56 results found
Da Silva Xavier G, Mondragon A, Mourougavelou V, et al., Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses in mice, Diabetologia, ISSN: 0012-186X
Background and Aims.Transcription Factor 7-Like 2 (TCF7L2) is a high mobility group (HMG) box-containing transcription factor and downstream effector of the Wntsignalling pathway. Single nucleotide polymorphisms in the TCF7L2gene have previously been associated with an increased risk of type 2 diabetes in genome-wide association studies. Loss of Tcf7l2function is associated with defective islet beta cell function and survival. Here, we explore the roles of TCF7L2 in the control of the counter-regulatory response to hypoglycaemia by generating mice deleted selectively for the Tcf7l2gene in pancreatic alpha cells.Methods.Alpha cell-selective deletion of Tcf7l2was achieved by crossing animals with floxed Tcf7l2alleles to mice bearing a Crerecombinase transgene driven by the preproglucagon promoter (PPGCre; Tcf7l2AKO). Glucose homeostasis and hormone secretion in vivoand in vitro, and islet cell mass, were measured using standard techniques.Results. Whilst glucose tolerance was unaffected in Tcf7l2AKO mice, glucose infusion rates were increased, and glucagon secretion tended to be lower, during hypoglycemic clamps. Tcf7l2AKO displayed lowered fasted plasma glucose concentration. Glucagon release at low glucose was impaired (p<0.05) in islets isolated from Tcf7l2AKO mice. Alpha cell mass was lowered in Tcf7l2AKO mice.Conclusions.The present findings demonstrate an alpha cell autonomous role for Tcf7l2 in the control of pancreatic glucagon secretion and the maintenance of alpha cell mass and function.
Mondragon A, Hodson D, Semplici F, et al., PAS-domain containing protein kinase (PASK) is required for the regulation of food intake and glucose homeostasis, Annual Professional Conference of the American Diabetes Association, Publisher: American Diabetes Association, ISSN: 0012-1797
Fletcher RS, Ratajczak J, Doig CL, et al., 2017, Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells., Mol Metab, Vol: 6, Pages: 819-832
OBJECTIVE: Augmenting nicotinamide adenine dinucleotide (NAD(+)) availability may protect skeletal muscle from age-related metabolic decline. Dietary supplementation of NAD(+) precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) appear efficacious in elevating muscle NAD(+). Here we sought to identify the pathways skeletal muscle cells utilize to synthesize NAD(+) from NMN and NR and provide insight into mechanisms of muscle metabolic homeostasis. METHODS: We exploited expression profiling of muscle NAD(+) biosynthetic pathways, single and double nicotinamide riboside kinase 1/2 (NRK1/2) loss-of-function mice, and pharmacological inhibition of muscle NAD(+) recycling to evaluate NMN and NR utilization. RESULTS: Skeletal muscle cells primarily rely on nicotinamide phosphoribosyltransferase (NAMPT), NRK1, and NRK2 for salvage biosynthesis of NAD(+). NAMPT inhibition depletes muscle NAD(+) availability and can be rescued by NR and NMN as the preferred precursors for elevating muscle cell NAD(+) in a pathway that depends on NRK1 and NRK2. Nrk2 knockout mice develop normally and show subtle alterations to their NAD+ metabolome and expression of related genes. NRK1, NRK2, and double KO myotubes revealed redundancy in the NRK dependent metabolism of NR to NAD(+). Significantly, these models revealed that NMN supplementation is also dependent upon NRK activity to enhance NAD(+) availability. CONCLUSIONS: These results identify skeletal muscle cells as requiring NAMPT to maintain NAD(+) availability and reveal that NRK1 and 2 display overlapping function in salvage of exogenous NR and NMN to augment intracellular NAD(+) availability.
