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Susan B Gurley, Sujoy Ghosh, Stacy A Johnson, Kengo Azushima, Rashidah Binte Sakban, Simi E George, Maeda Momoe, Timothy W Meyer, Thomas M Coffman
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD) worldwide, but its molecular pathogenesis is not well-defined and there are no specific treatments. In humans, there is a strong genetic component determining susceptibility to DN. However, specific genes controlling DN susceptibility in humans have not been identified. Here we describe a mouse model, combining type 1 diabetes with activation of the renin-angiotensin system (RAS), which develops robust kidney disease with features resembling human DN: heavy albuminuria, hypertension and glomerulosclerosis...
July 31, 2018: Diabetes
Bo-Yoon Park, Jae-Han Jeon, Younghoon Go, Hye Jin Ham, Jeong-Eun Kim, Eun Kyung Yoo, Woong Hee Kwon, Nam-Ho Jeoung, Yong Hyun Jeon, Seung-Hoi Koo, Byung-Gyu Kim, Ling He, Keun-Gyu Park, Robert A Harris, In-Kyu Lee
In fasting or diabetes, gluconeogenic genes are transcriptionally activated by glucagon stimulation of the cAMP-protein kinase A (PKA)-cAMP response element binding (CREB) signaling pathway. Previous work showed pyruvate dehydrogenase kinase (PDK) inhibition in skeletal muscle increases pyruvate oxidation which limits the availability of gluconeogenic substrates in the liver. However, in this study up regulation of hepatic PDK4 was found to promote glucagon-mediated expression of gluconeogenic genes whereas knockdown or inhibition of hepatic PDK4 caused the opposite effect on gluconeogenic gene expression and decreased hepatic glucose production...
July 31, 2018: Diabetes
Laura C Page, Amalia Gastaldelli, Sarah M Gray, David A D'Alessio, Jenny Tong
Emerging evidence supports the importance of ghrelin to defend against starvation-induced hypoglycemia. This effect may be mediated by inhibition of glucose-stimulated insulin secretion as well as reduced insulin sensitivity. However, administration of ghrelin during meal consumption also stimulates the release of glucagon-like peptide-1 (GLP-1), an incretin important in nutrient disposition. The objective of this study was to evaluate the interaction between ghrelin and GLP-1 on parameters of glucose tolerance following a mixed nutrient meal...
July 31, 2018: Diabetes
Seyed Mojtaba Ghiasi, Nicolai Krogh, Björn Tyrberg, Thomas Mandrup-Poulsen
Stress-related changes in β-cell mRNA levels result from a balance between gene transcription and mRNA decay. The regulation of RNA decay pathways has not been investigated in pancreatic β-cells. We found that no-go and nonsense-mediated RNA decay pathway components (RDPC) and exoribonuclease complexes were expressed in INS-1 cells and human islets. Pelo, Dcp2, Dis3L2, Upf2 and Smg1/5/6/7 were up-regulated by inflammatory cytokines in INS-1 cells under conditions where central β-cell mRNAs were down-regulated...
July 31, 2018: Diabetes
Sara Tezza, Moufida Ben Nasr, Francesca D'Addio, Andrea Vergani, Vera Usuelli, Simonetta Falzoni, Roberto Bassi, Sergio Dellepiane, Carmen Fotino, Chiara Rossi, Anna Maestroni, Anna Solini, Domenico Corradi, Elisa Giani, Chiara Mameli, Federico Bertuzzi, Marcus Guy Pezzolesi, Clive H Wasserfall, Mark A Atkinson, Ernst-Martin Füchtbauer, Camillo Ricordi, Franco Folli, Francesco Di Virgilio, Antonello Pileggi, Sirano Dhe-Paganon, Gian Vincenzo Zuccotti, Paolo Fiorina
Extracellular ATP (eATP) activates T cells by engaging the P2X7R receptor. We identified two loss-of-function P2X7R mutations that are protective against type 1 diabetes (T1D) and thus hypothesized that eATP/P2X7R signaling may represent an early step in T1D onset. Specifically, we observed that in newly diagnosed T1D patients, P2X7R is upregulated on CD8+ effector T cells in comparison to healthy controls. eATP is released at high levels by human/murine islets in vitro in high-glucose/inflammatory conditions, thus upregulating P2X7R on CD8+ T cells in vitro P2X7R blockade with oxidized ATP (oATP) reduces the CD8+ T cell-mediated autoimmune response in vitro and delays diabetes onset in NOD mice...
