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Journal articleBroichhagen J, Johnston NR, von Ohlen Y, et al., 2016,
Allosteric optical control of a class B G-protein-coupled receptor
, Angewandte Chemie - International Edition, Vol: 55, Pages: 5865-5868, ISSN: 1433-7851 -
Journal articleSayers SR, Reimann F, Gribble FM, et al., 2016,
Proglucagon Promoter Cre-Mediated AMPK Deletion in Mice Increases Circulating GLP-1 Levels and Oral Glucose Tolerance
, PLOS One, Vol: 11, ISSN: 1932-6203BackgroundEnteroendocrine L-cells synthesise and release the gut hormone glucagon-like peptide-1(GLP-1) in response to food transit. Deletion of the tumour suppressor kinase LKB1 fromproglucagon-expressing cells leads to the generation of intestinal polyps but no change incirculating GLP-1 levels. Here, we explore the role of the downstream kinase AMPactivatedprotein kinase (AMPK) in these cells.MethodLoss of AMPK from proglucagon-expressing cells was achieved using a preproglucagonpromoter-driven Cre (iGluCre) to catalyse recombination of floxed alleles of AMPKα1 andα2. Oral and intraperitoneal glucose tolerance were measured using standard protocols.L-cell mass was measured by immunocytochemistry. Hormone and peptide levels weremeasured by electrochemical-based luminescence detection or radioimmunoassay.ResultsRecombination with iGluCre led to efficient deletion of AMPK from intestinal L- and pancreaticalpha-cells. In contrast to mice rendered null for LKB1 using the same strategy, micedeleted for AMPK displayed an increase (WT: 0.05 ± 0.01, KO: 0.09±0.02%, p<0.01) in Lcellmass and elevated plasma fasting (WT: 5.62 ± 0.800 pg/ml, KO: 14.5 ± 1.870, p<0.01)and fed (WT: 15.7 ± 1.48pg/ml, KO: 22.0 ± 6.62, p<0.01) GLP-1 levels. Oral, but not intraperitoneal,glucose tolerance was significantly improved by AMPK deletion, whilst insulinand glucagon levels were unchanged despite an increase in alpha to beta cell ratio (WT:0.23 ± 0.02, KO: 0.33 ± 0.03, p<0.01).ConclusionAMPK restricts L-cell growth and GLP-1 secretion to suppress glucose tolerance. Targetedinhibition of AMPK in L-cells may thus provide a new therapeutic strategy in some forms oftype 2 diabetes.
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Journal articleHaythorne EA, Cane MC, Semplici F, et al., 2016,
Mitochondrial Ca2+ uniporter-b (MCUb) overexpression decreases glucose-stimulated mitochondrial calcium influx but increases basal cytosolic calcium and ATP content in clonal INS-1 (832/13) beta cells
, DIABETIC MEDICINE, Vol: 33, Pages: 41-41, ISSN: 0742-3071 -
Journal articleMarzban L, Tomas A, Becker TC, et al., 2016,
Erratum. Small Interfering RNA-Mediated Suppression of Proislet Amyloid Polypeptide Expression Inhibits Islet Amyloid Formation and Enhances Survival of Human Islets in Culture. Diabetes 2008;57:3045-3055.
, Diabetes, Vol: 65, Pages: 818-818, ISSN: 0012-1797 -
Journal articleBroichhagen J, von Ohlen Y, Johnston NR, et al., 2016,
Optical control of the glucagon-like peptide-1 receptor allosteric site
, DIABETIC MEDICINE, Vol: 33, Pages: 60-60, ISSN: 0742-3071 -
Journal articleMehta ZB, Fine N, Rutter GA, 2016,
The Type 2 diabetes genome-wide associated gene vacuolar protein sorting 13C (Vps13C) is dispensable in murine beta cells for normal insulin secretion and glucose tolerance
, DIABETIC MEDICINE, Vol: 33, Pages: 39-39, ISSN: 0742-3071 -
Journal articleRutter GA, 2016,
Disallowance of Acot7 in b-Cells is required for normal glucosetolerance and insulin secretion
, Diabetes, Vol: 65, Pages: 1268-1282, ISSN: 0012-1797Acot7, encoding acyl-CoA thioesterase-7, is one of ∼60 genes expressed ubiquitously across tissues but relatively silenced, or “disallowed”, in pancreatic β-cells. The capacity of ACOT7 to hydrolyse long-chain acyl-CoA esters suggests potential roles in β-oxidation, lipid biosynthesis, signal transduction or insulin exocytosis. Here, we explored the physiological relevance of β-cell-specific Acot7 silencing by re-expressing ACOT7 in these cells. ACOT7 overexpression in clonal MIN6 and INS1(832/13) β-cells impaired insulin secretion in response to glucose plus fatty acids. Furthermore, examined in a panel of transgenic mouse lines, we demonstrate that overexpression of mitochondrial ACOT7 selectively in the adult β-cell reduced glucose tolerance dose-dependently and impaired glucose-stimulated insulin secretion. By contrast, depolarisation-induced secretion was unaffected, arguing against a direct action on the exocytotic machinery. Acyl-CoA levels, ATP/ADP increases, membrane depolarization and Ca2+ fluxes were all markedly reduced in transgenic mouse islets, whereas glucose-induced O2-consumption was unchanged. Whilst glucose-induced increases in ATP/ADP ratio were similarly lowered after ACOT7 over-expression in INS1(832/13) cells, changes in mitochondrial membrane potential (ΔΨ) were unaffected, consistent with an action of Acot7 to increase cellular ATP consumption. Since Acot7 mRNA levels are increased in human islets in type 2 diabetes, inhibition of the enzyme might provide a novel therapeutic strategy.
