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Diabetes

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https://www.readbyqxmd.com/read/28637651/pivotal-role-of-o-glcnac-modification-in-cold-induced-thermogenesis-by-brown-adipose-tissue-through-mitochondrial-biogenesis
#1
Natsuko Ohashi, Katsutaro Morino, Shogo Ida, Osamu Sekine, Mengistu Lemecha, Shinji Kume, Shi-Young Park, Cheol Soo Choi, Satoshi Ugi, Hiroshi Maegawa
Adipose tissues considerably influence metabolic homeostasis, and both white (WAT) and brown adipose tissue (BAT) play significant roles in lipid and glucose metabolism. O-GlcNAc modification is characterized by the addition of N-acetylglucosamine to various proteins by O-GlcNAc transferase (Ogt), subsequently modulating various cellular processes. However, little is known about the role of O-GlcNAc modification in adipose tissues. Here, we report the critical role of O-GlcNAc modification in cold-induced thermogenesis...
June 21, 2017: Diabetes
https://www.readbyqxmd.com/read/28634176/impact-of-glycemic-variability-on-chromatin-remodeling-oxidative-stress-and-endothelial-dysfunction-in-type-2-diabetic-patients-with-target-hba1c-levels
#2
Sarah Costantino, Francesco Paneni, Rodolfo Battista, Lorenzo Castello, Giuliana Capretti, Sergio Chiandotto, Luigi Tanese, Giulio Russo, Dario Pitocco, Gaetano A Lanza, Massimo Volpe, Thomas F Lüscher, Francesco Cosentino
Intensive glycemic control (IGC) targeting HbA1c fails to show an unequivocal reduction of macrovascular complications in type 2 diabetes (T2D), however the underlining mechanisms remain elusive. Epigenetic changes are emerging as important mediators of cardiovascular damage and may play a role in this setting. This study investigates whether epigenetic regulation of the adaptor protein p66(Shc), a key driver of mitochondrial oxidative stress, contributes to persistent vascular dysfunction in T2D patients despite IGC...
June 20, 2017: Diabetes
https://www.readbyqxmd.com/read/28630133/dual-regulation-of-gluconeogenesis-by-insulin-and-glucose-in-the-proximal-tubules-of-the-kidney
#3
Motohiro Sasaki, Takayoshi Sasako, Naoto Kubota, Yoshitaka Sakurai, Iseki Takamoto, Tetsuya Kubota, Reiko Inagi, George Seki, Moritaka Goto, Kohjiro Ueki, Masaomi Nangaku, Takahito Jomori, Takashi Kadowaki
Growing attention has been focused on the roles of the proximal tubules (PTs) of the kidney in glucose metabolism, including the mechanism of regulation of gluconeogenesis. Here, we found that PT-specific IRS1/2 double-knockout mice, established by using the newly generated sodium-glucose cotransporter-2 (SGLT2)-Cre transgenic mice, exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. On the other hand, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor...
June 19, 2017: Diabetes
https://www.readbyqxmd.com/read/28611037/inhibition-of-renal-sodium-glucose-co-transport-with-empagliflozin-lowers-fasting-plasma-glucose-and-improves-beta-cell-function-in-subjects-with-impaired-fasting-glucose
#4
Muhammad Abdul-Ghani, Hussein Al Jobori, Giuseppe Daniele, John Adams, Eugenio Cersosimo, Curtis Triplitt, Ralph A DeFronzo
To examine the effect of renal sodium glucose co-transporter inhibition with empagliflozin on the fasting plasma glucose concentration and beta cell function in subjects with impaired fasting glucose (IFG).8 subjects with normal fasting glucose and 8 subjects with IFG received empagliflozin (25 mg/day) for 2 weeks. Fasting plasma glucose concentration and beta cell function was measured with a 9-step hyperglycemic clamp before and 48 hours and 14 days after the start of empagliflozin.Empagliflozin caused 50±4 and 45±4 grams glucosuria on day 2 in IFG and NFG subjects, respectively, and the glucosuria was maintained for 2 weeks in both groups...
