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https://www.readbyqxmd.com/read/27815568/diabetes-drug-effects-on-the-skeleton
#1
Manju Chandran
Diabetes be it type 1 or type 2 is associated with an increased risk of fragility fractures. The mechanisms underlying this increased risk are just being elucidated. Anti-diabetes medications are crucial for maintaining glucose control and for preventing micro- and macrovascular complications in diabetes. However, they may modulate fracture risk in diabetes in different ways. Thiazolidinediones have demonstrated an unfavorable effect on the skeleton, while metformin and sulfonylureas may have a neutral if not beneficial effect on bone...
November 4, 2016: Calcified Tissue International
https://www.readbyqxmd.com/read/27665170/amyloidogenesis-of-the-amylin-analogue-pramlintide
#2
Dayana Cabral da Silva, Giselle N Fontes, Luiza C S Erthal, Luís Maurício T R Lima
Amylin is a pancreatic peptide hormone co-secreted along with insulin by the β-cells. It is found in amyloid deposits in both type 2 diabetic individuals and elder non-diabetic. The triple proline amylinomimetic compound (25,28,29-Pro-human amylin) named pramlintide was designed aiming to solve the solubility and amyloid characteristics of human amylin. We have found by using ion mobility spectrometry-based mass spectrometry that pramlintide is able to assembly into multimers. Pramlintide formed amyloid fibrils in vitro in a pH-dependent kinetic process within a few hours, as followed by thioflavin T, quantification of soluble peptide and further characterized by transmission electron microscopy, atomic force microscopy and X-ray diffraction...
September 20, 2016: Biophysical Chemistry
https://www.readbyqxmd.com/read/27208332/mitigating-meal-related-glycemic-excursions-in-an-insulin-sparing-manner-during-closed-loop-insulin-delivery-the-beneficial-effects-of-adjunctive-pramlintide-and-liraglutide
#3
Jennifer L Sherr, Neha S Patel, Camille I Michaud, Miladys M Palau-Collazo, Michelle A Van Name, William V Tamborlane, Eda Cengiz, Lori R Carria, Eileen M Tichy, Stuart A Weinzimer
OBJECTIVE: Closed-loop (CL) insulin delivery effectively maintains glucose overnight but struggles when challenged with meals. Use of single-day, 30-μg/meal pramlintide lowers meal excursions during CL. We sought to further elucidate the potential benefits of adjunctive agents after 3-4 weeks of outpatient dose titration. RESEARCH DESIGN AND METHODS: Two CL studies were conducted: one evaluating adjunctive pramlintide and the other liraglutide. Ten subjects (age 16-23 years; A1C 7...
July 2016: Diabetes Care
https://www.readbyqxmd.com/read/27139251/synthesis-and-amylin-receptor-activity-of-glycomimetics-of-pramlintide-using-click-chemistry
#4
Lauren R Yule, Rebekah L Bower, Harveen Kaur, Renata Kowalczyk, Debbie L Hay, Margaret A Brimble
Pramlintide (Symlin®), a synthetic analogue of the neuroendocrine hormone amylin, is devoid of the tendency to form cytotoxic amyloid fibrils and is currently used in patients with type I and type II diabetes mellitus as an adjunctive therapy with insulin or insulin analogues. As part of an on-going search for a pramlintide analogue with improved pharmacokinetic properties, we herein report the synthesis of mono- and di-glycosylated analogues of pramlintide and their activity at the AMY1(a) receptor. Introduction of N-glycosylated amino acids into the pramlintide sequence afforded the native N-linked glycomimetics whilst use of Cu(i)-catalysed azide-alkyne 1,3-dipolar cycloaddition (click) chemistry delivered 1,2,3-triazole linked glycomimetics...
June 21, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27071768/impact-of-disease-duration-on-the-effects-of-pramlintide-in-type-1-diabetes-a-post-hoc-analysis-of-three-clinical-trials
#5
Kathrin Herrmann, Steven C Brunell, Yan Li, Ming Zhou, David G Maggs
INTRODUCTION: Adjunctive mealtime use of the amylin analog pramlintide improves postprandial hyperglycemia in patients with type 1 diabetes. This post hoc analysis of three randomized trials evaluated whether disease duration affected responses to pramlintide. METHODS: Patients received mealtime pramlintide 30 or 60 µg (n = 714) or placebo (n = 537) as an adjunct to insulin and were stratified into tertiles by diabetes duration at baseline. Efficacy and safety end points were assessed at week 26 using analysis of covariance and logistic regression models...
May 2016: Advances in Therapy
https://www.readbyqxmd.com/read/27071617/addressing-unmet-medical-needs-in-type-1-diabetes-a-review-of-drugs-under-development
#6
Friedrich Mittermayer, Erica Caveney, Claudia De Oliveira, G Alexander Fleming, Loukas Gourgiotis, Mala Puri, Li-Jung Tai, J Rick Turner
The incidence of type 1 diabetes (T1D) is increasing worldwide and there is a very large need for effective therapies. Besides pramlintide, there are essentially no pharmacologic therapies other than insulin currently approved for the treatment of T1D. Drugs already in use for type 2 diabetes and many new drugs are under clinical development for T1D, including compounds with both established and new mechanisms of action. Most of the new compounds in clinical development are currently in Phase 1 and Phase 2...
