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Diabetes New Target

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https://www.readbyqxmd.com/read/28214518/potentiating-slc-transporter-activity-emerging-drug-discovery-opportunities
#1
REVIEW
Marie-Laure Rives, Jonathan A Javitch, Alan D Wickenden
Maintaining the integrity of cellular membranes is critical to protecting metabolic activities and genetic information from the environment. Regulation of transport across membranes of essential chemicals, including water, nutrients, hormones and many drugs, is therefore key to cellular homeostasis and physiological processes. The two main transporter superfamilies are ATP-binding cassette (ABC) transporters that primarily function as efflux transporters, and the solute carrier (SLC) transporters. SLC transporters encompass 52 gene families with almost 400 different human transporter genes...
February 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28212750/conformational-rigidity-and-protein-dynamics-at-distinct-timescales-regulate-ptp1b-activity-and-allostery
#2
Meng S Choy, Yang Li, Luciana E S F Machado, Micha B A Kunze, Christopher R Connors, Xingyu Wei, Kresten Lindorff-Larsen, Rebecca Page, Wolfgang Peti
Protein function originates from a cooperation of structural rigidity, dynamics at different timescales, and allostery. However, how these three pillars of protein function are integrated is still only poorly understood. Here we show how these pillars are connected in Protein Tyrosine Phosphatase 1B (PTP1B), a drug target for diabetes and cancer that catalyzes the dephosphorylation of numerous substrates in essential signaling pathways. By combining new experimental and computational data on WT-PTP1B and ≥10 PTP1B variants in multiple states, we discovered a fundamental and evolutionarily conserved CH/π switch that is critical for positioning the catalytically important WPD loop...
February 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28208582/nutrients-in-energy-and-one-carbon-metabolism-learning-from-metformin-users
#3
REVIEW
Fedra Luciano-Mateo, Anna Hernández-Aguilera, Noemi Cabre, Jordi Camps, Salvador Fernández-Arroyo, Jose Lopez-Miranda, Javier A Menendez, Jorge Joven
Metabolic vulnerability is associated with age-related diseases and concomitant co-morbidities, which include obesity, diabetes, atherosclerosis and cancer. Most of the health problems we face today come from excessive intake of nutrients and drugs mimicking dietary effects and dietary restriction are the most successful manipulations targeting age-related pathways. Phenotypic heterogeneity and individual response to metabolic stressors are closely related food intake. Understanding the complexity of the relationship between dietary provision and metabolic consequences in the long term might provide clinical strategies to improve healthspan...
February 10, 2017: Nutrients
https://www.readbyqxmd.com/read/28208043/the-australasian-diabetes-data-network-first-national-audit-of-children-and-adolescents-with-type-1-diabetes
#4
Helen Phelan, Helen Clapin, Loren Bruns, Fergus J Cameron, Andrew M Cotterill, Jennifer J Couper, Elizabeth A Davis, Kim C Donaghue, Craig A Jefferies, Bruce R King, Richard O Sinnott, Elaine B Tham, Jerry K Wales, Timothy W Jones, Maria E Craig
OBJECTIVES: To assess glycaemic control, anthropometry and insulin regimens in a national sample of Australian children and adolescents with type 1 diabetes. DESIGN: Cross-sectional analysis of de-identified, prospectively collected data from the Australasian Diabetes Data Network (ADDN) registry. SETTING: Five paediatric diabetes centres in New South Wales, Queensland, South Australia, Victoria and Western Australia. PARTICIPANTS: Children and adolescents (aged 18 years or under) with type 1 diabetes of at least 12 months' duration for whom data were added to the ADDN registry during 2015...
February 20, 2017: Medical Journal of Australia
https://www.readbyqxmd.com/read/28207876/circulating-c1q-complement-tnf-related-protein-ctrp-1-ctrp9-ctrp12-and-ctrp13-concentrations-in-type-2-diabetes-mellitus-in-vivo-regulation-by-glucose
#5
Bo Bai, Bo Ban, Zunjing Liu, Man Man Zhang, Bee Kang Tan, Jing Chen
OBJECTIVES: The C1q complement/TNF-related protein (CTRP) superfamily, which includes the adipokine adiponectin, has been shown in animal models to have positive metabolic and cardiovascular effects. We sought to investigate circulating CTRP1, CTRP9, CTRP12 and CTRP13 concentrations in persons with type 2 diabetes mellitus (T2DM), with age and BMI matched controls, and to examine the effects of a 2 hour 75g oral glucose tolerance test (OGTT) on serum CTRP1, CTRP9, CTRP12 and CTRP13 levels in persons with T2DM...
