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Diabetes

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https://www.readbyqxmd.com/read/29669745/gpr119-agonism-increases-glucagon-secretion-during-insulin-induced-hypoglycemia
#1
Nina Xiaoyan Li, Stacey Brown, Tim Kowalski, Margaret Wu, Liming Yang, Ge Dai, Aleksandr Petrov, Yuyan Ding, Tamara Dlugos, H Blair Woods, Liangsu Wang, Mark Erion, Robert Sherwin, David E Kelley
Insulin-induced hypoglycemia in diabetes is associated with impaired glucagon secretion. Here we tested whether stimulation of GPR119, a G-protein coupled receptor expressed in pancreatic islet as well as enteroendocrine cells, and previously shown to stimulate insulin and incretin secretion might enhance glucagon secretion during hypoglycemia. In the study, GPR119 agonists were applied to isolated islets or perfused pancreata perfusions to assess insulin and glucagon secretion during hypoglycemia or hyperglycemic conditions...
April 18, 2018: Diabetes
https://www.readbyqxmd.com/read/29669744/erratum-polygenic-type-2-diabetes-prediction-at-the-limit-of-common-variant-detection-diabetes-2014-63-2172-2182
#2
Jason L Vassy, Marie-France Hivert, Bianca Porneala, Marco Dauriz, Jose C Florez, Josée Dupuis, David S Siscovick, Myriam Fornage, Laura J Rasmussen-Torvik, Claude Bouchard, James B Meigs
No abstract text is available yet for this article.
April 18, 2018: Diabetes
https://www.readbyqxmd.com/read/29666062/morning-hyperinsulinemia-primes-the-liver-for-glucose-uptake-and-glycogen-storage-later-in-the-day
#3
Mary Courtney Moore, Marta S Smith, Ben Farmer, Katie C Coate, Guillaume Kraft, Masakazu Shiota, Phillip E Williams, Alan D Cherrington
We observed that a 4h morning (AM) duodenal infusion of glucose vs saline doubled hepatic glucose uptake (HGU) and storage during a hyperinsulinemic hyperglycemic (HIHG) clamp that afternoon (PM). To separate the effects of AM hyperglycemia vs AM hyperinsulinemia on the PM response, we used hepatic balance and tracer (3 H-glucose) techniques in conscious dogs. From 0-240 min, dogs underwent a euinsulinemic hyperglycemic (GLC; n =7) or hyperinsulinemic euglycemic (INS; n =8) clamp. Tracer equilibration and basal sampling occurred from 240-360 min, followed by a HIHG clamp (360-600 min; 4xbasal insulin, 2xbasal glycemia) with portal glucose infusion (4 mg...
April 17, 2018: Diabetes
https://www.readbyqxmd.com/read/29661782/doc2b-protects-%C3%AE-cells-against-inflammatory-damage-and-enhances-function
#4
Arianne Aslamy, Eunjin Oh, Erika M Olson, Jing Zhang, Miwon Ahn, Abu Saleh Md Moin, Ragadeepthi Tunduguru, Vishal A Salunkhe, Rajakrishnan Veluthakal, Debbie C Thurmond
Loss of functional β-cell mass is an early feature of type 1 diabetes. To release insulin, β-cells require soluble n-ethylmaleimide-sensitive factor-attachment protein receptor (SNARE) complexes, as well as SNARE complex regulatory proteins like Double C2-domain protein β (DOC2B). We hypothesized that DOC2B deficiency or overabundance may confer susceptibility or protection, respectively, to the functional β-cell mass. Indeed, Doc2b +/- knockout mice show an unusually severe response to multiple-low-dose streptozotocin (MLD-STZ), resulting in more apoptotic β-cells and a smaller β-cell mass...
