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Thomas A. Lutz - One of the best experts on this subject based on the ideXlab platform.
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Systemic and Central Amylin, Amylin Receptor Signaling, and Their Physiological and Pathophysiological Roles in Metabolism.
Comprehensive Physiology, 2020Co-Authors: Christelle Le Foll, Thomas A. LutzAbstract:This article in the Neural and Endocrine Section of Comprehensive Physiology discusses the physiology and pathophysiology of the pancreatic hormone Amylin. Shortly after its discovery in 1986, Amylin has been shown to reduce food intake as a satiation signal to limit meal size. Amylin also affects food reward, sensitizes the brain to the catabolic actions of leptin, and may also play a prominent role in the development of certain brain areas that are involved in metabolic control. Amylin may act at different sites in the brain in addition to the area postrema (AP) in the caudal hindbrain. In particular, the sensitizing effect of Amylin on leptin action may depend on a direct interaction in the hypothalamus. The concept of central pathways mediating Amylin action became more complex after the discovery that Amylin is also synthesized in certain hypothalamic areas but the interaction between central and peripheral Amylin signaling remains currently unexplored. Amylin may also play a dominant pathophysiological role that is associated with the aggregation of monomeric Amylin into larger, cytotoxic molecular entities. This aggregation in certain species may contribute to the development of type 2 diabetes mellitus but also cardiovascular disease. Amylin receptor pharmacology is complex because several distinct Amylin receptor subtypes have been described, because other neuropeptides [e.g., calcitonin gene-related peptide (CGRP)] can also bind to Amylin receptors, and because some components of the functional Amylin receptor are also used for other G-protein coupled receptor (GPCR) systems. © 2020 American Physiological Society. Compr Physiol 10:811-837, 2020.
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Amylin brain circuitry
Peptides, 2020Co-Authors: Lavinia Boccia, Thomas A. Lutz, Salome Gamakharia, Bernd Coester, Lynda Whiting, Christelle Le FollAbstract: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.
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Amylin - Its role in the homeostatic and hedonic control of eating and recent developments of Amylin analogs to treat obesity.
Molecular metabolism, 2017Co-Authors: Christina N. Boyle, Thomas A. Lutz, Christelle Le FollAbstract:Abstract 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.
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The satiating hormone Amylin enhances neurogenesis in the area postrema of adult rats
Elsevier, 2016Co-Authors: Claudia G. Liberini, Tito Borner, Christina N. Boyle, Thomas A. LutzAbstract:Objective: Adult neurogenesis in the subgranular zone and subventricular zone is generally accepted, but its existence in other brain areas is still controversial. Circumventricular organs, such as the area postrema (AP) have recently been described as potential neurogenic niches in the adult brain. The AP is the major site of action of the satiating hormone Amylin. Amylin has been shown to promote the formation of neuronal projections originating from the AP in neonatal rodents but the role of Amylin in adult neurogenesis remains unknown. Methods: To test this, we first performed an RNA-sequencing of the AP of adult rats acutely injected with either Amylin (20 μg/kg), Amylin plus the Amylin receptor antagonist AC187 (500 μg/kg) or vehicle. Second, animals were subcutaneously equipped with minipumps releasing either Amylin (50 μg/kg/day) or vehicle for 3 weeks to assess cell proliferation and differentiation with the 5′-bromo-2-deoxyuridine (BrdU) technique. Results: Acute Amylin injections affected genes involved in pathways and processes that control adult neurogenesis. Amylin consistently upregulated NeuroD1 transcript and protein in the adult AP, and this effect was blocked by the co-administration of AC187. Further, chronic Amylin treatment increased the number of newly proliferated AP-cells and significantly promoted their differentiation into neurons rather than astrocytes. Conclusion: Our findings revealed a novel role of the satiating hormone Amylin in promoting neurogenesis in the AP of adult rats. Keywords: Amylin, Adult neurogenesis, Area postrema, BrdU, Circumventricular organ
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The interaction of Amylin with other hormones in the control of eating.
