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Jonathan M Locke, Cécile Saint-Martin, Thomas W Laver, Kashyap A Patel, Andrew R Wood, Seth A Sharp, Sian Ellard, Christine Bellanné-Chantelot, Andrew T Hattersley, Lorna W Harries, Michael N Weedon
There is wide variation in the age at diagnosis of diabetes in individuals with Maturity-Onset Diabetes of the Young (MODY) due to a mutation in the HNF1A gene. We hypothesised that common variants at the HNF1A locus (rs1169288, I27L; rs1800574, A98V), which are associated with type 2 diabetes susceptibility, may modify age at diabetes diagnosis in HNF1A-MODY individuals. Meta-analysis of two independent cohorts, comprising 781 HNF1A-MODY individuals, found no significant associations between genotype and age at diagnosis...
June 12, 2018: Diabetes
Chujun Yuan, Jiyuan Hu, Saj Parathath, Lisa Grauer, Courtney Blachford Cassella, Svetlana Bagdasarov, Ira J Goldberg, Ravichandran Ramasamy, Edward A Fisher
Guidelines to reduce cardiovascular risk in diabetes include aggressive LDL lowering, but benefits are attenuated compared to those in patients without diabetes. Consistent with this, we have reported in mice that hyperglycemia impaired atherosclerosis regression. Aldose reductase (AR) is thought to contribute to clinical complications of diabetes by directing glucose into pathways producing inflammatory metabolites. Mice have low levels of AR, thus, raising them to human levels would be a more clinically relevant model to study changes in diabetes under atherosclerosis regression conditions...
June 11, 2018: Diabetes
Nisha Vastani, Franziska Guenther, Clive Gentry, Amazon L Austin, Aileen J King, Stuart Bevan, David A Andersson
The mechanisms responsible for painful and insensate diabetic neuropathy are not completely understood. Here, we have investigated sensory neuropathy in the Ins2 +/Akita mouse, a hereditary model of diabetes. Akita mice become diabetic soon after weaning, and we show that this is accompanied by an impaired mechanical and thermal nociception and a significant loss of intraepidermal nerve fibers. Electrophysiological investigations of skin-nerve preparations identified a reduced rate of action potential discharge in Ins2 +/Akita mechanonociceptors compared to wildtype littermates, whereas the function of low threshold A-fibers was essentially intact...
June 6, 2018: Diabetes
Lunhua Liu, Karen Etsuko Inouye, Windy Rose Allman, Adam Steven Coleman, Shafiuddin Siddiqui, Gökhan Siddik Hotamisligil, Mustafa Akkoyunlu
Transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) is a receptor for the TNF superfamily cytokines, B cell activating factor (BAFF) and A Proliferation Inducing Ligand (APRIL). Here, we demonstrate that TACI-deficient mice subjected to high fat diet (HFD) are protected from weight gain and dysregulated glucose homeostasis. Resistance to HFD-induced metabolic changes in TACI-deficient mice does not involve TACI mediated adipogenesis. Instead, accumulation of M2 macrophages (Mϕs), eosinophils and type 2 innate lymphoid cells in visceral adipose tissue (VAT) is implicated in the protection from obesity induced assaults...
June 5, 2018: Diabetes
Chao Huang, Kiera P Fisher, Sandra S Hammer, Svetlana Navitskaya, Gary J Blanchard, Julia V Busik
Diabetic Retinopathy (DR) is a micro-vascular complication of diabetes and is the leading cause of vision loss in working-age adults. Recent studies have implicated the complement system as an emerging player in development of vascular damage and progression of DR. However, the role and activation of the complement system in DR is not well understood. Exosomes, small vesicles that are secreted into the extracellular environment, have a cargo of complement proteins in plasma suggesting that they can participate in causing vascular damage associated with DR...
