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https://www.readbyqxmd.com/read/28342771/the-area-postrema-ap-and-the-parabrachial-nucleus-pbn-are-important-sites-for-salmon-calcitonin-sct-to-decrease-evoked-phasic-dopamine-release-in-the-nucleus-accumbens-nac
#1
Lynda Whiting, James E McCutcheon, Christina N Neuner-Boyle, Mitchell F Roitman, Thomas A Lutz
The pancreatic hormone amylin and its agonist salmon calcitonin (sCT) act via the area postrema (AP) and the lateral parabrachial nucleus (PBN) to reduce food intake. Investigations of amylin and sCT signaling in the ventral tegmental area (VTA) and nucleus accumbens (NAc) suggest that the eating inhibitory effect of amylin is, in part, mediated through the mesolimbic 'reward' pathway. Indeed, administration of the sCT directly to the VTA decreased phasic dopamine release (DA) in the NAc. However, it is not known if peripheral amylin modulates the mesolimbic system directly or whether this occurs via the AP and PBN...
March 22, 2017: Physiology & Behavior
https://www.readbyqxmd.com/read/28325868/inositol-phosphates-and-phosphoinositides-activate-insulin-degrading-enzyme-while-phosphoinositides-also-mediate-binding-to-endosomes
#2
Eun Suk Song, HyeIn Jang, Hou-Fu Guo, Maria A Juliano, Luiz Juliano, Andrew J Morris, Emilia Galperin, David W Rodgers, Louis B Hersh
Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid β peptides. Polyanions activate IDE toward some substrates, yet an endogenous polyanion activator has not yet been identified. Here we report that inositol phosphates (InsPs) and phosphatdidylinositol phosphates (PtdInsPs) serve as activators of IDE. InsPs and PtdInsPs interact with the polyanion-binding site located on an inner chamber wall of the enzyme. InsPs activate IDE by up to ∼95-fold, affecting primarily Vmax The extent of activation and binding affinity correlate with the number of phosphate groups on the inositol ring, with phosphate positional effects observed...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28317098/cgrp-receptor-activity-in-mice-with-global-expression-of-human-receptor-activity-modifying-protein-1
#3
Keegan J Bohn, Baolin Li, Xiaofang Huang, Bianca N Mason, Anne-Sophie Wattiez, Adisa Kuburas, Christopher S Walker, Peiyi Yang, Jianliang Yu, Beverly A Heinz, Kirk W Johnson, Andrew F Russo
BACKGROUND AND PURPOSE: CGRP is a potent vasodilator and nociceptive neuropeptide linked to migraine. CGRP receptors are heterodimers of receptor activity-modifying protein-1 (RAMP1) and either calcitonin receptor-like receptor (CLR), which forms the canonical CGRP receptor, or calcitonin receptor (CTR), which forms the amylin-1 (AMY1 ) receptor. The goal of this study was to test whether transgenic mice globally expressing human RAMP1 (hRAMP1) have increased CGRP receptor activity and whether the receptors are sensitive to the human selective antagonist telcagepant...
March 20, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28292761/optimization-of-tolerability-and-efficacy-of-dual-amylin-and-calcitonin-receptor-agonist-kbp-089-through-dose-escalation-and-combination-with-a-glp-1-analogue
#4
Sofie Gydesen, Kim Vietz Andreassen, Sara Toftegaard Hjuler, Lars I Hellgren, Morten Asser Karsdal, Kim Henriksen
Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study, we investigated how to optimize tolerability, while maintaining efficacy of KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in HFD rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro, demonstrated a prolonged receptor activation, and potently reduced acute food intake. HFD rats dosed every or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and bodyweight in rats dosed every second day...
March 14, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28281109/neuropeptides-as-a-marker-for-chronic-headache
#5
REVIEW
Nuria Riesco, Eva Cernuda-Morollón, Julio Pascual
PURPOSE OF REVIEW: The purpose of this review is to revise current evidence on trigemino-vascular system (TVS) neuropeptides as potential biomarkers for chronic primary headaches, mainly for chronic migraine (CM). RECENT FINDINGS: Within sensory neuropeptides, released by an activated trigeminal nerve, calcitonin gene-related peptide (CGRP) levels seem to be a good biomarker of acute migraine and somewhat sensitive and specific for CM. CGRP, however, is not increased in 20-30% of CM patients, which suggests that CGRP is not the only neuropeptide involved in migraine pain generation and maintenance...