Diabetes obesity & metabolism, 2012Co-Authors: Thomas A. LutzAbstract:Twenty years of research established Amylin as an important control of energy homeostasis. Amylin controls nutrient and energy fluxes by reducing energy intake, by modulating nutrient utilization via an inhibition of postprandial glucagon secretion and by increasing energy disposal via a prevention of compensatory decreases of energy expenditure in weight reduced individuals. Like many other gastrointestinal hormones, Amylin is secreted in response to meals and it reduces eating by promoting meal-ending satiation. Not surprisingly, Amylin interacts with many of these hormones to control eating. These interactions seem to occur at different levels because Amylin seems to mediate the eating inhibitory effect of some of these gastrointestinal hormones, and the combination of some of these hormones seems to lead to a stronger reduction in eating than single hormones alone. Amylin's effect on eating is thought to be mediated by a stimulation of specific Amylin receptors in the area postrema. Secondary brain sites that were defined to mediate Amylin action - and hence potential additional sites of interaction with other hormones - include the nucleus of the solitary tract, the lateral parabrachial nucleus, the lateral hypothalamic area and other hypothalamic nuclei. The focus of this review is to summarize the current knowledge of Amylin interactions in the control of eating. In most cases, these interactions have only been studied at a descriptive rather than a mechanistic level and despite the clear knowledge on primary sites of Amylin action, the interaction sites between Amylin and other hormones are often unknown.
Florin Despa - One of the best experts on this subject based on the ideXlab platform.
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Amylin and diabetic cardiomyopathy – Amylin-induced sarcolemmal Ca2 + leak is independent of diabetic remodeling of myocardium
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2018Co-Authors: Miao Liu, Amanda Hoskins, Nirmal Verma, Donald M Bers, Sanda Despa, Florin DespaAbstract:Amylin is a pancreatic β-cell hormone co-secreted with insulin, plays a role in normal glucose homeostasis, and forms amyloid in the pancreatic islets of individuals with type-2 diabetes. Aggregated Amylin is also found in blood and extra-pancreatic tissues, including myocardium. Myocardial Amylin accumulation is associated with myocyte Ca2+ dysregulation in diabetic rats expressing human Amylin. Whether deposition of Amylin in the heart is a consequence of or a contributor to diabetic cardiomyopathy remains unknown. We used Amylin knockout (AKO) mice intravenously infused with either human Amylin (i.e, the aggregated form) or non-amyloidogenic (i.e., monomeric) rodent Amylin to test the hypothesis that aggregated Amylin accumulates in the heart in the absence of diabetes. AKO mice infused with human Amylin, but not rodent Amylin, showed Amylin deposits in the myocardium. Cardiac Amylin level was larger in males compared to females. Sarcolemmal Ca2+ leak and Ca2+ transients were increased in myocytes isolated from males infused with human Amylin while no significant changes occurred in either females injected with human Amylin or in rat Amylin-infused mice. In isolated cardiac myocytes, the Amylin receptor antagonist AC-187 did not effectively block the interaction of Amylin with the sarcolemma. In conclusion, circulating aggregated Amylin accumulates preferentially in male vs. female hearts and its effects on myocyte Ca2+ cycling do not require diabetic remodeling of the myocardium. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
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Amylin and diabetic cardiomyopathy - Amylin-induced sarcolemmal Ca2+ leak is independent of diabetic remodeling of myocardium.