2017: PloS One
https://www.readbyqxmd.com/read/28205039/a-pooled-analysis-of-clinical-pharmacology-trials-investigating-the-pharmacokinetic-and-pharmacodynamic-characteristics-of-fast-acting-insulin-aspart-in-adults-with-type-1-diabetes
#6
Tim Heise, Thomas R Pieber, Thomas Danne, Lars Erichsen, Hanne Haahr
BACKGROUND: Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation aiming to mimic the fast endogenous prandial insulin release more closely than currently available insulin products. In a post hoc analysis of pooled data from six clinical pharmacology trials, the pharmacological characteristics of faster aspart and IAsp were compared. METHODS: The analysis included 218 adult subjects with type 1 diabetes from six randomised, double-blind, crossover trials in the faster aspart clinical development programme...
February 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28203358/the-renal-effects-of-sglt2-inhibitors-and-a-mini-review-of-the-literature
#7
REVIEW
Vasileios Andrianesis, Spyridoula Glykofridi, John Doupis
Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new and promising class of antidiabetic agents which target renal tubular glucose reabsorption. Their action is based on the blockage of SGLT2 sodium-glucose cotransporters that are located at the luminal membrane of tubular cells of the proximal convoluted tubule, inducing glucosuria. It has been proven that they significantly reduce glycated hemoglobin (HbA1c), along with fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus (T2DM)...
December 2016: Therapeutic Advances in Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28196832/gpr55-a-new-promising-target-for-metabolism
#8
Eva Tuduri, Monica Imbernon, Rene Bautista, Marta Tojo, Johan Fernø, Carlos Diéguez, Rubén Nogueiras
GPR55 is a G-protein coupled receptor (GPCR) that has been identified as a new cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral tissues, this receptor has emerged as a regulator of multiple biological actions. Lysophosphatidylinositol (LPI) is generally accepted as the endogenous ligand of GPR55. In this review, we will focus on the role of GPR55 in energy balance and glucose metabolism. We will summarize its actions on feeding, nutrient partitioning, gastrointestinal motility and insulin secretion in preclinical models and the scarce data available in humans...
February 14, 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/28194400/eating-the-dead-to-keep-atherosclerosis-at-bay
#9
REVIEW
Megan L Brophy, Yunzhou Dong, Hao Wu, H N Ashiqur Rahman, Kai Song, Hong Chen
Atherosclerosis is the primary cause of coronary heart disease (CHD), ischemic stroke, and peripheral arterial disease. Despite effective lipid-lowering therapies and prevention programs, atherosclerosis is still the leading cause of mortality in the United States. Moreover, the prevalence of CHD in developing countries worldwide is rapidly increasing at a rate expected to overtake those of cancer and diabetes. Prominent risk factors include the hardening of arteries and high levels of cholesterol, which lead to the initiation and progression of atherosclerosis...
2017: Frontiers in Cardiovascular Medicine
https://www.readbyqxmd.com/read/28193552/rational-design-and-synthesis-of-some-ppar-%C3%AE-agonists-substituted-benzylideneamino-benzylidene-thiazolidine-2-4-diones
#10
Santosh S Chhajed, Shital Chaskar, Sanjay K Kshirsagar, G M Animeshchandra Haldar, Debarshi Kar Mahapatra
The peroxisome proliferator activator receptor-γ (PPAR-γ) remained the most successful target for management of diabetes mellitus. The present work endeavors rational designing of some novel PPAR-γ agonists bearing benzylideneamino-benzylidene-thiazolidine-2,4-dione scaffold. The research involved virtual screening of 37 different molecules by molecular docking studies performed by Molecular Design Suite (MDS) into the ligand binding domain of PPAR-γ receptor to explore the binding affinity and conformations of the molecules...
