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Diabetes

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https://www.readbyqxmd.com/read/28087565/perturbation-of-retinoid-homeostasis-increases-malformation-risk-in-embryos-exposed-to-pregestational-diabetes
#1
Leo M Y Lee, Maran B W Leung, Rachel C Y Kwok, Yun-Chung Leung, Chi-Chiu Wang, Peter J McCaffery, Andrew J Copp, Alisa S W Shum
Pregestational diabetes is highly associated with increased risk of birth defects. However, factors that can increase or reduce expressivity and penetrance of malformations in diabetic pregnancies remain poorly identified. All-trans retinoic acid (RA) plays crucial roles in embryogenesis. Here, we find that Cyp26a1, which encodes a key enzyme for catabolic inactivation of RA required for tight control of local RA concentrations, is significantly down-regulated in embryos of diabetic mice. Embryonic tissues expressing Cyp26a1 show reduced efficiency of RA clearance...
January 13, 2017: Diabetes
https://www.readbyqxmd.com/read/28082459/deletion-of-cd1d-in-adipocytes-aggravates-adipose-tissue-inflammation-and-insulin-resistance-in-obesity
#2
Jin Young Huh, Jeu Park, Jong In Kim, Yoon Jeong Park, Yun Kyung Lee, Jae Bum Kim
Adipose tissue inflammation is an important factor in obesity that promotes insulin resistance. Among various cell types in adipose tissue, immune cells actively regulate inflammatory responses and affect whole-body energy metabolism. In particular, invariant Natural Killer T (iNKT) cells contribute to mitigating dysregulation of systemic energy homeostasis by counteracting obesity-induced inflammation in adipose tissue. However, the molecular mechanisms by which adipose iNKT cells become activated and mediate anti-inflammatory roles in obese adipose tissue have not been thoroughly understood yet...
January 12, 2017: Diabetes
https://www.readbyqxmd.com/read/28082458/developmental-role-of-macrophage-cannabinoid-1-receptor-signaling-in-type-2-diabetes
#3
Tony Jourdan, Gergő Szanda, Resat Cinar, Grzegorz Godlewski, David J Holovac, Joshua K Park, Sarah Nicoloro, Yuefei Shen, Jie Liu, Avi Z Rosenberg, Ziyi Liu, Michael P Czech, George Kunos
Islet inflammation promotes β-cell loss and type-2 diabetes (T2D), a process replicated in Zucker Diabetic Fatty (ZDF) rats in which β-cell loss has been linked to cannabinoid-1 receptor (CB1R)-induced pro-inflammatory signaling in macrophages infiltrating pancreatic islets. Here, we analyzed CB1R signaling in macrophages and its developmental role in T2Dα. ZDF rats with global deletion of CB1R are protected from β-cell loss, hyperglycemia and nephropathy present in ZDF littermates. Adoptive transfer of CB1R(-/-) bone marrow to ZDF rats also prevents β-cell loss and hyperglycemia, but not nephropathy...
January 12, 2017: Diabetes
https://www.readbyqxmd.com/read/28082457/neu5gc-and-%C3%AE-1-3-gal-xenoantigen-knockout-does-not-affect-glycemia-homeostasis-and-insulin-secretion-in-pigs
#4
Apolline Salama, Mathilde Mosser, Xavier Lévêque, Andrea Perota, Jean-Paul Judor, Corentin Danna, Sylvie Pogu, Anne Mouré, Dominique Jégou, Nicolas Gaide, Jérôme Abadie, Olivier Gauthier, Jean-Paul Concordet, Stéphanie Le Bas-Bernardet, David Riochet, Ludmilla Le Berre, Jérémy Hervouet, David Minault, Pierre Weiss, Jérôme Guicheux, Sophie Brouard, Steffi Bosch, Irina Lagutina, Roberto Duchi, Giovanna Lazzari, Emanuele Cozzi, Gilles Blancho, Sophie Conchon, Cesare Galli, Jean-Paul Soulillou, Jean-Marie Bach
Xeno-cell therapy from neonate or adult pig pancreatic islets is one of the most promising alternatives to allograft in type-1 diabetes for addressing organ-shortage. However, in human, natural and elicited antibodies specific for pig xenoantigens, α(1,3)-galactose (GAL) and N-glycolylneuraminic acid (Neu5Gc), are likely to significantly contribute to xeno-islet rejection. We obtained double knockout pigs (DKO) lacking GAL and Neu5Gc. As Neu5Gc-/- mice exhibit glycemic dysregulations and pancreatic β-cell dysfunctions, we evaluated islet function and glucose metabolism regulation in DKO pigs...