Biochimica et biophysica acta. Molecular basis of disease, 2017Co-Authors: Miao Liu, Amanda Hoskins, Nirmal Verma, Donald M Bers, Sanda Despa, Florin DespaAbstract:Amylin is a pancreatic β-cell hormone co-secreted with insulin, plays a role in normal glucose homeostasis, and forms amyloid in the pancreatic islets of individuals with type-2 diabetes. Aggregated Amylin is also found in blood and extra-pancreatic tissues, including myocardium. Myocardial Amylin accumulation is associated with myocyte Ca2+ dysregulation in diabetic rats expressing human Amylin. Whether deposition of Amylin in the heart is a consequence of or a contributor to diabetic cardiomyopathy remains unknown. We used Amylin knockout (AKO) mice intravenously infused with either human Amylin (i.e, the aggregated form) or non-amyloidogenic (i.e., monomeric) rodent Amylin to test the hypothesis that aggregated Amylin accumulates in the heart in the absence of diabetes. AKO mice infused with human Amylin, but not rodent Amylin, showed Amylin deposits in the myocardium. Cardiac Amylin level was larger in males compared to females. Sarcolemmal Ca2+ leak and Ca2+ transients were increased in myocytes isolated from males infused with human Amylin while no significant changes occurred in either females injected with human Amylin or in rat Amylin-infused mice. In isolated cardiac myocytes, the Amylin receptor antagonist AC-187 did not effectively block the interaction of Amylin with the sarcolemma. In conclusion, circulating aggregated Amylin accumulates preferentially in male vs. female hearts and its effects on myocyte Ca2+ cycling do not require diabetic remodeling of the myocardium. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
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intraneuronal Amylin deposition peroxidative membrane injury and increased il 1β synthesis in brains of alzheimer s disease patients with type 2 diabetes and in diabetic hip rats
Journal of Alzheimer's Disease, 2016Co-Authors: Nirmal Verma, Miao Liu, Jing Chen, Haining Zhu, Martin Chow, Louis B Hersh, Florin DespaAbstract:Amylin is a hormone synthesized and co-secreted with insulin by pancreatic β-cells that crosses the blood-brain barrier and regulates satiety. Amylin from humans (but not rodents) has an increased propensity to aggregate into pancreatic islet amyloid deposits that contribute to β-cell mass depletion and development of type-2 diabetes by inducing oxidative stress and inflammation. Recent studies demonstrated that aggregated Amylin also accumulates in brains of Alzheimer's disease (AD) patients, preponderantly those with type-2 diabetes. Here, we report that, in addition to Amylin plaques and mixed Amylin-Aβ deposits, brains of diabetic patients with AD show Amylin immunoreactive deposits inside the neurons. Neuronal Amylin formed adducts with 4-hydroxynonenal (4-HNE), a marker of peroxidative membrane injury, and increased synthesis of the proinflammatory cytokine interleukin (IL)-1β. These pathological changes were mirrored in rats expressing human Amylin in pancreatic islets (HIP rats) and mice intravenously injected with aggregated human Amylin, but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat Amylin. In cultured primary hippocampal rat neurons, aggregated Amylin increased IL-1β synthesis via membrane destabilization and subsequent generation of 4-HNE. These effects were blocked by membrane stabilizers and lipid peroxidation inhibitors. Thus, elevated circulating levels of aggregated Amylin negatively affect the neurons causing peroxidative membrane injury and aberrant inflammatory responses independent of other confounding factors of diabetes. The present results are consistent with the pathological role of aggregated Amylin in the pancreas, demonstrate a novel contributing mechanism to neurodegeneration, and suggest a direct, potentially treatable link of type-2 diabetes with AD.
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neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of Amylin
Molecular Neurodegeneration, 2014Co-Authors: Sarah Srodulski, Savita Sharma, Adam B Bachstetter, Jennifer M Brelsfoard, Conrado Pascual, Xinmin Imon S Xie, Kathryn E Saatman, Linda J Van Eldik, Florin DespaAbstract:We recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment contains deposits of Amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells. Amylin deposition is promoted by chronic hypersecretion of Amylin (hyperAmylinemia), which is common in humans with obesity or pre-diabetic insulin resistance. Human Amylin oligomerizes quickly when oversecreted, which is toxic, induces inflammation in pancreatic islets and contributes to the development of T2D. Here, we tested the hypothesis that accumulation of oligomerized Amylin affects brain function. In contrast to Amylin from humans, rodent Amylin is neither amyloidogenic nor cytotoxic. We exploited this fact by comparing rats overexpressing human Amylin in the pancreas (HIP rats) with their littermate rats which express only wild-type (WT) non-amyloidogenic rodent Amylin. Cage activity, rotarod and novel object recognition tests were performed on animals nine months of age or older. Amylin deposition in the brain was documented by immunohistochemistry, and western blot. We also measured neuroinflammation by immunohistochemistry, quantitative real-time PCR and cytokine protein levels. Compared to WT rats, HIP rats show i) reduced exploratory drive, ii) impaired recognition memory and iii) no ability to improve the performance on the rotarod. The development of neurological deficits is associated with Amylin accumulation in the brain. The level of oligomerized Amylin in supernatant fractions and pellets from brain homogenates is almost double in HIP rats compared with WT littermates (P 50 μm diameter) were also occasionally seen in HIP rat brains. Accumulation of oligomerized Amylin alters the brain structure at the molecular level. Immunohistochemistry analysis with an ED1 antibody indicates possible activated microglia/macrophages which are clustering in areas positive for Amylin infiltration. Multiple inflammatory markers are expressed in HIP rat brains as opposed to WT rats, confirming that Amylin deposition in the brain induces a neuroinflammatory response. HyperAmylinemia promotes accumulation of oligomerized Amylin in the brain leading to neurological deficits through an oligomerized Amylin-mediated inflammatory response. Additional studies are needed to determine whether brain Amylin accumulation may predispose to diabetic brain injury and cognitive decline.