April 13, 2016: Current Diabetes Reviews
https://www.readbyqxmd.com/read/27061187/amylin-structure-function-relationships-and-receptor-pharmacology-implications-for-amylin-mimetic-drug-development
#7
REVIEW
Rebekah L Bower, Debbie L Hay
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...
June 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/26969516/non-insulin-drugs-to-treat-hyperglycaemia-in-type-1-diabetes-mellitus
#8
REVIEW
Christian Seerup Frandsen, Thomas Fremming Dejgaard, Sten Madsbad
Insulin treatment of individuals with type 1 diabetes has shortcomings and many patients do not achieve glycaemic and metabolic targets. Consequently, the focus is on novel non-insulin therapeutic approaches that reduce hyperglycaemia and improve metabolic variables without increasing the risk of hypoglycaemia or other adverse events. Several therapies given in conjunction with insulin have been investigated in clinical trials, including pramlintide, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter inhibitors, metformin, sulfonylureas, and thiazolidinediones...
September 2016: Lancet Diabetes & Endocrinology
https://www.readbyqxmd.com/read/26930181/effect-of-pramlintide-on-postprandial-glucose-fluxes-in-type-1-diabetes
#9
Ling Hinshaw, Michele Schiavon, Vikash Dadlani, Ashwini Mallad, Chiara Dalla Man, Adil Bharucha, Rita Basu, Jennifer R Geske, Rickey E Carter, Claudio Cobelli, Ananda Basu, Yogish C Kudva
CONTEXT: Early postprandial hyperglycemia and delayed hypoglycemia remain major problems in current management of type 1 diabetes (T1D). OBJECTIVE: Our objective was to investigate the effects of pramlintide, known to suppress glucagon and delay gastric emptying, on postprandial glucose fluxes in T1D. DESIGN: This was a single-center, inpatient, randomized, crossover study. PATIENTS: Twelve patients with T1D who completed the study were analyzed...
May 2016: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/26922873/amylin-mediated-control-of-glycemia-energy-balance-and-cognition
#10
REVIEW
Elizabeth G Mietlicki-Baase
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...
August 1, 2016: Physiology & Behavior
https://www.readbyqxmd.com/read/26655697/hypothalamic-amylin-acts-in-concert-with-leptin-to-regulate-food-intake
#11
Zhiying Li, Leah Kelly, Myriam Heiman, Paul Greengard, Jeffrey Michael Friedman
In this report we evaluated the functions of hypothalamic amylin in vivo and in vitro. Profiling of hypothalamic neurons revealed that islet amyloid polypeptide (Iapp, precursor to amylin) is expressed in neurons in the lateral hypothalamus, arcuate nucleus, medial preoptic area, and elsewhere. Hypothalamic expression of lapp is markedly decreased in ob/ob mice and normalized by exogenous leptin. In slices, amylin and leptin had similar electrophysiologic effects on lateral hypothalamic leptin receptor ObRb-expressing neurons, while the amylin antagonist AC187 inhibited their activity and blunted the effect of leptin...
December 1, 2015: Cell Metabolism
https://www.readbyqxmd.com/read/26652033/novel-therapeutic-interventions-for-p53-altered-tumors-through-manipulation-of-its-family-members-p63-and-p73
#12
Avinashnarayan Venkatanarayan, Payal Raulji, William Norton, Elsa R Flores
TP53 is highly mutated in human cancers, thus targeting this tumor suppressor pathway is highly desirable and will impact many cancer patients. (1,2) Therapeutic strategies to reactivate the p53-pathway have been challenging, (3,4) and no effective treatment exists. (5) We utilized the p53-family members, p63 and p73, which are not frequently mutated in cancer, to treat p53-defective cancers. The N-terminal splice variants of p63 and p73 are denoted as the TA and ΔN isoforms. We recently demonstrated that deletion of either ΔNp63 or ΔNp73 in p53-deficient mouse tumors results in tumor regression mediated by metabolic programming...
2016: Cell Cycle
https://www.readbyqxmd.com/read/26589105/immunogenicity-associated-with-metreleptin-treatment-in-patients-with-obesity-or-lipodystrophy
#13
Jean L Chan, Joy Koda, Joseph S Heilig, Elaine K Cochran, Phillip Gorden, Elif A Oral, Rebecca J Brown
OBJECTIVE: Recombinant human leptin (metreleptin) improves glycaemia and hypertriglyceridaemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize antimetreleptin antibody development, including in vitro neutralizing activity. DESIGN: Two randomized controlled studies in patients with obesity (twice-daily metreleptin ± pramlintide for 20-52 weeks; 2006-2009); two long-term, open-label studies in patients with lipodystrophy (once-daily or twice-daily metreleptin for 2 months to 12·3 years; 2000-2014)...