April 2017: Current Pain and Headache Reports
https://www.readbyqxmd.com/read/28275047/the-new-biology-and-pharmacology-of-glucagon
#6
REVIEW
T D Müller, B Finan, C Clemmensen, R D DiMarchi, M H Tschöp
In the last two decades we have witnessed sizable progress in defining the role of gastrointestinal signals in the control of glucose and energy homeostasis. Specifically, the molecular basis of the huge metabolic benefits in bariatric surgery is emerging while novel incretin-based medicines based on endogenous hormones such as glucagon-like peptide 1 and pancreas-derived amylin are improving diabetes management. These and related developments have fostered the discovery of novel insights into endocrine control of systemic metabolism, and in particular a deeper understanding of the importance of communication across vital organs, and specifically the gut-brain-pancreas-liver network...
April 2017: Physiological Reviews
https://www.readbyqxmd.com/read/28269785/the-link-between-type-2-diabetes-and-neurodegeneration-roles-for-amyloid-%C3%AE-amylin-and-tau-proteins
#7
Prashant Bharadwaj, Nadeeja Wijesekara, Milindu Liyanapathirana, Philip Newsholme, Lars Ittner, Paul Fraser, Giuseppe Verdile
A wealth of evidence indicates a strong link between type 2 diabetes (T2D) and neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanism remains unclear, T2D can exacerbate neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism, and central nervous system insulin resistance are features of both AD and T2D. The T2D phenotype (glucose dyshomeostasis, insulin resistance, impaired insulin signaling) also promotes AD pathology, namely accumulation of amyloid-β (Aβ) and hyperphosphorylated tau and can induce other aspects of neuronal degeneration including inflammatory and oxidative processes...
March 1, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28245771/current-drug-targets-in-obesity-pharmacotherapy-a-review
#8
Sangeeta P Bhat, Arun Sharma
Obesity, an impending global pandemic, is not being effectively controlled by current measures such as lifestyle modifications, bariatric surgery or available medications. Its toll on health and economy compels us to look for more effective measures. Fortunately, the advances in biology and molecular technology have been in our favour for delineating new pathways in the pathophysiology of obesity and have led to subsequent development of new drug targets. Development of anti-obesity drugs has often been riddled with problems in the past...
February 27, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28237459/amylin-acts-in-the-lateral-dorsal-tegmental-nucleus-to-regulate-energy-balance-through-gamma-aminobutyric-acid-signaling
#9
David J Reiner, Elizabeth G Mietlicki-Baase, Diana R Olivos, Lauren E McGrath, Derek J Zimmer, Kieran Koch-Laskowski, Joanna Krawczyk, Christopher A Turner, Emily E Noble, Joel D Hahn, Heath D Schmidt, Scott E Kanoski, Matthew R Hayes
BACKGROUND: The pancreatic- and brain-derived hormone amylin promotes negative energy balance and is receiving increasing attention as a promising obesity therapeutic. However, the neurobiological substrates mediating amylin's effects are not fully characterized. We postulated that amylin acts in the lateral dorsal tegmental nucleus (LDTg), an understudied neural processing hub for reward and homeostatic feeding signals. METHODS: We used immunohistochemical and quantitative polymerase chain reaction analyses to examine expression of the amylin receptor complex in rat LDTg tissue...
January 10, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28223444/basal-glucose-can-be-controlled-but-the-prandial-problem-persists-it-s-the-next-target
#10
Matthew C Riddle
Both basal and postprandial elevations contribute to the hyperglycemic exposure of diabetes, but current therapies are mainly effective in controlling the basal component. Inability to control postprandial hyperglycemia limits success in maintaining overall glycemic control beyond the first 5 to 10 years after diagnosis, and it is also related to the weight gain that is common during insulin therapy. The "prandial problem"-comprising abnormalities of glucose and other metabolites, weight gain, and risk of hypoglycemia-deserves more attention...