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Journal articleDuca FA, Cote CD, Rasmussen BA, et al., 2016,
Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats (vol 21, pg 506, 2015)
, NATURE MEDICINE, Vol: 22, Pages: 217-217, ISSN: 1078-8956- Author Web Link
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Journal articleMarmugi A, Parnis J, Chen X, et al., 2016,
Sorcin links pancreatic β cell lipotoxicity to ER Ca2+ stores
, Diabetes, Vol: 65, Pages: 1009-1021, ISSN: 0012-1797Preserving β cell function during the development of obesity and insulin resistance would limit the worldwide epidemic of type 2 diabetes (T2DM). Endoplasmic reticulum (ER) calcium (Ca2+) depletion induced by saturated free fatty acids and cytokines causes β cell ER stress and apoptosis, but the molecular mechanisms behind these phenomena are still poorly understood. Here, we demonstrate that palmitate-induced sorcin (SRI) down-regulation, and subsequent increases in glucose-6-phosphatase catalytic subunit-2 (G6PC2) levels contribute to lipotoxicity. SRI is a calcium sensor protein involved in maintaining ER Ca2+ by inhibiting ryanodine receptor activity and playing a role in terminating Ca2+-induced Ca2+ release. G6PC2, a GWAS gene associated with fasting blood glucose, is a negative regulator of glucose-stimulated insulin secretion (GSIS). High fat feeding in mice and chronic exposure of human islets to palmitate decreases endogenous SRI expression while levels of G6PC2 mRNA increase. Sorcin null mice are glucose intolerant, with markedly impaired GSIS and increased expression of G6pc2. Under high fat diet, mice overexpressing SRI in the β cell display improved glucose tolerance, fasting blood glucose and GSIS, whereas G6PC2 levels are decreased and cytosolic and ER Ca2+ are increased in transgenic islets. SRI may thus provide a target for intervention in T2DM.
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Journal articleAkalestou E, Christakis I, Solomou A, et al., 2016,
Proglucagon-derived peptides do not significantly affect acute exocrine pancreas in rat
, Pancreas, Vol: 45, Pages: 967-973, ISSN: 1536-4828Objectives: Reports have suggested a link between treatment with glucagon-like peptide 1 (GLP-1) analogues and an increased risk of pancreatitis. Oxyntomodulin, a dual agonist of both GLP-1 and glucagon receptors, is currently being investigated as a potential anti-obesity therapy, but little is known about the pancreatic safety of this approach. The aim of this study was to investigate the acute effect of oxyntomodulin and other proglucagon-derived peptides on the rat exocrine pancreas. Methods: GLP-1, oxyntomodulin, glucagon and exendin-4 were infused into anaesthetised rats to measure plasma amylase concentration changes. Additionally, the effect of each peptide on both amylase release and proliferation in rat pancreatic acinar (AR42J) and primary isolated ductal cells was determined. Results: Plasma amylase did not increase post infusion of individual peptides, compared to vehicle and cholecystokinin (CCK); however, oxyntomodulin inhibited plasma amylase when co-administered with CCK. None of the peptides caused a significant increase in proliferation rate or amylase secretion from acinar and ductal cells. Conclusions: the investigated peptides do not have an acute effect on the exocrine pancreas with regard to proliferation and plasma amylase, when administered individually. Oxyntomodulin appears to be a potent inhibitor of amylase release, potentially making it a safer anti-obesity agent regarding pancreatitis, compared to GLP-1 agonists.
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