June 13, 2017: Diabetes
https://www.readbyqxmd.com/read/28607108/kv2-1-clustering-contributes-to-insulin-exocytosis-and-rescues-human-%C3%AE-cell-dysfunction
#5
Jianyang Fu, Xiaoqing Dai, Gregory Plummer, Kunimasa Suzuki, Austin Bautista, John M Githaka, Laura Senior, Mette Jensen, Dafna Greitzer-Antes, Jocelyn E Manning Fox, Herbert Y Gaisano, Christopher B Newgard, Nicolas Touret, Patrick E MacDonald
Insulin exocytosis is regulated by ion channels that control excitability and Ca(2+) influx. Channels also play an increasingly appreciated role in microdomain structure. In this study, we examine the mechanism by which the voltage-dependent K(+) (Kv) channel Kv2.1 (KCNB1) facilitates depolarization-induced exocytosis in INS 832/13 cells and β-cells from human donors with and without type 2 diabetes (T2D). We find that Kv2.1, but not Kv2.2 (KCNB2), forms clusters of 6-12 tetrameric channels at the plasma membrane and facilitates insulin exocytosis...
June 12, 2017: Diabetes
https://www.readbyqxmd.com/read/28607107/myeloid-sirtuin-6-deficiency-causes-insulin-resistance-in-high-fat-diet-fed-mice-by-eliciting-macrophage-polarization-toward-an-m1-phenotype
#6
Youngyi Lee, Sun-O Ka, Hye-Na Cha, Yu-Na Chae, Mi-Kyung Kim, So-Young Park, Eun Ju Bae, Byung-Hyun Park
Obesity-related insulin resistance is closely associated with macrophage accumulation and subsequent cytokine release in local tissues. Sirtuin (Sirt) 6 is known to exert an anti-inflammatory function but its role in macrophages in the context of obesity has not been investigated. Here, we generated myeloid-specific Sirt6 knockout mice (mS6KO) and investigated the metabolic characteristics after high-fat diet (HFD) feeding for 16 weeks. Compared with their wild type littermates, HFD-fed mS6KO mice exhibited greater increases in body weight, fasting blood glucose- and insulin-levels, hepatic steatosis, glucose intolerance, and insulin resistance...
June 12, 2017: Diabetes
https://www.readbyqxmd.com/read/28607106/ubash3a-mediates-risk-for-type-1-diabetes-through-inhibition-of-t-cell-receptor-induced-nf-%C3%AE%C2%BAb-signaling
#7
Yan Ge, Taylor K Paisie, Jeremy R B Newman, Lauren M McIntyre, Patrick Concannon
Although over 40 type 1 diabetes (T1D) risk loci have been mapped in humans, the causative genes and variants for T1D are largely unknown. Here, we investigated a candidate gene in the 21q22.3 risk locus-UBASH3A, which is primarily expressed in T cells where it is thought to play a largely redundant role. Genetic variants in UBASH3A have been shown to be associated with several autoimmune diseases in addition to T1D. However, the molecular mechanism underlying these genetic associations is unresolved. Our study reveals a previously unrecognized role of UBASH3A in human T cells: UBASH3A attenuates the NF-κB signal transduction upon T cell receptor (TCR) stimulation by specifically suppressing the activation of the IKK complex...
June 12, 2017: Diabetes
https://www.readbyqxmd.com/read/28607105/acyl-coa-thioesterase-1-acot1-regulates-ppar%C3%A3-to-couple-fatty-acid-flux-with-oxidative-capacity-during-fasting
#8
Mallory P Franklin, Aishwarya Sathyanarayan, Douglas G Mashek
Hepatic acyl-CoA thioesterase 1 (ACOT1) catalyzes the conversion of acyl-CoAs to fatty acids (FAs) and Coenzyme A. We sought to determine the role of ACOT1 in hepatic lipid metabolism in C57Bl/6J male mice one week following adenovirus-mediated Acot1 knockdown. Acot1 knockdown reduced liver triglyceride (TG) due to enhanced TG hydrolysis and subsequent FA oxidation. In vitro experiments demonstrated that Acot1 knockdown led to greater TG turnover and FA oxidation, suggesting that ACOT1 is important for controlling the rate of FA oxidation...
June 12, 2017: Diabetes
https://www.readbyqxmd.com/read/28603140/mining-the-genome-for-therapeutic-targets
#9
Jose C Florez
Current pharmacological options for type 2 diabetes do not cure the disease. Despite the availability of multiple drug classes that modulate glycemia effectively and minimize long-term complications, these agents do not reverse pathogenesis, and in practice they are not selected to correct the molecular profile specific to the patient. Pharmaceutical companies find drug development programs increasingly costly and burdensome, and many promising compounds fail before launch to market. Human genetics can help advance the therapeutic enterprise...