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Amylin Interacts with Aβ and May Accelerate the Development of Dementia
Biophysical Journal, 2014Co-Authors: Kaleena Jackson, Simon Xie, Florin DespaAbstract:Epidemiologically, type-2 diabetes (T2D) doubles the risk for dementia linked to cerebrovascular disease and/or Alzheimer's disease (AD). We have recently found that, in addition to plaques laden with Aβ, the brain of demented T2D patients also contains large deposits of Amylin, a protein that makes up the pancreatic amyloid in T2D. Deposition of Amylin (or islet amyloid polypeptide; IAPP) is promoted by hyperAmylinemia, a key component of the metabolic syndrome. In the brain, Amylin was identified in the blood vessel wall, perivascular space and tissue parenchyma. Moreover, we found Amylin forming the core protein deposit of some amyloid plaques or co-localized with Aβ in combined plaques suggesting an Amylin-Aβ pathology. Intriguingly, Amylin deposition was also detected in brain specimens from patients with AD without clinically apparent diabetes. Amylin pathology in AD brain was similar to that in brain samples from the T2D patients group, including buildup on blood vessel walls and parenchyma. In contrast, brain specimens from age-matched healthy humans show only sporadic Amylin deposits in blood vessels and brain parenchyma. Cerebral deposition of Amylin in non-diabetic AD patients may be due to insulin resistance, which is common in aging.To test the impact of hyperAmylinemia on brain function, we use a rat model of T2D expressing human Amylin in the pancreas (the HIP rat). We found that the infiltration of oligomerized Amylin in cortical arteries induces lipid peroxidation and triggers an inflammatory response. As a result, HIP rats display changes in spontaneous activity and coordination. In contrast, rats matched for weight, glucose and age, but expressing only the non-amyloidogenic rat Amylin, show no Amylin accumulation and no behavioral changes.In conclusion, hyperAmylinemia promotes Amylin deposition in the brain contributing to the development of cerebrovascular injury and neurological deficit.
Yifat Miller - One of the best experts on this subject based on the ideXlab platform.
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unique inversion events of residues around the backbone in the turn domain of β arches in Amylin fibrils
ACS Chemical Neuroscience, 2019Co-Authors: Yoav Atsmonraz, Vered Winemanfisher, Michal Baram, Yifat MillerAbstract:Orientational inversion events of residues along the turn domains of Amylin fibrils have been detected. This exceptional phenomenon has been observed in isolated Amylin fibrils and in the cross-seeding Amylin-Aβ and Amylin-NAC fibrils. These new findings provide new avenues for detection of side chain flipping and side chain inversion events in turn domains and loops of various proteins.
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Unique Inversion Events of Residues around the Backbone in the Turn Domain of β‑Arches in Amylin Fibrils
2018Co-Authors: Yoav Atsmon-raz, Vered Wineman-fisher, Michal Baram, Yifat MillerAbstract:Orientational inversion events of residues along the turn domains of Amylin fibrils have been detected. This exceptional phenomenon has been observed in isolated Amylin fibrils and in the cross-seeding Amylin-Aβ and Amylin-NAC fibrils. These new findings provide new avenues for detection of side chain flipping and side chain inversion events in turn domains and loops of various proteins
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structural insights into the polymorphism of self assembled Amylin oligomers
ChemInform, 2016Co-Authors: Vered Winemanfisher, Yifat MillerAbstract:Type 2 diabetes (T2D) affects over 300 million people worldwide. The main component, found in the pancreas of 95 % of T2D patients, is Amylin oligomers and fibrils. So far, four different molecular structures of the self-assembled Amylin oligomers have been observed experimentally: two ssNMR models and two crystal models. This review illustrates that there are further self-assembled Amylin oligomers that differ in the orientations of the side chains along the β-arch and are all derived from the two ssNMR models. This review focuses on polymorphism of the self-assembled Amylin oligomers. It also provides the various pathway mechanisms which lead to various Amylin oligomers. Finally, it illustrates that interactions of Amylin oligomers with further amyloids, such as Aβ oligomers, increase the polymorphism by forming polymorphic states of Amylin-Aβ oligomers with various pathway mechanisms. The polymorphism of Amylin oligomers and the polymorphism of the cross-seeding Amylin-Aβ oligomers phenomena could contribute to explaining, at least in part, the still unknown origins of the pathological conditions, and may assist in preventing aggregation in amyloidogenic diseases with drug design and other therapeutic approaches.