Nguyen-Tu M-S, Leclerc I, da Silva-Xavier G, et al., 2016, Role of the type 2 diabetes GWAS gene TCF7L2 in LKB1-mediated regulation of insulin secretion in the murine beta cell, 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S169-S169, ISSN: 0012-186X
Semplici F, Mondragon A, Macintyre B, et al., 2016, Cell type-specific deletion in mice reveals roles for PAS kinase in insulin and glucagon production, DIABETOLOGIA, Vol: 59, Pages: 1938-1947, ISSN: 0012-186X
Mitchell RK, Mondragon A, Chen L, et al., 2015, Selective disruption of Tcf7l2 in the pancreatic beta cell impairs secretory function and lowers beta cell mass, HUMAN MOLECULAR GENETICS, Vol: 24, Pages: 1390-1399, ISSN: 0964-6906
Sun G, Da Silva Xavier G, Gorman T, et al., 2015, LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia, Molecular Metabolism, Vol: 4, Pages: 277-286, ISSN: 2212-8778
Aims/Hypothesis: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production invivo is unclear. Methods: Here, we ablated LKB1 (αLKB1KO), or the catalytic alpha subunits of AMPK (αAMPKdKO, -α1KO, -α2KO), selectively in ~45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (. PPG) Cre. Results: Blood glucose levels in male αLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p<0.01). αLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p<0.001) in αAMPKα1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p=0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in αLKB1KO, αAMPKdKO, and -α1KO, but not -α2KO islets. Conclusions/Interpretation: An LKB1-dependent signalling cassette, involving but not restricted to AMPKα1, is required in pancreatic alpha cells for the control of glucagon release by glucose.
Zatyka M, Xavier GDS, Bellomo EA, et al., 2015, Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram syndrome 1 protein, which negatively regulates its expression, HUMAN MOLECULAR GENETICS, Vol: 24, Pages: 814-827, ISSN: 0964-6906
Locke JM, Xavier GDS, Dawe HR, et al., 2014, Increased expression of miR-187 in human islets from individuals with type 2 diabetes is associated with reduced glucose-stimulated insulin secretion, DIABETOLOGIA, Vol: 57, Pages: 122-128, ISSN: 0012-186X
Mondragon A, Davidsson D, Kyriakoudi S, et al., 2014, Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia, PLOS ONE, Vol: 9, ISSN: 1932-6203
Xavier GDS, Bellomo EA, McGinty JA, et al., 2013, Animal Models of GWAS-Identified Type 2 Diabetes Genes, JOURNAL OF DIABETES RESEARCH, ISSN: 2314-6745
Xavier GDS, Mondragon A, Sun G, et al., 2012, Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice, DIABETOLOGIA, Vol: 55, Pages: 2667-2676, ISSN: 0012-186X
da Silva Xavier G, 2012, Protein kinases and pancreatic islet function, Protein kinases, Editors: da Silva Xavier, Publisher: Intech, ISBN: 978-953-51-0640-1
da Silva Xavier G, Others M, 2012, Protein Kinases, Online, Publisher: InTech, ISBN: 978-953-51-0640-1
Proteins are the work horses of the cell. As regulators of protein function, protein kinases are involved in the control of cellular functions via intricate signalling pathways, allowing for fine tuning of physiological functions. This book is a collaborative effort, with contribution from experts in their respective fields, reflecting the spirit of collaboration - across disciplines and borders - that exists in modern science. Here, we review the existing literature and, on occasions, provide novel data on the function of protein kinases in various systems. We also discuss the implications of these findings in the context of disease, treatment, and drug development.
