitis; Protein Aggregation, Pathological
PubMed: 32841886
DOI: 10.1016/j.domaniend.2020.106532 -
Physiology & Behavior Sep 2014Amylin is a pancreas-derived neuropeptide that acts in the central nervous system (CNS) to reduce food intake. Much of the literature describing the anorectic effects of... (Review)
Review
Amylin is a pancreas-derived neuropeptide that acts in the central nervous system (CNS) to reduce food intake. Much of the literature describing the anorectic effects of amylin are focused on amylin's actions in the area postrema, a hindbrain circumventricular structure. Although the area postrema is certainly an important site that mediates the intake-suppressive effects of amylin, several pieces of evidence indicate that amylin may also promote negative energy balance through action in additional CNS nuclei, including hypothalamic and mesolimbic structures. Therefore, this review highlights the distributed neural network mediating the feeding effects of amylin signaling with special attention being devoted to the recent discovery that the ventral tegmental area is physiologically relevant for amylin-mediated control of feeding. The production of amylin by alternative, extra-pancreatic sources and its potential relevance to food intake regulation is also considered. Finally, the utility of amylin and amylin-like compounds as a component of combination pharmacotherapies for the treatment of obesity is discussed.
Topics: Animals; Appetite Regulation; Central Nervous System; Eating; Energy Metabolism; Humans; Islet Amyloid Polypeptide; Obesity
PubMed: 24480072
DOI: 10.1016/j.physbeh.2014.01.013