April 16, 2018: Diabetes
https://www.readbyqxmd.com/read/29661781/relation-of-aortic-stiffness-to-left-ventricular-remodelling-in-younger-adults-with-type-2-diabetes
#5
Gaurav S Gulsin, Daniel J Swarbrick, William H Hunt, Eylem Levelt, Matthew Pm Graham-Brown, Kelly S Parke, Joanne V Wormleighton, Florence Y Lai, Thomas Yates, Emma G Wilmot, David R Webb, Melanie J Davies, Gerry P McCann
Individuals with type 2 diabetes have a three-to-five-fold increased risk of developing heart failure. Diabetic cardiomyopathy is typified by left ventricular (LV) concentric remodelling, which is a recognised predictor of adverse cardiovascular events. Although the mechanisms underlying LV remodelling in type 2 diabetes are unclear, progressive aortic stiffening may be a key determinant. The aim of this study was to assess the relationship between aortic stiffness and LV geometry in younger adults with type 2 diabetes, using multiparametric cardiovascular magnetic resonance imaging...
April 16, 2018: Diabetes
https://www.readbyqxmd.com/read/29654212/modifying-enzymes-are-elicited-by-er-stress-generating-epitopes-that-are-selectively-recognized-by-cd4-t-cells-in-patients-with-type-1-diabetes
#6
Meghan L Marre, John W McGinty, I-Ting Chow, Megan E DeNicola, Noah W Beck, Sally C Kent, Alvin C Powers, Rita Bottino, David M Harlan, Carla J Greenbaum, William W Kwok, Jon D Piganelli, Eddie A James
In spite of tolerance mechanisms, some individuals develop T cell mediated autoimmunity. Post-translational modifications that increase the affinity of epitope presentation and/or recognition represent one means through which self-tolerance mechanisms can be circumvented. We investigated T cell recognition of peptides that correspond to modified beta cell antigens in subjects with type 1 diabetes. Modified peptides elicited enhanced proliferation by autoreactive T cell clones. Endoplasmic reticulum (ER) stress in insulinoma cells increased cytosolic calcium and the activity of tissue transglutaminase 2 (tTG2)...
April 13, 2018: Diabetes
https://www.readbyqxmd.com/read/29650774/genetic-variants-in-cpa6-and-prpf31-are-associated-with-variation-in-response-to-metformin-in-individuals-with-type-2-diabetes
#7
Daniel M Rotroff, Sook Wah Yee, Kaixin Zhou, Skylar W Marvel, Hetal S Shah, John R Jack, Tammy M Havener, Monique M Hedderson, Michiaki Kubo, Mark A Herman, He Gao, Josyf C Mychaleckyi, Howard L McLeod, Alessandro Doria, Kathleen M Giacomini, Ewan R Pearson, Michael J Wagner, John B Buse, Alison A Motsinger-Reif
Metformin is the first line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA1c response to metformin treatment, and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6 , were associated with worse and better metformin response, respectively (p<5×10-6 ), and meta-analysis in independent cohorts displayed similar associations with metformin response (p=1...
April 12, 2018: Diabetes
https://www.readbyqxmd.com/read/29650773/cannabinoid-type-1-receptors-are-upregulated-during-acute-activation-of-brown-adipose-tissue
#8
Minna Lahesmaa, Olof Eriksson, Thorsten Gnad, Vesa Oikonen, Marco Bucci, Jussi Hirvonen, Kalle Koskensalo, Jarmo Teuho, Tarja Niemi, Markku Taittonen, Salla Lahdenpohja, Mueez U Din, Merja Haaparanta-Solin, Alexander Pfeifer, Kirsi A Virtanen, Pirjo Nuutila
Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans. Obesity is associated with up-regulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and decrease cardiometabolic risk factors. These effects may partly be mediated via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents. To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography (PET) radioligand [18 F]FMPEP- d 2 , and in parallel measured BAT activation with the glucose analogue [18 F]FDG...