July 31, 2018: Diabetes
Maarten Brom, Lieke Joosten, Cathelijne Frielink, Hanneke Peeters, Desirée Bos, Monica van Zanten, Otto Boerman, Martin Gotthardt
The changes in beta cell mass (BCM) durning the development and progression of diabetes could potentially be measured by radionuclide imaging using radiolabeled exendin. In this study we investigated the potential of 111 In-exendin in a rat model that closely mimics the development of type 1 diabetes in humans: BioBreeding Diabetes Prone (BBDP) rats. BBDP rats of 4-18 weeks of age were injected intravenously with 111 In-exendin and SPECT images were acquired. The accumulation of the radiotracer was measured as well as the beta cell mass and grade of insulitis by histology...
July 25, 2018: Diabetes
Jiajia Zhang, Yixiang Li, Huan Li, Biao Zhu, Li Wang, Bei Guo, Lin Xiang, Jing Dong, Min Liu, Guangda Xiang
Growth differentiation factor 11 (GDF11) has been shown to promote stem cell activity and rejuvenate the function of multiple organs in old mice, but little is known about the functions of GDF11 in the diabetic rat model of hindlimb ischemia. Here, we found that systematic replenishment of GDF11 rescued angiogenic function of endothelial progenitor cells (EPCs), and subsequently improved vascularization and increased blood flow in diabetic rats with hindlimb ischemia. Conversely, anti-GDF11 monoclonal antibody treatment caused impairment of vascularization, and thus decreased blood flow...
July 19, 2018: Diabetes
Eun-Hee Koh, Natasha Chernis, Pradip K Saha, Liuling Xiao, David A Bader, Bokai Zhu, Kimal Rajapakshe, Mark P Hamilton, Xia Liu, Dimuthu Perera, Xi Chen, Brian York, Michael Trauner, Cristian Coarfa, Mandeep Bajaj, David D Moore, Tuo Deng, Sean E McGuire, Sean M Hartig
Chronic inflammation accompanies obesity and limits subcutaneous white adipose tissue (WAT) expandability, accelerating the development of insulin resistance and type 2 diabetes mellitus (T2DM). MicroRNAs influence expression of many metabolic genes in fat cells, but physiological roles in WAT remain poorly characterized. Here, we report expression of the microRNA miR-30a in subcutaneous WAT corresponds with insulin sensitivity in obese mice and humans. To examine the hypothesis that restoration of miR-30a expression in WAT improves insulin sensitivity, we injected adenovirus (Adv) expressing miR-30a into the subcutaneous fat pad of diabetic mice...
July 12, 2018: Diabetes
Melis Karaca, Juliette Martin-Levilain, Mariagrazia Grimaldi, Lingzi Li, Eva Dizin, Yalin Emre, Pierre Maechler
Ammonia detoxification and gluconeogenesis are major hepatic functions mutually connected through amino acid metabolism. The liver is rich in glutamate dehydrogenase (GDH) that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate and ammonia, thus bridging amino acid to glucose pathways. Here we generated inducible liver-specific GDH knockout mice (Hep Glud1 -/- ) in order to explore the role of hepatic GDH on metabolic homeostasis. Investigation of nitrogen metabolism revealed altered ammonia homeostasis in Hep Glud1 -/- mice characterized by increased circulating ammonia associated with reduced detoxification process into urea...
July 12, 2018: Diabetes
Ian M Williams, P Mason McClatchey, Deanna P Bracy, Francisco A Valenzuela, David H Wasserman
Before insulin can stimulate muscle glucose uptake, it must be delivered to skeletal muscle (SkM) through the microvasculature. Insulin delivery is determined by SkM perfusion and the rate of insulin movement across the capillary endothelium. The endothelium, therefore, plays a central role in regulating insulin access to SkM. Nitric oxide (NO) is a key regulator of endothelial function. NO stimulates arterial vasodilation which increases SkM perfusion and the capillary surface area for insulin exchange. The effects of NO on trans-endothelial insulin efflux (TIE), however, are unknown...