June 4, 2018: Diabetes
Stephanie J Loomis, Man Li, Nisa M Maruthur, Abigail S Baldridge, Kari E North, Hao Mei, Alanna Morrison, April P Carson, James S Pankow, Eric Boerwinkle, Robert Scharpf, Laura J Rasmussen-Torvik, Josef Coresh, Priya Duggal, Anna Köttgen, Elizabeth Selvin
Fructosamine and glycated albumin are potentially useful alternatives to hemoglobin A1c (HbA1c) as diabetes biomarkers. The genetic determinants of fructosamine and glycated albumin, however, are unknown. We performed genome-wide association studies of fructosamine and glycated albumin among 2,104 black and 7,647 white participants without diabetes in the Atherosclerosis Risk in Communities (ARIC) Study and replicated findings in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Among whites, rs34459162, a novel missense SNP in RCN3, was associated with fructosamine (p=5...
May 29, 2018: Diabetes
Béatrice Romier, Corinne Ivaldi, Hervé Sartelet, Andrea Heinz, Christian E H Schmelzer, Roselyne Garnotel, Alexandre Guillot, Jessica Jonquet, Eric Bertin, Jean-Louis Guéant, Jean-Marc Alberto, Jean-Pierre Bronowicki, Johanne Amoyel, Thinhinane Hocine, Laurent Duca, Pascal Maurice, Amar Bennasroune, Laurent Martiny, Laurent Debelle, Vincent Durlach, Sébastien Blaise
Affecting more than 30% of the western population, non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications including non-alcoholic steatohepatitis (NASH), cancer, hypertension and atherosclerosis. Insulin resistance and obesity are described as potential causes of NAFLD. However, we surmised that factors such as extracellular matrix remodeling of large blood vessels, skin or lungs may also participate in the progression of liver diseases. We studied the effects of elastin-derived peptides (EDPs), biomarkers of aging, on the NAFLD progression...
May 25, 2018: Diabetes
Ze-Bei Zhang, Cheng-Chao Ruan, Jing-Rong Lin, Lian Xu, Xiao-Hui Chen, Ya-Nan Du, Meng-Xia Fu, Ling-Ran Kong, Ding-Liang Zhu, Ping-Jin Gao
Obesity increases the risk of vascular diseases, including aortic aneurysm (AA). Perivascular adipose tissue (PVAT) surrounding arteries are altered during obesity. However, the underlying mechanism of adipose tissue, especially PVAT, in the pathogenesis of AA is still unclear. Here we showed that angiotensin II (AngII) infusion increases the incidence of AA in leptin-deficient obese mice ( ob/ob ) and high-fat diet (HFD) induced obese mice with adventitial inflammation. Furthermore, transcriptome analysis revealed that platelet derived growth factor-D (PDGF-D) was highly expressed in the PVAT of ob/ob mice...
May 24, 2018: Diabetes
Célia Bidu, Quentin Escoula, Sandrine Bellenger, Aymé Spor, Maxime Galan, Audrey Geissler, André Bouchot, Dominique Dardevet, Béatrice Morio-Liondor, Patrice D Cani, Laurent Lagrost, Michel Narce, Jérome Bellenger
Altering the gut microbiome may be beneficial to the host, and it recently arose as a promising strategy to manage obesity. Here, we investigated the relative contribution of ω3 polyunsaturated fatty acid (PUFA)-mediated alterations in the microbiota to metabolic parameter changes in mice. Four groups were compared: male fat-1 transgenic mice (with constitutive production of ω3 PUFAs) and male WT littermates fed either an obesogenic (high fat/high sucrose, HFHS) or a control diet. Unlike WT mice, HFHS-fed fat-1 mice were protected against obesity, glucose intolerance and hepatic steatosis...
May 23, 2018: Diabetes
Michelle R Marasco, Abass M Conteh, Christopher A Reissaus, John E Cupit V, Evan M Appleman, Raghavendra G Mirmira, Amelia K Linnemann
Production of reactive oxygen species (ROS) is a key instigator of β-cell dysfunction in diabetes. The pleiotropic cytokine IL-6 has previously been linked to β-cell autophagy but has not been studied in the context of β-cell antioxidant response. We used a combination of animal models of diabetes and analysis of cultured human islets and rodent β-cells to study how IL-6 influences antioxidant response. We show that IL-6 couples autophagy to antioxidant response to reduce β-cell and human islet ROS. β cell-specific loss of IL-6 signaling in vivo renders mice more susceptible to oxidative damage and cell death by the selective β-cell toxins streptozotocin and alloxan...