June 11, 2017: Diabetes
https://www.readbyqxmd.com/read/28603139/how-should-we-think-about-the-role-of-the-brain-in-glucose-homeostasis-and-diabetes
#10
Jennifer D Deem, Kenjiro Muta, Jarrad M Scarlett, Gregory J Morton, Michael W Schwartz
No abstract text is available yet for this article.
June 11, 2017: Diabetes
https://www.readbyqxmd.com/read/28603138/single-molecule-combinatorial-therapeutics-for-treating-obesity-and-diabetes
#11
Matthias Tschöp, Richard DiMarchi
No abstract text is available yet for this article.
June 11, 2017: Diabetes
https://www.readbyqxmd.com/read/28596237/the-snare-protein-syntaxin1a-plays-an-essential-role-in-biphasic-exocytosis-of-the-incretin-hormone-glucagon-like-peptide-1
#12
Sarah E Wheeler, Holly M Stacey, Yasaman Nahaei, Stephen J Hale, Alexandre B Hardy, Frank Reimann, Fiona M Gribble, Pierre Larraufie, Herbert Y Gaisano, Patricia L Brubaker
Exocytosis of the hormone, glucagon-like peptide-1 (GLP-1), by the intestinal L-cell is essential for the incretin effect after nutrient ingestion, and is critical for the actions of dipeptidylpeptidase IV inhibitors that enhance GLP-1 levels in patients with type 2 diabetes. 2-Photon microscopy revealed that exocytosis of GLP-1 is biphasic, with a 1(st) peak at 1-6min and a 2(nd) peak at 7-12min after stimulation with forskolin. Approximately 75% of the exocytotic events were represented by compound granule fusion, and the remainder were accounted for by full fusion of single granules, under basal and stimulated conditions...
June 8, 2017: Diabetes
https://www.readbyqxmd.com/read/28596236/acute-hypoglycemia-in-healthy-humans-impairs-insulin-stimulated-glucose-uptake-and-glycogen-synthase-in-skeletal-muscle-a-randomized-clinical-study
#13
Thomas S Voss, Mikkel H Vendelbo, Ulla Kampmann, Janne R Hingst, Jørgen F P Wojtaszewski, Mads V Svart, Niels Møller, Niels Jessen
Hypoglycemia is the leading limiting factor in glycemic management of insulin-treated diabetes. Skeletal muscle is the predominant site of insulin-mediated glucose disposal and our study was designed to test to what extent insulin induced hypoglycemia affects glucose uptake in skeletal muscle and whether hypoglycemia counter-regulation modulates insulin and catecholamine signaling and glycogen synthase activity in skeletal muscle.Nine healthy volunteers were examined on three randomized study days in a crossover design: i) hyperinsulinemic hypoglycemia (bolus insulin), ii) hyperinsulinemic euglycemia (bolus insulin and glucose infusion) and iii) saline control with skeletal muscle biopsies taken just before, 30 min and 75 min after insulin/saline injection...
June 8, 2017: Diabetes
https://www.readbyqxmd.com/read/28592408/recovery-of-corneal-sensitivity-and-increase-in-nerve-density-and-wound-healing-in-diabetic-mice-after-pedf-plus-dha-treatment
#14
Jiucheng He, Thang Luong Pham, Azucena Kakazu, Haydee E P Bazan
Diabetic keratopathy decreases corneal sensation and tear secretion, and delays wound healing after injury. In the current study, we tested the effect of treatment with pigment epithelium-derived factor (PEDF) in combination with docosahexaenoic acid (DHA) on corneal nerve regeneration in a mouse model of diabetes with or without corneal injury. The study was performed in streptozotocin (STZ)-induced diabetic mice (C57BL/6). Ten weeks after STZ injection, diabetic mice showed significant decreases of corneal sensitivity, tear production and epithelial subbasal nerve density when compared with age-matched normal mice...
June 7, 2017: Diabetes
https://www.readbyqxmd.com/read/28588100/higher-plasma-methylglyoxal-levels-are-associated-with-incident-cardiovascular-disease-in-individuals-with-type-1-diabetes-a-12-year-follow-up-study
#15
Nordin M J Hanssen, Jean L J M Scheijen, Anders Jorsal, Hans-Henrik Parving, Lise Tarnow, Peter Rossing, Coen D A Stehouwer, Casper G Schalkwijk
Methylglyoxal (MGO), a major precursor for advanced glycation endproducts (AGEs), is increased in diabetes. In diabetic rodents, inhibition of MGO prevents cardiovascular disease (CVD). Whether plasma MGO levels are associated with incident CVD in people with type 1 diabetes is unknown. We included 159 individuals with persistent normoalbuminuria and 162 individuals with diabetic nephropathy (DN) from the outpatient clinic at Steno Diabetes Center. We measured MGO at baseline. We recorded fatal and non-fatal CVD over a median follow-up of 12...