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Insight into the Metal Binding Sites in Amylin Aggregates
Biophysical Journal, 2015Co-Authors: Vered Wineman-fisher, Yifat MillerAbstract:Amylin peptide consists of 37 residues. The aggregation of Amylin is one of the symptoms of type 2 diabetes (T2D). Amylin's oligomers that are toxic lead to β-cells death and thus to decreasing of insulin's release to the blood and to progressing of T2D. The factors that affect Amylin aggregation are elusive, however it is known that Amylin peptides are found with insulin and zinc ions in the pancreatic β-cells and that zinc ions bind to Amylin oligomers and may inhibit Amylin aggregation. So far, it is unknown how zinc ions bind Amylin oligomers at the atomic resolution. Understanding the mechanism of zinc-binding sites in Amylin oligomers is important for effective drug design to prevent and alleviate aggregation. We constructed Amylin oligomers based on ssNMR and x-ray crystallography. These experimental studies illustrate four different Amylin oligomeric models, which differ in the orientation of His18 in accordance of the core domain of Amylin. Other ssNMR study proposed that the binding site of zinc ions is His18. We applied molecular dynamics simulations to examine our constructed models. Two main conclusions had been obtained from our simulations. First, the binding site of zinc in Amylin is His18 which is located outside the core domain. Second, the zinc:Amylin ratio is 1:2.
D G Parkes - One of the best experts on this subject based on the ideXlab platform.
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Antiobesity effects of the β-cell hormone Amylin in combination with phentermine or sibutramine in diet-induced obese rats
International Journal of Obesity, 2008Co-Authors: J D Roth, J L Trevaskis, J Athanacio, N C Kesty, T Coffey, Christian Weyer, J Wilson, C Mack, D G ParkesAbstract:Objective: To characterize the interactive effects of Amylin with phentermine or sibutramine on food intake, body weight/composition and gene expression in diet-induced obese (DIO) rats. Design: DIO rats were intraperitoneally injected with a single dose of Amylin (10 μg kg^−1) and/or phentermine (1 mg kg^−1) or chronically infused with Amylin (100 μg kg^−1 d^−1) or vehicle with or without phentermine (0.5–10 mg kg^−1 d^−1) or sibutramine (3 mg kg^−1 d^−1) using two surgically implanted subcutaneous osmotic mini-pumps. Measurements: Twenty-four hour food intake, locomotor activity and components of meal microstructure (meal size, latency, duration and intermeal interval) were measured following acute administration (Amylin, phentermine or Amylin+phentermine). Body weight and composition (for Amylin and/or sibutramine or phentermine) and metabolism-related gene mRNA expression in the liver (fatty acid synthase, stearoyl-CoA desaturase-1 and carnitine palmitoyltransferase-1) and brown fat (β-adrenergic receptors and uncoupling protein-1) were measured (for Amylin and/or phentermine) after sustained infusion (2 weeks). Results: Acute co-administration of Amylin (10 μg kg^−1) and phentermine (1 mg kg^−1) reduced acute food intake (up to 19 h) more than either monotherapy. In two studies, sustained subcutaneous infusion of Amylin for 2 weeks decreased cumulative food intake (22%) and vehicle-corrected body weight gain (∼4–8%). Phentermine's anorexigenic (10–17%) and weight-reducing effects (∼0–5%) were only evident at the highest dose tested (10 mg kg^−1 d^−1). Combination of Amylin (100 μg kg^−1 d^−1) and phentermine reduced food intake (30–43%), body weight (8–12%) and adiposity to a greater extent than either monotherapy. Amylin prevented phentermine-induced reductions in UCP-1 mRNA in brown adipose tissue. When Amylin+sibutramine were infused, mathematically additive decreases in food intake (up to 45%) and body weight (up to 12%) were evident. Similar to Amylin+phentermine treatment, Amylin+sibutramine mediated weight loss was attributable to significant reductions in fat mass. Conclusions: Combined treatment of DIO rats with the pancreatic β-cell hormone Amylin and phentermine or sibutramine resulted in additive anorexigenic, weight- and fat-reducing effects.