May 21, 2018: Diabetes
Jessica M Adams, Hongjuan Pei, Darleen A Sandoval, Randy J Seeley, Rui B Chang, Stephen D Liberles, David P Olson
Glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) impact appetite and body weight are still not fully understood. Here, we determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the acute and chronic effects of the GLP1RA liraglutide on food intake, visceral illness, body weight and neural network activation. We found that mice lacking GLP-1Rs in vGAT -expressing GABAergic neurons responded identically to controls in all parameters measured, whereas deletion of GLP-1Rs in vGlut2 -expressing glutamatergic neurons eliminated liraglutide-induced weight loss and visceral illness and severely attenuated its effects on feeding...
May 18, 2018: Diabetes
Yuanyang Wang, Shuai Yan, Bing Xiao, Shengkai Zuo, Qianqian Zhang, Guilin Chen, Yu Yu, Di Chen, Qian Liu, Yi Liu, Yujun Shen, Ying Yu
Gluconeogenesis is drastically increased in patients with type 2 diabetes and accounts for increased fasting plasma glucose concentrations. Circulating prostaglandin (PG) F2α is also markedly elevated in diabetes mellitus; however, whether and how PGF2α regulates hepatic glucose metabolism remain unknown. Here, we demonstrated that PGF2α receptor (F-prostanoid receptor; FP) was upregulated in livers of mice upon fasting- and diabetic stress. Hepatic deletion of the FP receptor suppressed fasting-induced hepatic gluconeogenesis, whereas FP overexpression enhanced hepatic gluconeogenesis in mice...
May 17, 2018: Diabetes
Carla J Greenbaum, Cate Speake, Jeffrey Krischer, Jane Buckner, Peter A Gottlieb, Desmond A Schatz, Kevan C Herold, Mark A Atkinson
The early to mid-1980s were an inflection point in the history of type 1 diabetes research. Two landmark events occurred: the initiation of immune-based interventions seeking to prevent type 1 diabetes and the presentation of an innovative model describing the disorder's natural history. Both formed the basis for hundreds of subsequent studies designed to achieve a dramatic therapeutic goal-a means to prevent and/or reverse type 1 diabetes. However, the need to screen large numbers of individuals and prospectively monitor them using immunologic and metabolic tests for extended periods of time suggested such efforts would require a large collaborative network...
May 16, 2018: Diabetes
Kazutaka Ueda, Eiki Takimoto, Qing Lu, Pangyen Liu, Nobuaki Fukuma, Yusuke Adachi, Ryo Suzuki, Shengpu Chou, Wendy Baur, Mark J Aronovitz, Andrew S Greenberg, Issei Komuro, Richard H Karas
Women gain weight and their diabetes risk increases as they transition through menopause; these changes can in part be reversed by hormone therapy. However, the underlying molecular mechanisms mediating these effects are unknown. A novel knock-in mouse line with the selective blockade of the membrane-initiated estrogen receptor (ER) pathway was employed, and we found that the lack of this pathway precipitated excessive weight gain and glucose intolerance independent of food intake, and that this was accompanied by impaired adaptive thermogenesis and reduced physical activity...
May 15, 2018: Diabetes
Anil Kumar, Liora S Katz, Anna M Schulz, Misung Kim, Lee B Honig, Lucy Li, Bennett Davenport, Dirk Homann, Adolfo Garcia-Ocaña, Mark A Herman, Cole M Haynes, Jerry E Chipuk, Donald K Scott
Patients with both major forms of diabetes would benefit from therapies that increase β-cell mass. Glucose is a natural mitogen that drives adaptive β-cell mass expansion by promoting β-cell proliferation. We previously demonstrated that carbohydrate response element binding protein (ChREBPα) is required for glucose-stimulated β-cell proliferation, and that overexpression of ChREBPα amplifies the proliferative effect of glucose. Here we found that ChREBPα reprogrammed anabolic metabolism to promote proliferation...