January 12, 2017: Diabetes
https://www.readbyqxmd.com/read/28082456/obesity-associated-alterations-in-glucose-metabolism-are-reversed-by-chronic-bilateral-stimulation-of-the-abdominal-vagus-nerve
#5
Charles-Henri Malbert, Chloé Picq, Jean-Louis Divoux, Christine Henry, Michael Horowitz
Acute vagal stimulation modifies glucose and insulin metabolism, but the effect of chronic bilateral vagal stimulation is not known. Our aim was to quantify the changes in whole body and organ-specific insulin sensitivities, 12 weeks after permanent, bilateral, vagal stimulation performed at the abdominal level in adult mini-pigs. In 15 adult mini-pigs, stimulating electrodes were placed around the dorsal and ventral vagi using laparoscopy and connected to a dual channel stimulator placed subcutaneously. Animals were divided into three groups based on stimulation and body weight i...
January 12, 2017: Diabetes
https://www.readbyqxmd.com/read/28073831/deletion-of-protein-kinase-c-lambda-in-pomc-neurons-predisposes-to-diet-induced-obesity
#6
Mauricio D Dorfman, Jordan E Krull, Jarrad M Scarlett, Stephan J Guyenet, Mini P Sajan, Vincent Damian, Hong T Nguyen, Michael Leitges, Gregory J Morton, Robert V Farese, Michael W Schwartz, Joshua P Thaler
Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the hypothalamic regulation of energy and glucose homeostasis in divergent ways. Here we show that CNS action of the PI3K signaling intermediate atypical protein kinase C (aPKC) constrains food intake, weight gain, and glucose intolerance in both rats and mice. Pharmacologic inhibition of CNS aPKC activity acutely increases food intake and worsens glucose tolerance in chow-fed rodents and causes excess weight gain during high fat diet (HFD) feeding...
January 10, 2017: Diabetes
https://www.readbyqxmd.com/read/28073830/adiponectin-deficiency-impairs-maternal-metabolic-adaptation-to-pregnancy-in-mice
#7
Liping Qiao, Jean-Sebastien Wattez, Samuel Lee, Amanda Nguyen, Jerome Schaack, William W Hay, Jianhua Shao
Hypoadiponectinemia has been widely observed in patients with gestational diabetes. To investigate the causal role of hypoadiponectinemia in gestational diabetes, adiponectin gene knockout (Adipoq(-/-)) and wild-type (WT) mice were crossed to produce pregnant mouse models with or without adiponectin deficiency. Adenoviral vector-mediated in vivo transduction was used to reconstitute adiponectin during late pregnancy. Results showed that Adipoq(-/-) dams developed glucose intolerance and hyperlipidemia in late pregnancy...
January 10, 2017: Diabetes
https://www.readbyqxmd.com/read/28073829/dutpase-dut-is-mutated-in-a-novel-monogenic-syndrome-with-diabetes-and-bone-marrow-failure
#8
Reinaldo Sousa Dos Santos, Mathilde Daures, Anne Philippi, Sophie Romero, Lorella Marselli, Piero Marchetti, Valérie Senée, Delphine Bacq, Céline Besse, Baz Baz, Laura Marroquí, Sarah Ivanoff, Julien Masliah-Planchon, Marc Nicolino, Jean Soulier, Gérard Socié, Decio L Eizirik, Jean-François Gautier, Cécile Julier
We describe a new syndrome characterized by early onset diabetes mellitus, associated with bone marrow failure affecting mostly the erythrocytic lineage. Using whole exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase (DUT) gene (NCBI Gene ID: 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) isoforms. We found the same homozygous mutation in an unrelated consanguineous patient with diabetes and bone marrow aplasia from a family with two affected siblings, while none of the >60,000 subjects from the Exome Aggregation Consortium (ExAC) was homozygous for this mutation...