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antiobesity effects of the beta cell hormone Amylin in combination with phentermine or sibutramine in diet induced obese rats
International Journal of Obesity, 2008Co-Authors: J D Roth, J L Trevaskis, J Athanacio, N C Kesty, T Coffey, J K Wilson, Christine M Mack, Christian Weyer, D G ParkesAbstract:To characterize the interactive effects of Amylin with phentermine or sibutramine on food intake, body weight/composition and gene expression in diet-induced obese (DIO) rats. DIO rats were intraperitoneally injected with a single dose of Amylin (10 μg kg−1) and/or phentermine (1 mg kg−1) or chronically infused with Amylin (100 μg kg−1 d−1) or vehicle with or without phentermine (0.5–10 mg kg−1 d−1) or sibutramine (3 mg kg−1 d−1) using two surgically implanted subcutaneous osmotic mini-pumps. Twenty-four hour food intake, locomotor activity and components of meal microstructure (meal size, latency, duration and intermeal interval) were measured following acute administration (Amylin, phentermine or Amylin+phentermine). Body weight and composition (for Amylin and/or sibutramine or phentermine) and metabolism-related gene mRNA expression in the liver (fatty acid synthase, stearoyl-CoA desaturase-1 and carnitine palmitoyltransferase-1) and brown fat (β-adrenergic receptors and uncoupling protein-1) were measured (for Amylin and/or phentermine) after sustained infusion (2 weeks). Acute co-administration of Amylin (10 μg kg−1) and phentermine (1 mg kg−1) reduced acute food intake (up to 19 h) more than either monotherapy. In two studies, sustained subcutaneous infusion of Amylin for 2 weeks decreased cumulative food intake (22%) and vehicle-corrected body weight gain (∼4–8%). Phentermine's anorexigenic (10–17%) and weight-reducing effects (∼0–5%) were only evident at the highest dose tested (10 mg kg−1 d−1). Combination of Amylin (100 μg kg−1 d−1) and phentermine reduced food intake (30–43%), body weight (8–12%) and adiposity to a greater extent than either monotherapy. Amylin prevented phentermine-induced reductions in UCP-1 mRNA in brown adipose tissue. When Amylin+sibutramine were infused, mathematically additive decreases in food intake (up to 45%) and body weight (up to 12%) were evident. Similar to Amylin+phentermine treatment, Amylin+sibutramine mediated weight loss was attributable to significant reductions in fat mass. Combined treatment of DIO rats with the pancreatic β-cell hormone Amylin and phentermine or sibutramine resulted in additive anorexigenic, weight- and fat-reducing effects.
Miao Liu - One of the best experts on this subject based on the ideXlab platform.
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Amylin and diabetic cardiomyopathy – Amylin-induced sarcolemmal Ca2 + leak is independent of diabetic remodeling of myocardium
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2018Co-Authors: Miao Liu, Amanda Hoskins, Nirmal Verma, Donald M Bers, Sanda Despa, Florin DespaAbstract:Amylin is a pancreatic β-cell hormone co-secreted with insulin, plays a role in normal glucose homeostasis, and forms amyloid in the pancreatic islets of individuals with type-2 diabetes. Aggregated Amylin is also found in blood and extra-pancreatic tissues, including myocardium. Myocardial Amylin accumulation is associated with myocyte Ca2+ dysregulation in diabetic rats expressing human Amylin. Whether deposition of Amylin in the heart is a consequence of or a contributor to diabetic cardiomyopathy remains unknown. We used Amylin knockout (AKO) mice intravenously infused with either human Amylin (i.e, the aggregated form) or non-amyloidogenic (i.e., monomeric) rodent Amylin to test the hypothesis that aggregated Amylin accumulates in the heart in the absence of diabetes. AKO mice infused with human Amylin, but not rodent Amylin, showed Amylin deposits in the myocardium. Cardiac Amylin level was larger in males compared to females. Sarcolemmal Ca2+ leak and Ca2+ transients were increased in myocytes isolated from males infused with human Amylin while no significant changes occurred in either females injected with human Amylin or in rat Amylin-infused mice. In isolated cardiac myocytes, the Amylin receptor antagonist AC-187 did not effectively block the interaction of Amylin with the sarcolemma. In conclusion, circulating aggregated Amylin accumulates preferentially in male vs. female hearts and its effects on myocyte Ca2+ cycling do not require diabetic remodeling of the myocardium. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
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Amylin and diabetic cardiomyopathy - Amylin-induced sarcolemmal Ca2+ leak is independent of diabetic remodeling of myocardium.