April 12, 2018: Diabetes
https://www.readbyqxmd.com/read/29643061/supplemental-oxygen-improves-in-vivo-mitochondrial-oxidative-phosphorylation-flux-in-sedentary-obese-adults-with-type-2-diabetes
#9
Melanie Cree-Green, Rebecca L Scalzo, Kylie Harrall, Bradley R Newcomer, Irene E Schauer, Amy G Huebschmann, Shawna McMillin, Mark S Brown, David Orlicky, Leslie Knaub, Kristen J Nadeau, P Mason Mcclatchey, Timothy A Bauer, Judith G Regensteiner, Jane E B Reusch
Type 2 diabetes is associated with impaired exercise capacity. Alterations in both muscle perfusion and mitochondrial function can contribute to exercise impairment. We hypothesized that impaired muscle mitochondrial function in type 2 diabetes is mediated, in part, by decreased tissue oxygen delivery and would improve with oxygen supplementation. Ex vivo muscle mitochondrial content and respiration assessed from biopsy samples demonstrated expected differences in obese individuals with (N=18) and without (N=17) diabetes...
April 11, 2018: Diabetes
https://www.readbyqxmd.com/read/29625991/t-3-induces-both-markers-of-maturation-and-aging-in-pancreatic-%C3%AE-cells
#10
Cristina Aguayo-Mazzucato, Terence B Lee, Michelle Matzko, Amanda DiIenno, Habib Rezanejad, Preeti Ramadoss, Thomas Scanlan, Ann Marie Zavacki, P Reed Larsen, Anthony Hollenberg, Clark Colton, Arun Sharma, Susan Bonner-Weir
Previously we showed thyroid hormone (T3 ) enhanced β-cell functional maturation through induction of Mafa High levels of T3 have been linked to decreased lifespan in mammals, and low levels to lengthened lifespan, suggesting a relationship between thyroid hormone and aging. Here we show T3 increased p16 Ink4a (a β-cell senescence marker and effector) mRNA in rodent and human β-cells. The kinetics of Mafa and p16 Ink4a induction suggested both genes as targets of thyroid hormone via TH receptor (THR) binding to specific response elements (TRE)...
April 6, 2018: Diabetes
https://www.readbyqxmd.com/read/29622583/a-pharmacogenetic-approach-to-the-treatment-of-patients-with-pparg-mutations
#11
Maura Agostini, Erik Schoenmakers, Junaid Beig, Louise Fairall, Istvan Szatmari, Odelia Rajanayagam, Frederick W Muskett, Claire Adams, A David Marais, Stephen O'Rahilly, Robert K Semple, Laszlo Nagy, Amit R Majithia, John W R Schwabe, Dirk J Blom, Rinki Murphy, Krishna Chatterjee, David B Savage
Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many cases. Missense mutations in PPARG are present in ∼1:500 people. Whilst mutations are often binarily classified as 'benign' or 'deleterious', prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic 'endogenous' (e.g. prostaglandin J2 (PGJ2)) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some PPARγ mutants...
April 5, 2018: Diabetes
https://www.readbyqxmd.com/read/29618580/oxidative-stress-inhibits-healthy-adipose-expansion-through-suppression-of-srebf1-mediated-lipogenic-pathway
#12
Yosuke Okuno, Atsunori Fukuhara, Erika Hashimoto, Hironori Kobayashi, Sachiko Kobayashi, Michio Otsuki, Iichiro Shimomura
Recent studies have emphasized the association of adipose oxidative stress (Fat ROS) with the pathogenesis of metabolic disorders in obesity. However, the causal roles of Fat ROS in metabolic disturbances in vivo remain unclear because no mouse model has been available in which oxidative stress is manipulated targeting adipocytes. In this research, we generated two models of Fat ROS-manipulated mice and evaluated the metabolic features in diet-induced obesity. Fat ROS-eliminated mice in which Cat and Sod1 were overexpressed in adipocytes exhibited adipose expansion with decreased ectopic lipid accumulation and improved insulin sensitivity...