February 7, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28188802/crosstalk-of-metabolic-factors-and-neurogenic-signaling-in-adult-neurogenesis-implication-of-metabolic-regulation-for-mental-and-neurological-diseases
#11
Chong Gao, Qi Wang, Sookja K Chung, Jiangang Shen
Metabolic disorders like diabetes and obesity are commonly companied with neurological diseases and psychiatric disorders. Accumulating evidences indicated that cellular metabolic factors affect adult neurogenesis and have modulating effects on neurodegenerative disorders and psychiatric diseases. Adult neurogenesis contains multiple steps including proliferation of neural stem cells, lineage commitments of neural progenitor cells, maturation into functional neurons, and integration into neuronal network. Many intrinsic and extrinsic factors produced from neural stem/progenitor cells and their microenvironment or neurogenic niche take roles in modulating neurogenesis and contribute to the brain repair and functional recoveries in many neurological diseases and psychiatric disorders...
February 7, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28181428/new-potential-targets-of-glucagon-like-peptide-1-receptor-agonists-in-pancreatic-%C3%AE-cells-and-hepatocytes
#12
Won Young Lee
It is well known that both insulin resistance and decreased insulin secretory capacity are important factors in the pathogenesis of type 2 diabetes mellitus (T2DM). In addition to genetic factors, obesity and lipotoxicity can increase the risk of T2DM. Glucagon-like peptide 1 (GLP-1) receptor agonists are novel antidiabetic drugs with multiple effects. They can stimulate glucose-dependent insulin secretion, inhibit postprandial glucagon release, delay gastric emptying, and induce pancreatic β-cell proliferation...
February 8, 2017: Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28180059/jnk-at-the-crossroad-of-obesity-insulin-resistance-and-cell-stress-response
#13
REVIEW
Giovanni Solinas, Barbara Becattini
BACKGROUND: The cJun-N-terminal-kinase (JNK) plays a central role in the cell stress response, with outcomes ranging from cell death to cell proliferation and survival, depending on the specific context. JNK is also one of the most investigated signal transducers in obesity and insulin resistance, and studies have identified new molecular mechanisms linking obesity and insulin resistance. Emerging evidence indicates that whereas JNK1 and JNK2 isoforms promote the development of obesity and insulin resistance, JNK3 activity protects from excessive adiposity...
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28179884/cellular-signaling-pathways-in-insulin-resistance-systems-biology-analyses-of-microarray-dataset-reveals-new-drug-target-gene-signatures-of-type-2-diabetes-mellitus
#14
Syed Aun Muhammad, Waseem Raza, Thanh Nguyen, Baogang Bai, Xiaogang Wu, Jake Chen
Purpose: Type 2 diabetes mellitus (T2DM) is a chronic and metabolic disorder affecting large set of population of the world. To widen the scope of understanding of genetic causes of this disease, we performed interactive and toxicogenomic based systems biology study to find potential T2DM related genes after cDNA differential analysis. Methods: From the list of 50-differential expressed genes (p < 0.05), we found 9-T2DM related genes using extensive data mapping. In our constructed gene-network, T2DM-related differentially expressed seeder genes (9-genes) are found to interact with functionally related gene signatures (31-genes)...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28176326/identification-of-novel-inhibitors-of-the-amino-acid-transporter-b-0-at1-slc6a19-a-potential-target-to-induce-protein-restriction-and-to-treat-type-2-diabetes
#15
Qi Cheng, Nishank Shah, Angelika Bröer, Stephen Fairweather, Yang Jiang, Dieter Schmoll, Ben Corry, Stefan Bröer
BACKGROUND AND PURPOSE: The neutral amino acid transporter B(0) AT1 (SLC6A19) has recently been identified as a possible target to treat type 2 diabetes and related disorders. B(0) AT1 mediates the Na(+) -dependent uptake of all neutral amino acids. For surface expression and catalytic activity, B(0) AT1 requires coexpression of collectrin (TMEM27). In this study, we established tools to identify and evaluate novel inhibitors of B(0) AT1. EXPERIMENTAL APPROACH: A CHO-based cell line was generated, stably expressing collectrin and B(0) AT1...