June 6, 2017: Diabetes
https://www.readbyqxmd.com/read/28588099/age-dependent-decline-in-the-coordinated-ca-2-and-insulin-secretory-dynamics-in-human-pancreatic-islets
#16
Matthew J Westacott, Nikki L Farnsworth, Joshua R St Clair, Greg Poffenberger, Audrey Heintz, Nurin L Ludin, Nathaniel J Hart, Alvin C Powers, Richard K P Benninger
Aging is associated with increased risk for type2 diabetes, resulting from reduced insulin sensitivity and secretion. Reduced insulin secretion can result from reduced proliferative capacity and reduced islet function. Mechanisms underlying altered β-cell function in aging are poorly understood in mouse and human islets and the impact of aging on intra-islet communication has not been characterized. Here, we examine how β-cell [Ca(2+)] and electrical communication are impacted during aging in mouse and human islets...
June 6, 2017: Diabetes
https://www.readbyqxmd.com/read/28576837/hypothalamic-inflammation-in-human-obesity-is-mediated-by-environmental-and-genetic-factors
#17
Carina Kreutzer, Sönke Peters, Dominik M Schulte, Daniela Fangmann, Kathrin Türk, Stephan Wolff, Thilo van Eimeren, Markus Ahrens, Jan Beckmann, Clemens Schafmayer, Thomas Becker, Tina Kerby, Axel Rohr, Christian Riedel, Femke-Anouska Heinsen, Frauke Degenhardt, Andre Franke, Philip Rosenstiel, Nana Zubek, Christian Henning, Sandra Freitag-Wolf, Astrid Dempfle, Aristea Psilopanagioti, Helen Petrou-Papadaki, Lennart Lenk, Olav Jansen, Stefan Schreiber, Matthias Laudes
Obesity is associated with hypothalamic inflammation (HI) in animal models. In the present study we examined the mediobasal hypothalamus (MBH) of 57 obese human subjects and 54 age- and sex- matched non-obese controls by MRI and analyzed the T2-hyperintensity as a measure of HI. Obese subjects exhibited T2-hyperintensity in the left but not the right MBH which was strongly associated with systemic low-grade inflammation. MRI-spectroscopy revealed the number of neurons in the left hypothalamic region to be similar in obese versus control subjects suggesting functional but not structural impairment due to the inflammatory process...
June 2, 2017: Diabetes
https://www.readbyqxmd.com/read/28572303/maternal-exercise-improves-glucose-tolerance-in-female-offspring
#18
Kristin I Stanford, Hirokazu Takahashi, Kawai So, Ana Barbara Alves-Wagner, Noah B Prince, Adam C Lehnig, Kristen M Getchell, Min-Young Lee, Michael F Hirshman, Laurie J Goodyear
Poor maternal diet can lead to metabolic disease in offspring whereas maternal exercise may have beneficial effects on offspring health. Here, we determined if maternal exercise could reverse the detrimental effects of maternal high fat feeding on offspring metabolism of female mice. C57BL/6 female mice were fed a chow (21%) or high-fat (60%) diet and further divided by housing in static cages or cages with running wheels for 2 weeks prior to breeding and throughout gestation. Females were bred with chow-fed sedentary C57BL/6 males...