May 15, 2018: Diabetes
Cécile L Bandet, Rana Mahfouz, Julien Véret, Athanassia Sotiropoulos, Maxime Poirier, Paola Giussani, Mélanie Campana, Erwann Philippe, Agnieszka Blachnio-Zabielska, Raphaëlle Ballaire, Xavier Le Liepvre, Olivier Bourron, Dušan Berkeš, Jan Górski, Pascal Ferré, Hervé Le Stunff, Fabienne Foufelle, Eric Hajduch
One main mechanism of insulin resistance (IR), a key feature of type-2 diabetes, is the accumulation of saturated fatty acids (FA) in muscles of obese and type-2 diabetic patients. Understanding the mechanism underlying lipid-induced IR is therefore a crucial challenge. Saturated FA are metabolized into lipid-derivatives called ceramides and their accumulation plays a central role in the development of muscle IR. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi through a transporter called CERT, where they are converted into different sphingolipid species...
May 14, 2018: Diabetes
Jonathan D Douros, Alfor G Lewis, Eric P Smith, JingJing Niu, Megan Capozzi, April Wittmann, Jonathan Campbell, Jenny Tong, Constance Wagner, Parinaz Mahbod, Randy Seeley, David A D'Alessio
Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of β-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, β-cell specific Glp1r knockdown ( Glp1r β-cell-ko )...
May 14, 2018: Diabetes
Isaac Asare-Bediako, Rebecca L Paszkiewicz, Stella P Kim, Orison O Woolcott, Cathryn M Kolka, Miguel A Burch, Morvarid Kabir, Richard N Bergman
While the β-cells secrete insulin, it is the liver with its first-pass insulin extraction (FPE) that regulates the amount of insulin allowed into circulation for action on target tissues. The metabolic clearance rate of insulin, of which FPE is the dominant component, is reported to be a major determinant of insulin sensitivity (SI). We studied the intricate relationship between FPE, SI and fasting insulin. We used a direct method of measuring FPE, the paired portal/peripheral infusion protocol (PPII) where insulin is infused step-wise, either via the portal vein or a peripheral vein in healthy young dogs (n =12)...
May 11, 2018: Diabetes
Andres Cardenas, Valerie Gagné-Ouellet, Catherine Allard, Diane Brisson, Patrice Perron, Luigi Bouchard, Marie-France Hivert
Maternal hyperglycemia during pregnancy is associated with excess fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study (>850,000 CpG sites) of term placentas and prenatal maternal glycemic response 2-hour post oral glucose challenge at 24-30 weeks of gestation among 448 mother-infant pairs. Maternal 2-hour glycemia post-load was strongly associated with lower DNA methylation of 4 CpGs (FDR q<0...
May 11, 2018: Diabetes
Wei Wang, Chuan Yang, Xiao Yi Wang, Li Yan Zhou, Guo Juan Lao, Dan Liu, Chuan Wang, Meng Die Hu, Ting Ting Zeng, Li Yan, Meng Ren
Diabetic wounds are recalcitrant to healing. However, the mechanism causing this dysfunction is not fully understood. High expression of matrix metalloproteinase-9 (MMP-9) is indicative of poor wound healing. Here, we show that specificity protein-1 (Sp1), a regulator of MMP-9, binds directly to its promoter and enhances its expression. Additionally, we demonstrated that Sp1 is the direct target of two miRNAs, miR-129 and -335, which are significantly downregulated in diabetic skin tissues. In vitro experiments confirmed that miR-129 or -335 overexpression inhibits MMP-9 promoter activity and protein expression by targeting Sp1, whereas the inhibition of these miRNAs has the opposite effect...
May 10, 2018: Diabetes
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