Biochimica et biophysica acta. Molecular basis of disease, 2017Co-Authors: Miao Liu, Amanda Hoskins, Nirmal Verma, Donald M Bers, Sanda Despa, Florin DespaAbstract:Amylin is a pancreatic β-cell hormone co-secreted with insulin, plays a role in normal glucose homeostasis, and forms amyloid in the pancreatic islets of individuals with type-2 diabetes. Aggregated Amylin is also found in blood and extra-pancreatic tissues, including myocardium. Myocardial Amylin accumulation is associated with myocyte Ca2+ dysregulation in diabetic rats expressing human Amylin. Whether deposition of Amylin in the heart is a consequence of or a contributor to diabetic cardiomyopathy remains unknown. We used Amylin knockout (AKO) mice intravenously infused with either human Amylin (i.e, the aggregated form) or non-amyloidogenic (i.e., monomeric) rodent Amylin to test the hypothesis that aggregated Amylin accumulates in the heart in the absence of diabetes. AKO mice infused with human Amylin, but not rodent Amylin, showed Amylin deposits in the myocardium. Cardiac Amylin level was larger in males compared to females. Sarcolemmal Ca2+ leak and Ca2+ transients were increased in myocytes isolated from males infused with human Amylin while no significant changes occurred in either females injected with human Amylin or in rat Amylin-infused mice. In isolated cardiac myocytes, the Amylin receptor antagonist AC-187 did not effectively block the interaction of Amylin with the sarcolemma. In conclusion, circulating aggregated Amylin accumulates preferentially in male vs. female hearts and its effects on myocyte Ca2+ cycling do not require diabetic remodeling of the myocardium. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
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intraneuronal Amylin deposition peroxidative membrane injury and increased il 1β synthesis in brains of alzheimer s disease patients with type 2 diabetes and in diabetic hip rats
Journal of Alzheimer's Disease, 2016Co-Authors: Nirmal Verma, Miao Liu, Jing Chen, Haining Zhu, Martin Chow, Louis B Hersh, Florin DespaAbstract:Amylin is a hormone synthesized and co-secreted with insulin by pancreatic β-cells that crosses the blood-brain barrier and regulates satiety. Amylin from humans (but not rodents) has an increased propensity to aggregate into pancreatic islet amyloid deposits that contribute to β-cell mass depletion and development of type-2 diabetes by inducing oxidative stress and inflammation. Recent studies demonstrated that aggregated Amylin also accumulates in brains of Alzheimer's disease (AD) patients, preponderantly those with type-2 diabetes. Here, we report that, in addition to Amylin plaques and mixed Amylin-Aβ deposits, brains of diabetic patients with AD show Amylin immunoreactive deposits inside the neurons. Neuronal Amylin formed adducts with 4-hydroxynonenal (4-HNE), a marker of peroxidative membrane injury, and increased synthesis of the proinflammatory cytokine interleukin (IL)-1β. These pathological changes were mirrored in rats expressing human Amylin in pancreatic islets (HIP rats) and mice intravenously injected with aggregated human Amylin, but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat Amylin. In cultured primary hippocampal rat neurons, aggregated Amylin increased IL-1β synthesis via membrane destabilization and subsequent generation of 4-HNE. These effects were blocked by membrane stabilizers and lipid peroxidation inhibitors. Thus, elevated circulating levels of aggregated Amylin negatively affect the neurons causing peroxidative membrane injury and aberrant inflammatory responses independent of other confounding factors of diabetes. The present results are consistent with the pathological role of aggregated Amylin in the pancreas, demonstrate a novel contributing mechanism to neurodegeneration, and suggest a direct, potentially treatable link of type-2 diabetes with AD.