January 10, 2017: Diabetes
https://www.readbyqxmd.com/read/28073828/an-activating-mutation-in-stat3-results-in-neonatal-diabetes-through-reduced-insulin-synthesis
#9
Teresa Velayos, Rosa Martínez, Milagros Alonso, Koldo Garcia-Etxebarria, Anibal Aguayo, Cristina Camarero, Inés Urrutia, Idoia Martínez de LaPiscina, Raquel Barrio, Izortze Santin, Luis Castaño
Neonatal diabetes mellitus (NDM) is a rare form of diabetes diagnosed within the first six months of life. Genetic studies have allowed the identification of several genes linked to the development of NDM, however genetic causes for around 20% of the cases remain to be clarified.Most cases of NDM involve isolated diabetes, but sometimes it appears in association with other pathological conditions, including autoimmune diseases. Recent reports have linked activating mutations in STAT3 with early-onset autoimmune disorders that include diabetes of autoimmune origin, however the functional impact of STAT3 activating mutations have not been characterized at the pancreatic β cell level...
January 10, 2017: Diabetes
https://www.readbyqxmd.com/read/28069642/alpha-1-antitrypsin-enhances-islet-engraftment-by-suppression-of-instant-blood-mediated-inflammatory-reaction
#10
Jingjing Wang, Zhen Sun, Wenyu Gou, David B Adams, Wanxing Cui, Katherine A Morgan, Charlie Strange, Hongjun Wang
Islet cell transplantation has limited effectiveness because of an instant blood-mediated inflammatory reaction (IBMIR) that occurs immediately after cell infusion and leads to dramatic β cell death. In intraportal islet transplantation models using mouse and human islets, we demonstrated that alpha-1 antitrypsin (AAT, Prolastin-C), a serine protease inhibitor used for the treatment of AAT deficiency, inhibits IBMIR and cytokine-induced inflammation in islets. In mice, more diabetic recipients reached normoglycemia after intraportal islet transplantation when they were treated with AAT compared to mice treated with saline...
January 9, 2017: Diabetes
https://www.readbyqxmd.com/read/28069641/differential-impact-of-chronic-hyperglycemia-on-humoral-versus-cellular-primary-alloimmunity
#11
Nicholas H Bishop, Michelle K Nelsen, K Scott Beard, Ronald G Gill
Diabetes is prevalent among solid organ transplant recipients and is universal among islet transplant recipients. While diabetes is often considered to result in an immune compromised state, the impact of chronic hyperglycemia on host alloimmunity is not clear. Potential immune modifying effects of obesity, autoimmunity, or diabetogenic agents like streptozotocin may confound understanding alloimmunity in experimental models of diabetes. Therefore, we sought to determine the role of chronic hyperglycemia due to insulinopenia on alloimmunity using the non-autoimmune, spontaneously diabetic H-2(b)-expressing C57BL/6 Ins2(Akita) mice (Akita)...
January 9, 2017: Diabetes
https://www.readbyqxmd.com/read/28057699/glucagon-like-peptide-1-and-its-analogues-act-in-the-dorsal-raphe-and-modulate-central-serotonin-to-reduce-appetite-and-body-weight
#12
Rozita H Anderberg, Jennifer E Richard, Kim Eerola, Lorena Lopez Ferreras, Elin Banke Nordbeck, Caroline Hansson, Hans Nissbrandt, Filip Berqquist, Fiona M Gribble, Frank Reimann, Ingrid Wernstedt-Asterholm, Christophe Lamy, Karolina P Skibicka
Glucagon-like peptide-1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as anti-obesity strategies. Surprisingly whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the CNS. Serotonin depletion impaired the ability of exendin-4, a clinically utilized GLP-1 analogue, to reduce body weight in rats, suggesting serotonin is a critical mediator of the energy balance impact of GLP-1R activation...