March 2017: Diabetes Care
https://www.readbyqxmd.com/read/28165287/cgrp-receptor-antagonist-activity-of-olcegepant-depends-on-the-signalling-pathway-measured
#11
Christopher S Walker, Ann C Raddant, Michael J Woolley, Andrew F Russo, Debbie L Hay
Background Calcitonin gene-related peptide (CGRP) is a neuropeptide that acts in the trigeminovascular system and is believed to play an important role in migraine. CGRP activates two receptors that are both present in the trigeminovascular system; the CGRP receptor and the amylin 1 (AMY1) receptor. CGRP receptor antagonists, including olcegepant (BIBN4096BS) and telcagepant (MK-0974), can treat migraine. This study aimed to determine the effectiveness of these antagonists at blocking CGRP receptor signalling in trigeminal ganglia (TG) neurons and transfected CGRP and AMY1 receptors in Cos7 cells, to better understand their mechanism of action...
January 1, 2017: Cephalalgia: An International Journal of Headache
https://www.readbyqxmd.com/read/28118069/rationale-for-treatment-options-for-mealtime-glucose-control-in-patients-with-type-2-diabetes
#12
REVIEW
Stephen L Aronoff
While glycemic control is routinely assessed using HbA1c and fasting glucose measures, postprandial glucose (PPG) is also an important contributor of overall glycemia. Furthermore, PPG excursions have been linked to complications of diabetes. This review examines the effects of glucose-lowering therapies (including treatments administered at mealtime) on postprandial hyperglycemia in patients with type 2 diabetes. A PubMed search was conducted to identify clinical studies of treatments for mealtime glucose control in type 2 diabetes...
March 2017: Postgraduate Medicine
https://www.readbyqxmd.com/read/28109166/a-novel-dual-amylin-and-calcitonin-receptor-agonist-kbp-089-induces-weight-loss-through-a-reduction-in-fat-but-not-lean-mass-while-improving-food-preference
#13
Sofie Gydesen, Sara Toftegaard Hjuler, Zenia Freving, Kim Vietz Andreassen, Nina Sonne, Lars I Hellgren, Morten Asser Karsdal, Kim Henriksen
BACKGROUND AND PURPOSE: Obesity and associated co-morbidities, such as type 2 diabetes and non-alcoholic fatty liver disease, are major health challenges. Hence, there is an important need to develop weight loss therapies with the ability to reduce the co-morbidities. EXPERIMENTAL APPROACH: The effect of the dual amylin and calcitonin receptor agonist (DACRA), KBP-089, on body weight, glucose homeostasis and fatty acid accumulation in liver and muscle tissue and on food preference was investigated...
April 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28093996/challenges-related-to-glycemic-control-in-type-2-diabetes-mellitus-patients
#14
Masoumeh Kheirandish, Hamidreza Mahboobi, Maryam Yazdanparast, Mohammad Amjad Kamal
Diabetes mellitus (DM) is a chronic disease with long-term complications. Glycemic control is an important part in management of DM. The first line in treatment of type 2 DM (T2DM) is diet and life style change. Metformin is the first choice of medication in T2DM patients. Sulfonylureas have high risk of hypoglycemia. Glinides are associated with lower risk of hypoglycemia in comparison to sulfonylureas. Also α-glucosidase inhibitors decrease the polysacarides digestion in small intestine and less effective in comparison to metformin and sulfonylureas in lowering hemoglobin A1c (HbA1c)...
January 15, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/28090343/amylin-leptin-synergy-is-absent-in-extreme-obesity-and-not-restored-by-calorie-restriction-induced-weight-loss-in-rats
#15
J L Trevaskis, C Wittmer, J Athanacio, P S Griffin, D G Parkes, J D Roth
OBJECTIVE: Co-administration of amylin and leptin induces synergistic and clinically meaningful (>10%) weight loss that is attenuated as the degree of obesity increases. We explored whether calorie restriction (CR) could restore amylin/leptin synergy in very obese rats. METHODS: Sprague Dawley rats on high-fat diet (696 ± 8 g, n = 72) were randomized to three cohorts (C1-C3). Rats in C1 were administered vehicle, rat amylin (50 µg kg(-1) d(-1)), murine leptin (125 µg kg(-1) d(-1)) or amylin and leptin for 28 days (n = 6 per group) via subcutaneous minipump...