Dominguez V, Raimondi C, Somanath S, et al., 2011, Class II Phosphoinositide 3-Kinase Regulates Exocytosis of Insulin Granules in Pancreatic beta Cells, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 4216-4225, ISSN: 0021-9258
Locke JM, Da Silva Xavier G, Rutter GA, et al., 2011, Erratum to: An alternative polyadenylation signal in TCF7L2 generates isoforms that inhibit T cell factor/lymphoid-enhancer factor (TCF/LEF)-dependent target genes., Diabetologia, Vol: 54
Locke JM, Da Silva Xavier G, Rutter GA, et al., 2011, Erratum: An alternative polyadenylation signal in TCF7L2 generates isoforms that inhibit T cell factor/lymphoid-enhancer factor (TCF/LEF)-dependent target genes (Diabetologia DOI: 10.1007/s00125-011-2290-6), Diabetologia, Vol: 54, ISSN: 0012-186X
Locke JM, Xavier GDS, Rutter GA, et al., 2011, An alternative polyadenylation signal in TCF7L2 generates isoforms that inhibit T cell factor/lymphoid-enhancer factor (TCF/LEF)-dependent target genes, DIABETOLOGIA, Vol: 54, Pages: 3078-3082, ISSN: 0012-186X
Meur G, Qian Q, Xavier GDS, et al., 2011, Nucleo-cytosolic Shuttling of FoxO1 Directly Regulates Mouse Ins2 but Not Ins1 Gene Expression in Pancreatic Beta Cells (MIN6), JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 13647-13656, ISSN: 0021-9258
Pullen TJ, Xavier GDS, Kelsey G, et al., 2011, miR-29a and miR-29b Contribute to Pancreatic beta-Cell-Specific Silencing of Monocarboxylate Transporter 1 (Mct1), MOLECULAR AND CELLULAR BIOLOGY, Vol: 31, Pages: 3182-3194, ISSN: 0270-7306
Xavier GDS, Farhan H, Kim H, et al., 2011, Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion, DIABETOLOGIA, Vol: 54, Pages: 819-827, ISSN: 0012-186X
An R, Xavier GDS, Semplici F, et al., 2010, Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is HIPK2-dependent and affects PDX1 subnuclear localization, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 399, Pages: 155-161, ISSN: 0006-291X
Noordeen NA, Khera TK, Sun G, et al., 2010, Carbohydrate-Responsive Element-Binding Protein (ChREBP) Is a Negative Regulator of ARNT/HIF-1 beta Gene Expression in Pancreatic Islet beta-Cells, DIABETES, Vol: 59, Pages: 153-160, ISSN: 0012-1797
Rutter GA, Pullen TJ, 2010, miR-29a, miR-29b and miR-124 contribute to pancreatic beta cell specific silencing of monocarboxylate transporter 1 (Mct1/Slc16a1), 46th Annual Meeting of the European-Association-for-the- Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S35-S36, ISSN: 0012-186X
Sun G, Tarasov AI, McGinty J, et al., 2010, Ablation of AMP-activated protein kinase alpha 1 and alpha 2 from mouse pancreatic beta cells and RIP2.Cre neurons suppresses insulin release in vivo, DIABETOLOGIA, Vol: 53, Pages: 924-936, ISSN: 0012-186X
Voronina SG, Barrow SL, Simpson AWM, et al., 2010, Dynamic Changes in Cytosolic and Mitochondrial ATP Levels in Pancreatic Acinar Cells, GASTROENTEROLOGY, Vol: 138, Pages: 1976-U111, ISSN: 0016-5085
Xavier GDS, Sun G, Qian Q, et al., 2010, ChREBP regulates Pdx-1 and other glucose-sensitive genes in pancreatic beta-cells, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 402, Pages: 252-257, ISSN: 0006-291X
Nicolson TJ, Bellomo EA, Wijesekara N, et al., 2009, Insulin Storage and Glucose Homeostasis in Mice Null for the Granule Zinc Transporter ZnT8 and Studies of the Type 2 Diabetes-Associated Variants, DIABETES, Vol: 58, Pages: 2070-2083, ISSN: 0012-1797
Xavier GDS, Loder MK, McDonald A, et al., 2009, TCF7L2 Regulates Late Events in Insulin Secretion From Pancreatic Islet beta-Cells, DIABETES, Vol: 58, Pages: 894-905, ISSN: 0012-1797
Barrow SL, Voronina SG, Xavier GDS, et al., 2008, ATP depletion inhibits Ca2+ release, influx and extrusion in pancreatic acinar cells but not pathological Ca2+ responses induced by bile, PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, Vol: 455, Pages: 1025-1039, ISSN: 0031-6768
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