January 5, 2017: Diabetes
https://www.readbyqxmd.com/read/28052966/role-of-adipose-tissue-insulin-resistance-in-the-natural-history-of-t2dm-results-from-the-san-antonio-metabolism-study
#13
Amalia Gastaldelli, Melania Gaggini, Ralph A DeFronzo
In the transition from normal glucose tolerance (NGT) to type 2 diabetes mellitus (T2DM), the role of β-cell dysfunction and peripheral insulin resistance (IR) is well established. However, the impact of dysfunctional adipose tissue has not been fully elucidated. The aim of the present study is to evaluate the role of resistance to the antilipolytic effect of insulin (Adipo-IR) in a large group of NGT, IGT and T2DM subjects.302 subjects with varying glucose tolerance received OGTT and euglycemic insulin clamp...
January 4, 2017: Diabetes
https://www.readbyqxmd.com/read/28052965/the-sglt2-inhibitor-dapagliflozin-prevents-cardiomyopathy-in-a-diabetic-lipodystrophic-mouse-model
#14
Michael Joubert, Benoît Jagu, David Montaigne, Xavier Marechal, Angela Tesse, Audrey Ayer, Lucile Dollet, Cédric Le May, Gilles Toumaniantz, Alain Manrique, Flavien Charpentier, Bart Staels, Jocelyne Magré, Bertand Cariou, Xavier Prieur
Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for heart failure (HF). T2DM is associated with altered cardiac energy metabolism, leading to ectopic lipid accumulation and glucose overload, the exact contribution of these two parameters remaining unclear. To provide new insight into the mechanism driving the development of diabetic cardiomyopathy, we studied a unique model of T2DM: lipodystrophic Bscl2(-/-) (seipin knockout (SKO)) mice. Echocardiography and cardiac magnetic resonance imaging revealed hypertrophic cardiomyopathy with left ventricular dysfunction in SKO mice and these two abnormalities were strongly correlated with hyperglycemia...
January 4, 2017: Diabetes
https://www.readbyqxmd.com/read/28052964/whole-genome-bisulfite-sequencing-of-human-pancreatic-islets-reveals-novel-differentially-methylated-regions-in-type-2-diabetes-pathogenesis
#15
Petr Volkov, Karl Bacos, Jones K Ofori, Jonathan Lou S Esguerra, Lena Eliasson, Tina Rönn, Charlotte Ling
Current knowledge about the role of epigenetics in type 2 diabetes (T2D) remains limited. Only a few studies have investigated DNA methylation of selected candidate genes or a very small fraction of genomic CpG sites in human pancreatic islets, the tissue of primary pathogenic importance for diabetes. Our aim was to characterize the whole-genome DNA methylation landscape in human pancreatic islets, to identify differentially methylated regions (DMRs) in diabetic islets, and to investigate the function of DMRs in islet biology...
January 4, 2017: Diabetes
https://www.readbyqxmd.com/read/28028078/ire1%C3%AE-in-pomc-neurons-is-required-for-thermogenesis-and-glycemia
#16
Ting Yao, Zhuo Deng, Yong Gao, Jia Sun, Xingxing Kong, Yiru Huang, Zhenyan He, Yanchao Xu, Yongsheng Chang, Kai-Jiang Yu, Brianna G Findley, Eric D Berglund, Rui-Tao Wang, Hongbo Guo, Hong Chen, Xu Li, Randal J Kaufman, Jianqun Yan, Tiemin Liu, Kevin W Williams
Whether neuronal inositol-requiring enzyme 1(Ire1) is required for the proper regulation of energy balance and glucose homeostasis is unclear. We found that pro-opiomelanocortin (Pomc)-specific deficiency of Ire1α accelerated diet-induced obesity concomitant with a decrease in energy expenditure. This hypometabolic phenotype included deficits in thermogenic responses to diet and cold exposure as well as 'beiging' of white adipose tissue. We also demonstrate that loss of Ire1α in Pomc neurons impaired whole-body glucose and insulin tolerance as well as hepatic insulin sensitivity...