December 2016: Obesity Science & Practice
https://www.readbyqxmd.com/read/28071890/peptide-conjugates-of-benzene-carboxylic-acids-as-agonists-and-antagonists-of-amylin-aggregation
#16
Adam A Profit, Jayson Vedad, Ruel Z B Desamero
Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37 residue peptide hormone that is stored and co-secreted with insulin. hIAPP plays a pivotal role in type 2 diabetes and is the major component of amyloid deposits found in the pancreas of patients afflicted with the disease. The self-assembly of hIAPP and the formation of amyloid is linked to the death of insulin producing β-cells. Recent findings suggest that soluble hIAPP oligomers are the cytotoxic species responsible for β-cell loss whereas amyloid fibrils themselves may indeed be innocuous...
January 27, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28059785/amylin-enhances-amyloid-%C3%AE-peptide-brain-to-blood-efflux-across-the-blood-brain-barrier
#17
Loqman A Mohamed, Haihao Zhu, Youssef M Mousa, Erming Wang, Wei Qiao Qiu, Amal Kaddoumi
Findings from Alzheimer's disease (AD) mouse models showed that amylin treatment improved AD pathology and enhanced amyloid-β (Aβ) brain to blood clearance; however, the mechanism was not investigated. Using the Tg2576 AD mouse model, a single intraperitoneal injection of amylin significantly increased Aβ serum levels, and the effect was abolished by AC253, an amylin receptor antagonist, suggesting that amylin effect could be mediated by its receptor. Subsequent mechanistic studies showed amylin enhanced Aβ transport across a cell-based model of the blood-brain barrier (BBB), an effect that was abolished when the amylin receptor was inhibited by two amylin antagonists and by siRNA knockdown of amylin receptor Ramp3...
December 3, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28054630/disaggregation-of-amylin-aggregate-by-novel-conformationally-restricted-aminobenzoic-acid-containing-%C3%AE-%C3%AE-and-%C3%AE-%C3%AE-hybrid-peptidomimetics
#18
Ashim Paul, Sourav Kalita, Sujan Kalita, Piruthivi Sukumar, Bhubaneswar Mandal
Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the diabetic population has type 2 diabetes mellitus (T2DM). Aggregates of Amylin hormone, which is co-secreted with insulin from the pancreatic β-cells, inhibit the activities of insulin and glucagon and cause T2DM. Importance of the conformationally restricted peptides for drug design against T2DM has been invigorated by recent FDA approval of Symlin, which is a large conformationally restricted peptide. However, Symlin still has some issues including solubility, oral bioavailability and cost of preparation...
January 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/27995166/quantitative-data-describing-the-impact-of-the-flavonol-rutin-on-in-vivo-blood-glucose-and-fluid-intake-profiles-and-survival-of-human-amylin-transgenic-mice
#19
Jacqueline F Aitken, Kerry M Loomes, Isabel Riba-Garcia, Richard D Unwin, Gordana Prijic, Ashley S Phillips, Anthony R J Phillips, Donghai Wu, Sally D Poppitt, Ke Ding, Perdita E Barran, Andrew W Dowsey, Garth J S Cooper
Here we provide data describing the time-course of blood-glucose and fluid-intake profiles of diabetic hemizygous human-amylin (hA) transgenic mice orally treated with rutin, and matched control mice treated with water. We employed "parametric change-point regression analysis" for investigation of differences in time-course profiles between the control and rutin-treatment groups to extract, for each animal, baseline levels of blood glucose and fluid-intake, the change-point time at which blood glucose (diabetes-onset) and fluid-intake (polydipsia-onset) accelerated away from baseline, and the rate of this acceleration...
February 2017: Data in Brief
https://www.readbyqxmd.com/read/27938937/amylin-and-leptin-co-regulators-of-energy-homeostasis-and-neuronal-development
#20
REVIEW
Barry E Levin, Thomas A Lutz
While the regulation of energy homeostasis by amylin is already well-characterized, emerging data suggest that amylin is also crucial for the development of neural pathways in the hypothalamus and caudal hindbrain (area postrema, AP; nucleus tractus solitarius, NTS). Exciting new findings demonstrate crucial amylin-leptin interactions in altering the activity of specific hypothalamic and AP neurons, and a role for amylin as a novel class of 'leptin sensitizers' which enhance leptin signaling in both leptin-sensitive and -resistant individuals, in part by stimulating IL-6 production by hypothalamic microglia...
December 6, 2016: Trends in Endocrinology and Metabolism: TEM
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