June 1, 2017: Diabetes
https://www.readbyqxmd.com/read/28566273/an-expanded-genome-wide-association-study-of-type-2-diabetes-in-europeans
#19
Robert A Scott, Laura J Scott, Reedik Mägi, Letizia Marullo, Kyle J Gaulton, Marika Kaakinen, Natalia Pervjakova, Tune H Pers, Andrew D Johnson, John D Eicher, Anne U Jackson, Teresa Ferreira, Yeji Lee, Clement Ma, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Lu Qi, Natalie R Van Zuydam, Anubha Mahajan, Han Chen, Peter Almgren, Ben F Voight, Harald Grallert, Martina Müller-Nurasyid, Janina S Ried, William N Rayner, Neil Robertson, Lennart C Karssen, Elisabeth M van Leeuwen, Sara M Willems, Christian Fuchsberger, Phoenix Kwan, Tanya M Teslovich, Pritam Chanda, Man Li, Yingchang Lu, Christian Dina, Dorothee Thuillier, Loic Yengo, Longda Jiang, Thomas Sparso, Hans A Kestler, Himanshu Chheda, Lewin Eisele, Stefan Gustafsson, Mattias Frånberg, Rona J Strawbridge, Rafn Benediktsson, Astradur B Hreidarsson, Augustine Kong, Gunnar Sigurðsson, Nicola D Kerrison, Jian'an Luan, Liming Liang, Thomas Meitinger, Michael Roden, Barbara Thorand, Tõnu Esko, Evelin Mihailov, Caroline Fox, Ching-Ti Liu, Denis Rybin, Bo Isomaa, Valeriya Lyssenko, Tiinamaija Tuomi, David J Couper, James S Pankow, Niels Grarup, Christian T Have, Marit E Jørgensen, Torben Jørgensen, Allan Linneberg, Marilyn C Cornelis, Rob M van Dam, David J Hunter, Peter Kraft, Qi Sun, Sarah Edkins, Katharine R Owen, John Rb Perry, Andrew R Wood, Eleftheria Zeggini, Juan Tajes-Fernandes, Goncalo R Abecasis, Lori L Bonnycastle, Peter S Chines, Heather M Stringham, Heikki A Koistinen, Leena Kinnunen, Bengt Sennblad, Thomas W Mühleisen, Markus M Nöthen, Sonali Pechlivanis, Damiano Baldassarre, Karl Gertow, Steve E Humphries, Elena Tremoli, Norman Klopp, Julia Meyer, Gerald Steinbach, Roman Wennauer, Johan G Eriksson, Satu Mӓnnistö, Leena Peltonen, Emmi Tikkanen, Guillaume Charpentier, Elodie Eury, Stéphane Lobbens, Bruna Gigante, Karin Leander, Olga McLeod, Erwin P Bottinger, Omri Gottesman, Douglas Ruderfer, Matthias Blüher, Peter Kovacs, Anke Tonjes, Nisa M Maruthur, Chiara Scapoli, Raimund Erbel, Karl-Heinz Jöckel, Susanne Moebus, Ulf de Faire, Anders Hamsten, Michael Stumvoll, Panagiotis Deloukas, Peter J Donnelly, Timothy M Frayling, Andrew T Hattersley, Samuli Ripatti, Veikko Salomaa, Nancy L Pedersen, Bernhard O Boehm, Richard N Bergman, Francis S Collins, Karen L Mohlke, Jaakko Tuomilehto, Torben Hansen, Oluf Pedersen, Inês Barroso, Lars Lannfelt, Erik Ingelsson, Lars Lind, Cecilia M Lindgren, Stephane Cauchi, Philippe Froguel, Ruth Jf Loos, Beverley Balkau, Heiner Boeing, Paul W Franks, Aurelio Barricarte Gurrea, Domenico Palli, Yvonne T van der Schouw, David Altshuler, Leif C Groop, Claudia Langenberg, Nicholas J Wareham, Eric Sijbrands, Cornelia M van Duijn, Jose C Florez, James B Meigs, Eric Boerwinkle, Christian Gieger, Konstantin Strauch, Andres Metspalu, Andrew D Morris, Colin Na Palmer, Frank B Hu, Unnur Thorsteinsdottir, Kari Stefansson, Josée Dupuis, Andrew P Morris, Michael Boehnke, Mark I McCarthy, Inga Prokopenko
To characterise type 2 diabetes (T2D) associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D cases and 132,532 controls of European ancestry after imputation using the 1000 Genomes multi-ethnic reference panel. Promising association signals were followed-up in additional data sets (of 14,545 or 7,397 T2D cases and 38,994 or 71,604 controls). We identified 13 novel T2D-associated loci (p<5×10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes...
May 31, 2017: Diabetes
https://www.readbyqxmd.com/read/28559246/neprilysin-is-required-for-angiotensin-1-7-s-ability-to-enhance-insulin-secretion-via-its-proteolytic-activity-to-generate-angiotensin-1-2
#20
Gurkirat S Brar, Breanne M Barrow, Matthew Watson, Ryan Griesbach, Edwina Choung, Andrew Welch, Bela Ruzsicska, Daniel P Raleigh, Sakeneh Zraika
Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1-7) by angiotensin converting enzyme 2 (ACE2) and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1-7)-mediated GSIS...
May 30, 2017: Diabetes
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