April 4, 2018: Diabetes
https://www.readbyqxmd.com/read/29615440/inhibition-of-soluble-epoxide-hydrolase-2-ameliorates-diabetic-keratopathy-and-impaired-wound-healing-in-mouse-corneas
#13
Haijing Sun, Patrick Lee, Chenxi Yan, Nan Gao, Jiemei Wang, Xianqun Fan, Fu-Shin Yu
EPHX2 (soluble Epoxide Hydrolase 2, sEH) converts biologically active epoxyeicosatrienoic acids (EETs), anti-inflammatory and pro-fibrinolytic effectors into the less biologically active metabolites, dihydroxyeicostrienoic acids. We sought to characterize the expression and the function of EPHX2 in diabetic corneas and during wound healing. The expression of EPHX2 at both mRNA and protein levels, as well as sEH enzymatic activity, were markedly upregulated in the tissues/cells, including corneal epithelial cells as well as the retina of human type-2, mouse type-1 (STZ-induced) and/or type-2 diabetes...
April 3, 2018: Diabetes
https://www.readbyqxmd.com/read/29610263/cardiac-dysfunction-and-metabolic-inflexibility-in-a-mouse-model-of-diabetes-without-dyslipidaemia
#14
Maria Rohm, Dragana Savic, Vicky Ball, M Kate Curtis, Sarah Bonham, Roman Fischer, Nathalie Legrave, James I MacRae, Damian J Tyler, Frances M Ashcroft
Diabetes is a well-established risk factor for heart disease leading to impaired cardiac function and a metabolic switch towards fatty acid usage. Here, we investigated if hyperglycaemia/hypoinsulinaemia in the absence of dyslipidaemia is sufficient to drive these changes, and if they can be reversed by restoring euglycaemia. Using the βV59M mouse model, in which diabetes can be rapidly induced and reversed, we show that stroke volume and cardiac output were reduced within two weeks of diabetes induction. Flux through pyruvate dehydrogenase was decreased, as measured in vivo by hyperpolarized [1-13 C]pyruvate magnetic resonance spectroscopy...
April 2, 2018: Diabetes
https://www.readbyqxmd.com/read/29602791/endogenous-glucose-production-and-hormonal-changes-in-response-to-canagliflozin-and-liraglutide-combination-therapy
#15
Robert Martinez, Hussein Al-Jobori, Ali M Ali, John Adams, Muhammad Abdul-Ghani, Curtis Triplitt, Ralph DeFronzo, Eugenio Cersosimo
The decrement in plasma glucose concentration with SGLT2i is blunted by a rise in endogenous glucose production (EGP). We investigated the ability of incretin treatment to offset the EGP increase. T2DM (n=36) subjects were randomized to: (i) CANAgliflozin (ii) LIRAglutide (iii) CANA/LIRA. EGP was measured with 3-3 H-glucose with/without drug for 360 minutes. In the pre-treatment studies EGP (mg/kg•min) was comparable and decreased (2.2±0.1 to 1.7±0.2) during 300-360 minute period (p<0.01). The decrement in EGP was attenuated with CANA (2...
March 30, 2018: Diabetes
https://www.readbyqxmd.com/read/29588286/circulating-sphingolipids-insulin-homa-ir-and-homa-b-the-strong-heart-family-study
#16
Rozenn N Lemaitre, Chaoyu Yu, Andrew Hoofnagle, Nair Hari, Paul Jensen, Amanda M Fretts, Jason G Umans, Barbara V Howard, Colleen M Sitlani, David S Siscovick, Irena B King, Nona Sotoodehnia, Barbara McKnight
Experimental studies suggest ceramides may play a role in insulin resistance. However, the relationships of circulating ceramides and related sphingolipids with plasma insulin have been underexplored in humans. We measured 15 ceramide and sphingomyelin species in fasting baseline samples from the Strong Heart Family Study, a prospective cohort of American Indians. We examined sphingolipid associations with both baseline and follow-up measures of plasma insulin, Homeostatic Model Assessment of Insulin Resistance (HOMAIR) and Homeostatic Model Assessment of β-cell function (HOMAB) after adjustment for risk factors...