December 27, 2016: Diabetes
https://www.readbyqxmd.com/read/28028077/endogenous-%C3%AE-2a-adrenoceptor-operated-sympathoadrenergic-tones-attenuate-insulin-secretion-via-camp-trpm2-signaling
#17
Kiyonori Ito, Katsuya Dezaki, Masashi Yoshida, Hodaka Yamada, Rina Miura, Rauza Sukma Rita, Susumu Ookawara, Kaoru Tabei, Masanobu Kawakami, Kazuo Hara, Yoshiyuki Morishita, Toshihiko Yada, Masafumi Kakei
In pancreatic β-cells, pharmacological concentrations of catecholamines, including adrenaline, have been used to inhibit insulin release and explore the multiple mechanisms involved. However, the significance of these signaling pathways for physiological adrenergic functions in β-cells is largely unknown. In the process of glucose-induced insulin secretion, opening of background current through non-selective cation channels (NSCCs) might facilitate membrane depolarization by closure of the ATP-sensitive K(+) channels...
December 27, 2016: Diabetes
https://www.readbyqxmd.com/read/28028076/inorganic-nitrate-mimics-exercise-stimulated-muscular-fiber-type-switching-and-myokine-and-gaba-release
#18
Lee D Roberts, Tom Ashmore, Ben D McNally, Steven A Murfitt, Bernadette O Fernandez, Martin Feelisch, Ross Lindsay, Mario Siervo, Elizabeth A Williams, Andrew J Murray, Julian L Griffin
Exercise is an effective intervention for prevention and treatment of type 2 diabetes. Skeletal muscle combines multiple signals contributing to the beneficial effects of exercise on cardiometabolic health. Inorganic nitrate increases exercise efficiency, tolerance and performance. The transcriptional regulator peroxisome proliferator-activated receptorγ coactivator1α (PGC1α) coordinates the exercise-stimulated skeletal muscle fiber-type switch from glycolytic fast-twitch (type IIb) to oxidative slow-twitch (type I) and intermediate (type IIa) fibers; an effect reversed in insulin resistance and diabetes...
December 27, 2016: Diabetes
https://www.readbyqxmd.com/read/28028075/an-increased-diagnostic-sensitivity-of-truncated-gad65-autoantibodies-in-type-1-diabetes-may-be-related-to-hla-dq8
#19
Axel Wester, Hanna Skärstrand, Alexander Lind, Anita Ramelius, Annelie Carlsson, Elisabeth Cedervall, Björn Jönsson, Sten A Ivarsson, Helena Elding Larsson, Karin Larsson, Bengt Lindberg, Jan Neiderud, Malin Fex, Carina Törn, Åke Lernmark
N-terminally truncated (96-585) GAD65 (tGAD65) autoantibodies may better delineate type 1 diabetes than full-length GAD65 (fGAD65) autoantibodies. We aimed to compare the diagnostic sensitivity and specificity between fGAD65 and tGAD65 autoantibodies for type 1 diabetes in relation to HLA-DQ. Sera from newly diagnosed type 1 diabetes children and adolescents (n=654) and healthy controls (n=605) were analyzed in radiobinding assays for fGAD65 (fGADA), tGAD65 (tGADA) and commercial (125)I-GAD65 (RSRGADA) autoantibodies...
December 27, 2016: Diabetes
https://www.readbyqxmd.com/read/28028074/chaperone-driven-degradation-of-a-misfolded-proinsulin-mutant-in-parallel-with-restoration-of-wild-type-insulin-secretion
#20
Corey N Cunningham, Kaiyu He, Anoop Arunagiri, Adrienne W Paton, James C Paton, Peter Arvan, Billy Tsai
In heterozygous patients with a diabetic syndrome called Mutant INS-gene-induced Diabetes of Youth (MIDY), there is decreased insulin secretion when mutant proinsulin expression prevents wild type (WT) proinsulin from exiting the endoplasmic reticulum (ER), which is essential for insulin production. Our previous results revealed that mutant Akita proinsulin is triaged by ER-associated degradation (ERAD). We now find that the ER chaperone Grp170 participates in the degradation process by shifting Akita proinsulin from high molecular weight (MW) complexes towards smaller oligomeric species that are competent to undergo ERAD...
December 27, 2016: Diabetes
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