July 12, 2018: Diabetes
Rajakrishnan Veluthakal, Oleg G Chepurny, Colin A Leech, Frank Schwede, George G Holz, Debbie C Thurmond
Glucose metabolism stimulates Cdc42-Pak1 activity and initiates F-actin cytoskeleton remodeling in pancreatic β-cells so that cytoplasmic secretory granules can translocate to the plasma membrane where insulin exocytosis occurs. Since glucose metabolism also generates cAMP in β-cells, the crosstalk of cAMP signaling with Cdc42-Pak1 activation might be of fundamental importance to glucose-stimulated insulin secretion (GSIS). Previously, the cAMP-regulated guanine nucleotide exchange factor Epac2 was established to mediate a potentiation of GSIS by cAMP-elevating agents...
July 9, 2018: Diabetes
Linkang Zhou, Miao Yu, Muhammad Arshad, Wenmin Wang, Ye Lu, Jingyi Gong, Yangnan Gu, Peng Li, Li Xu
Metabolic homeostasis is maintained by an interplay among tissues, organs, intracellular organelles, and molecules. Cidea and Cidec are lipid droplet (LD)-associated proteins that promote lipid storage in brown and white adipose tissue (BAT and WAT, respectively). Using ob/ob/Cidea -/- , ob/ob/Cidec -/- , and ob/ob/Cidea -/- /Cidec -/- mouse models and CIDE -deficient cells, we studied metabolic regulation during severe obesity to identify ways to maintain metabolic homeostasis and promote antiobesity effects...
July 9, 2018: Diabetes
Alison S Baskin, Joyce D Linderman, Robert J Brychta, Suzanne McGehee, Esti Anflick-Chames, Cheryl Cero, James W Johnson, Alana E O'Mara, Laura A Fletcher, Brooks P Leitner, Courtney J Duckworth, Shan Huang, Hongyi Cai, H Martin Garraffo, Corina M Millo, William Dieckmann, Vladimir Tolstikov, Emily Y Chen, Fei Gao, Niven R Narain, Michael A Kiebish, Peter J Walter, Peter Herscovitch, Kong Y Chen, Aaron M Cypess
β3-adrenergic receptor (AR) agonists are approved to treat only overactive bladder. However, rodent studies suggest that these drugs could have other beneficial effects on human metabolism. We performed tissue receptor profiling and showed that the human β3-AR mRNA is also highly expressed in gallbladder and brown adipose tissue (BAT). We next studied the clinical implications of this distribution in twelve healthy men given one-time randomized doses of placebo; the approved dose of 50 mg; and 200 mg of the β3-AR agonist mirabegron...
July 6, 2018: Diabetes
Paula M Miotto, Paul J LeBlanc, Graham P Holloway
While molecular approaches altering mitochondrial content have implied a direct relationship between mitochondrial bioenergetics and insulin sensitivity, paradoxically, consumption of a high fat (HF) diet increases mitochondrial content while inducing insulin-resistance. We hypothesized that despite the induction of mitochondrial biogenesis, consumption of a HF diet would impair mitochondrial ADP sensitivity in skeletal muscle of mice, and therefore manifest in mitochondrial dysfunction in the presence of ADP concentrations indicative of skeletal muscle biology...
July 6, 2018: Diabetes
Paola Cassis, Domenico Cerullo, Cristina Zanchi, Daniela Corna, Vincenzo Lionetti, Fabrizio Giordano, Rubina Novelli, Sara Conti, Valentina Casieri, Marco Matteucci, Monica Locatelli, Giulia Taraboletti, Sebastian Villa, Sara Gastoldi, Giuseppe Remuzzi, Ariela Benigni, Carlamaria Zoja
In patients with diabetes, impaired activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), the plasma metalloprotease that cleaves highly thrombogenic VWF multimers is a major risk factor of cardiovascular events. Here, using Adamts13 -/- mice made diabetic by streptozotocin, we investigated the impact of the lack of ADAMTS13 on the development of diabetes-associated end-organ complications. Adamts13 -/- mice experienced shortened lifespan compared with their wild-type diabetic littermates...