July 2016: Clinical Endocrinology
https://www.readbyqxmd.com/read/26424675/role-of-amylin-in-type-1-and-type-2-diabetes
#14
Laura Hieronymus, Stacy Griffin
PURPOSE: The pathophysiology of diabetes has historically focused on alterations in insulin secretion and function; however, diabetes involves multiple hormonal alterations, including abnormal regulation of amylin. This review discusses the physiologic functions of amylin in glucose homeostasis and the rationale for amylin replacement in type 1 and 2 diabetes. The use of pramlintide, a synthetic amylin analog, is also discussed. CONCLUSIONS: Amylin, formed primarily in pancreatic islet β cells, is cosecreted with insulin in response to caloric intake...
December 2015: Diabetes Educator
https://www.readbyqxmd.com/read/26407043/analysis-of-the-ability-of-pramlintide-to-inhibit-amyloid-formation-by-human-islet-amyloid-polypeptide-reveals-a-balance-between-optimal-recognition-and-reduced-amyloidogenicity
#15
Hui Wang, Zachary Ridgway, Ping Cao, Bela Ruzsicska, Daniel P Raleigh
The hormone human islet amyloid polypeptide (hIAPP or amylin) plays a role in glucose metabolism, but forms amyloid in the pancreas in type 2 diabetes (T2D) and is associated with β-cell death and dysfunction in the disease. Inhibitors of islet amyloid have therapeutic potential; however, there are no clinically approved inhibitors, and the mode of action of existing inhibitors is not well understood. Rat IAPP (rIAPP) differs from hIAPP at six positions, does not form amyloid, and is an inhibitor of amyloid formation by hIAPP...
November 10, 2015: Biochemistry
https://www.readbyqxmd.com/read/26071095/amylin-pharmacology-physiology-and-clinical-potential
#16
REVIEW
Debbie L Hay, Steve Chen, Thomas A Lutz, David G Parkes, Jonathan D Roth
Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. Here, we review the literature in rodents and in humans on amylin research since its discovery as a hormone about 25 years ago. Amylin is a 37-amino-acid peptide that activates its specific receptors, which are multisubunit G protein-coupled receptors resulting from the coexpression of a core receptor protein with receptor activity-modifying proteins, resulting in multiple receptor subtypes. Amylin's major role is as a glucoregulatory hormone, and it is an important regulator of energy metabolism in health and disease...
July 2015: Pharmacological Reviews
https://www.readbyqxmd.com/read/25903685/computational-re-engineering-of-amylin-sequence-with-reduced-amyloidogenic-potential
#17
Mohamed R Smaoui, Jérôme Waldispühl
BACKGROUND: The aggregation of amyloid proteins into fibrils is associated with neurodegenerative diseases such as Alzheimer's and Type II Diabetes. Different methods have explored ways to impede and inhibit amyloid aggregation. Most attempts in the literature involve applying stress to the environment around amyloids. Varying pH levels, modifying temperature, applying pressure through protein crowding and ligand docking are classical examples of these methods. However, environmental stress usually affects molecular pathways and protein functions in the cell and is challenging to construct in vivo...
2015: BMC Structural Biology
https://www.readbyqxmd.com/read/25809921/complete-characterization-of-the-mutation-landscape-reveals-the-effect-on-amylin-stability-and-amyloidogenicity
#18
Mohamed Raef Smaoui, Jérôme Waldispühl
Type-II diabetes is believed to be partially aggravated by the emergence of toxic amylin protein deposits in the extracellular space of the pancreas β-cells. Amylin, the regulatory hormone that is co-secreted with insulin, has been observed to misfold into toxic structures. Pramlintide, an FDA approved injectable amylin analog mutated at positions 25, 28, and 29 was therefore developed to create a more stable, soluble, less-aggregating, and equipotent peptide that is used as an adjunctive therapy for diabetes...
June 2015: Proteins
https://www.readbyqxmd.com/read/25777526/probing-the-binding-affinity-of-amyloids-to-reduce-toxicity-of-oligomers-in-diabetes
#19
Mohamed Raef Smaoui, Henri Orland, Jérôme Waldispühl
MOTIVATION: Amyloids play a role in the degradation of β-cells in diabetes patients. In particular, short amyloid oligomers inject themselves into the membranes of these cells and create pores that disrupt the strictly controlled flow of ions through the membranes. This leads to cell death. Getting rid of the short oligomers either by a deconstruction process or by elongating them into longer fibrils will reduce this toxicity and allow the β-cells to live longer. RESULTS: We develop a computational method to probe the binding affinity of amyloid structures and produce an amylin analog that binds to oligomers and extends their length...
July 15, 2015: Bioinformatics
https://www.readbyqxmd.com/read/25738213/the-impact-of-diabetes-and-diabetes-medications-on-bone-health
#20
REVIEW
Matthew P Gilbert, Richard E Pratley
Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fractures despite increased body weight and normal or higher bone mineral density. The mechanisms by which T2DM increases skeletal fragility are unclear. It is likely that a combination of factors, including a greater risk of falling, regional osteopenia, and impaired bone quality, contributes to the increased fracture risk. Drugs for the treatment of T2DM may also impact on the risk for fractures. For example, thiazolidinediones accelerate bone loss and increase the risk of fractures, particularly in older women...
April 2015: Endocrine Reviews
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