March 27, 2018: Diabetes
https://www.readbyqxmd.com/read/29581126/sdf-1-is-an-autocrine-insulin-desensitizing-factor-in-adipocytes
#17
Jihoon Shin, Atsunori Fukuhara, Toshiharu Onodera, Shunbun Kita, Chieko Yokoyama, Michio Otsuki, Iichiro Shimomura
Insulin desensitization occurs not only under obese diabetic condition, but also in the fasting state. However, little is known about the common secretory factor(s) that are regulated under these two insulin-desensitized conditions. Here, using database analysis, in vitro , and in vivo experiments, we identified SDF-1 as an insulin-desensitizing factor in adipocytes, overexpressed in both fasting and obese adipose tissues. Exogenously added SDF-1 induced ERK signal, which phosphorylated and degraded IRS-1 protein in adipocytes, decreasing insulin-mediated signaling and glucose uptake...
March 26, 2018: Diabetes
https://www.readbyqxmd.com/read/29563152/adrenaline-stimulates-glucagon-secretion-by-tpc2-dependent-ca-2-mobilization-from-acidic-stores-in-pancreatic-%C3%AE-cells
#18
Alexander Hamilton, Quan Zhang, Albert Salehi, Mara Willems, Jakob G Knudsen, Anna K Ringgaard, Caroline E Chapman, Alejandro Gonzalez-Alvarez, Nicoletta C Surdo, Manuela Zaccolo, Davide Basco, Paul R V Johnson, Reshma Ramracheya, Guy A Rutter, Antony Galione, Patrik Rorsman, Andrei I Tarasov
Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of β-adrenergic receptors but the downstream mechanisms have only been partially elucidated. Here we have examined the effects of adrenaline in mouse and human α-cells by a combination of electrophysiology, imaging of Ca2+ and PKA activity and hormone release measurements. We found that stimulation of glucagon secretion correlated with a PKA- and EPAC2-dependent (inhibited by PKI and ESI-05, respectively) elevation of [Ca2+ ]i in α-cells, which occurred without stimulation of electrical activity, persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin and thapsigargin...
March 21, 2018: Diabetes
https://www.readbyqxmd.com/read/29559443/pericyte-derived-dickkopf2-regenerates-damaged-penile-neurovasculature-through-an-angiopoietin-1-tie2-pathway
#19
Guo Nan Yin, Hai-Rong Jin, Min-Ji Choi, Anita Limanjaya, Kalyan Ghatak, Nguyen Nhat Minh, Jiyeon Ock, Mi-Hye Kwon, Kang-Moon Song, Heon Joo Park, Ho Min Kim, Young-Guen Kwon, Ji-Kan Ryu, Jun-Kyu Suh
Penile erection requires well-coordinated interactions between vascular and nervous system. Penile neurovascular dysfunction is a major cause of erectile dysfunction (ED) in patients with diabetes, which causes poor response to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2), a Wnt antagonist, is known to promote angiogenesis. Here, using DKK2-Tg mice or DKK2 protein administration, we demonstrate that overexpression of DKK2 in diabetic mice enhances penile angiogenesis and neural regeneration and restores erectile function...
March 20, 2018: Diabetes
https://www.readbyqxmd.com/read/29549163/nrf2-mediated-antioxidant-defense-and-peroxiredoxin-6-are-linked-to-biosynthesis-of-palmitic-acid-ester-of-9-hydroxystearic-acid
#20
Ondrej Kuda, Marie Brezinova, Jan Silhavy, Vladimir Landa, Vaclav Zidek, Chandra Dodia, Franziska Kreuchwig, Marek Vrbacky, Laurence Balas, Thierry Durand, Norbert Hübner, Aron B Fisher, Jan Kopecky, Michal Pravenec
Fatty acid esters of hydroxy fatty acids (FAHFAs) are lipid mediators with promising anti-diabetic and anti-inflammatory properties that are formed in white adipose tissue (WAT) via de novo lipogenesis, but their biosynthetic enzymes are unknown. Using a combination of lipidomics in WAT, QTL mapping and correlation analyses in rat BXH/HXB recombinant inbred strains, and response to oxidative stress in murine models, we elucidated the potential pathway of biosynthesis of several FAHFAs.Comprehensive analysis of WAT samples identified ∼160 regioisomers documenting the complexity of this lipid class...
March 16, 2018: Diabetes
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