July 5, 2018: Diabetes
Rocky L Baker, Braxton L Jamison, Timothy A Wiles, Robin S Lindsay, Gene Barbour, Brenda Bradley, Thomas Delong, Rachel S Friedman, Maki Nakayama, Kathryn Haskins
We recently established that hybrid insulin peptides (HIPs), formed in islet beta-cells by fusion of insulin C-peptide fragments to peptides of Chromogranin A or Islet Amyloid Polypeptide, are ligands for diabetogenic CD4 T cell clones. The goal of this study was to investigate whether HIP-reactive T cells were indicative of ongoing autoimmunity. MHC class II tetramers were used to investigate the presence, phenotype and function of HIP-reactive and insulin-reactive T cells in non-obese diabetic (NOD) mice...
July 5, 2018: Diabetes
Javier A Carrero, Nicholas D Benshoff, Kimberly Nalley, Emil R Unanue
The role of interferons, either pathogenic or protective, during autoimmune diabetes remains controversial. Herein, we examine the progression of diabetes in non-obese diabetic (NOD) mice lacking the type I (IFNAR) or type II (IFNGR) interferon receptors and, for the first time, in mice deficient in both receptors (DKO). All mice were bred, maintained, and monitored in a single specific pathogen-free facility with high female and low male diabetes incidence. Our expectation was that removal of interferon signaling would reduce autoimmune destruction...
July 3, 2018: Diabetes
Vasumathi Kameswaran, Maria Golson, Mireia Ramos-Rodríguez, Kristy Ou, Yue J Wang, Jia Zhang, Lorenzo Pasquali, Klaus H Kaestner
Type 2 diabetes mellitus (T2DM) is characterized by the inability of the insulin-producing β-cells to overcome insulin resistance. We previously identified an imprinted region on chromosome 14, the DLK1 - MEG3 locus, as being down-regulated in human T2D islets. Here, using targeted epigenetic modifiers, we prove that increased methylation at the promoter of Meg3 in mouse βTC6 β-cells results in decreased transcription of the maternal transcripts associated with this locus. As a result, the sensitivity of β-cells to cytokine-mediated oxidative stress was increased...
July 3, 2018: Diabetes
Sandrine Luce, Sophie Guinoiseau, Alexis Gadault, Franck Letourneur, Bertrand Blondeau, Patrick Nitschke, Eric Pasmant, Michel Vidaud, François Lemonnier, Christian Boitard
Key requirements in type 1 diabetes are in setting up new assays as diagnostic biomarkers that will apply to prediabetes, likely T-lymphocyte assays, and in designing antigen-specific therapies to prevent its development. New preclinical models of T1D will be required to help advancing both aims. By crossing mouse strains that lack either murine major histocompatibility complex class-I, class-II genes and insulin genes, we developed YES mice that instead expresses human HLA-A*02:01, HLA-DQ8 and insulin genes as transgenes...
July 2, 2018: Diabetes
Zhilian Li, Yan Li, Jessica M Overstreet, Sungjin Chung, Aolei Niu, Xiaofeng Fan, Suwan Wang, Yinqiu Wang, Ming-Zhi Zhang, Raymond C Harris
Previous studies by us and others have indicated that renal epidermal growth factor receptors (EGFR) are activated in models of diabetic nephropathy (DN) and EGFR activity inhibition protects against progressive DN in type I diabetes. We examined whether inhibition of EGFR activation would affect the development of DN in a model of accelerated type II diabetes, BKS db/db with eNOS knockout (eNOS-/- db/db ). eNOS-/- db/db mice received vehicle or erlotinib, an inhibitor of EGFR tyrosine kinase activity beginning at 8 weeks of age and were sacrificed at 20 weeks of age...
June 29, 2018: Diabetes
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