February 8, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28175964/painting-a-new-picture-of-personalised-medicine-for-diabetes
#16
REVIEW
Mark I McCarthy
The current focus on delivery of personalised (or precision) medicine reflects the expectation that developments in genomics, imaging and other domains will extend our diagnostic and prognostic capabilities, and enable more effective targeting of current and future preventative and therapeutic options. The clinical benefits of this approach are already being realised in rare diseases and cancer but the impact on management of complex diseases, such as type 2 diabetes, remains limited. This may reflect reliance on inappropriate models of disease architecture, based around rare, high-impact genetic and environmental exposures that are poorly suited to our emerging understanding of type 2 diabetes...
February 7, 2017: Diabetologia
https://www.readbyqxmd.com/read/28174291/local-sphingosine-kinase-1-activity-improves-islet-transplantation
#17
Darling Rojas-Canales, Daniella Penko, Kay K Myo Min, Kate A Parham, Heshan Peiris, Rainer V Haberberger, Stuart M Pitson, Chris Drogemuller, Damien J Keating, Shane T Grey, Patrick T Coates, Claudine S Bonder, Claire F Jessup
Pancreatic islet transplantation is a promising clinical treatment for type I diabetes (T1D), but success is limited by extensive beta cell death in the immediate post-transplant period, and impaired islet function in the longer term. Following transplantation, appropriate vascular remodelling is crucial to ensure the survival and function of engrafted islets. The sphingosine kinase pathway is an important regulator of vascular beds, but its role in the survival and function of transplanted islets is unknown...
February 7, 2017: Diabetes
https://www.readbyqxmd.com/read/28166816/the-achru-cpp-versus-usual-care-for-older-adults-with-type-2-diabetes-and-multiple-chronic-conditions-and-their-family-caregivers-study-protocol-for-a-randomized-controlled-trial
#18
Maureen Markle-Reid, Jenny Ploeg, Kimberly D Fraser, Kathryn Ann Fisher, Noori Akhtar-Danesh, Amy Bartholomew, Amiram Gafni, Andrea Gruneir, Sandra P Hirst, Sharon Kaasalainen, Caralyn Kelly Stradiotto, John Miklavcic, Carlos Rojas-Fernandez, Cheryl A Sadowski, Lehana Thabane, Jean A C Triscott, Ross Upshur
BACKGROUND: Many community-based self-management programs have been developed for older adults with type-2 diabetes mellitus (T2DM), bolstered by evidence from randomized controlled trials (RCTs) that T2DM can be prevented and managed through lifestyle modifications. However, the evidence for their effectiveness is contradictory and weakened by reliance on single-group designs and/or small samples. Additionally, older adults with multiple chronic conditions (MCC) are often excluded because of recruiting and retention challenges...
February 6, 2017: Trials
https://www.readbyqxmd.com/read/28164571/establishment-of-a-novel-myelodysplastic-syndrome-mds-xenotransplantation-model
#19
Ling Ma, Xia Zhang, Zhiqiong Wang, Yan Chen, Jia Wei, Lihua Hu
BACKGROUND: Myelodysplastic syndrome (MDS) is a clonal disease of the elderly characterized by chronic cytopenia, dysplasia, and a high risk of progression to acute myeloid leukemia (AML). Up until now, few animal models that fully recapitulate clinical features of this disease have been available. METHODS: This study aimed to establish a new MDS xenograft model utilizing a human MDS-derived cell line with heterozygous Y641C mutation of EZH2 (SKM-1). 1 x 107 SKM-1 cells were inoculated into anti-mouse CD122 monoantibody conditioned nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice by intravenous injection...
September 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28164323/effects-of-exercise-induced-apelin-levels-on-skeletal-muscle-and-their-capillarization-in-type-2-diabetic-rats
#20
Jun Seok Son, Hee-Jae Kim, Yeri Son, Hojun Lee, Song Ah Chae, Je Kyung Seong, Wook Song
INTRODUCTION: Exercise-induced apelin as a myokine is believed to play a role in the improvement of type 2 diabetes mellitus(T2DM) and capillarization. Here, we evaluated the association between exercise-induced apelin and muscle capillarization. METHODS: Zucker rats underwent a treadmill exercise program. Body composition, muscle strength, muscle size, muscle capillarization, and insulin resistance(Homeostatic Model Assessment[HOMA-IR]) were measured. Apelin levels of skeletal muscle and plasma were then analyzed...
February 6, 2017: Muscle & Nerve
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