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The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes Shimoda M; Kanda Y; Hamamoto S; Tawaramoto K; Hashiramoto M; Matsuki M; Kaku KDiabetologia 2011[May]; 54 (5): 1098-108AIMS/HYPOTHESIS: We investigated the molecular mechanism by which the human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells in diabetic db/db mice. METHODS: Male db/db and m/m mice aged 10 weeks received liraglutide or vehicle for 2 days or 2 weeks. In addition to morphological and biochemical analysis of pancreatic islets, gene expression profiles in the islet core area were investigated by laser capture microdissection and real-time RT-PCR. RESULTS: Liraglutide treatment for 2 weeks improved metabolic variables and insulin sensitivity in db/db mice. Liraglutide also increased glucose-stimulated insulin secretion (GSIS) and islet insulin content in both mouse strains and reduced triacylglycerol content in db/db mice. Expression of genes involved in cell differentiation and proliferation in both mouse strains was regulated by liraglutide, which, in db/db mice, downregulated genes involved in pro-apoptosis, endoplasmic reticulum (ER) stress and lipid synthesis, and upregulated genes related to anti-apoptosis and anti-oxidative stress. In the 2 day experiment, liraglutide slightly improved metabolic variables in db/db mice, but GSIS, insulin and triacylglycerol content were not affected. In db/db mice, liraglutide increased gene expression associated with cell differentiation, proliferation and anti-apoptosis, and suppressed gene expression involved in pro-apoptosis; it had no effect on genes related to oxidative stress or ER stress. Morphometric results for cell proliferation, cell apoptosis and oxidative stress in db/db mice islets were consistent with the results of the gene expression analysis. CONCLUSIONS/INTERPRETATION: Liraglutide increases beta cell mass not only by directly regulating cell kinetics, but also by suppressing oxidative and ER stress, secondary to amelioration of glucolipotoxicity.|Animals[MESH]|Diabetes Mellitus/*drug therapy/metabolism[MESH]|Eating/drug effects[MESH]|Endoplasmic Reticulum/*drug effects[MESH]|Glucagon-Like Peptide 1/*analogs & derivatives/therapeutic use[MESH]|Humans[MESH]|Immunohistochemistry[MESH]|Insulin-Secreting Cells/*drug effects[MESH]|Islets of Langerhans/cytology/*drug effects/*metabolism[MESH]|Liraglutide[MESH]|Male[MESH]|Mice[MESH]|Microdissection[MESH]|Oxidative Stress/*drug effects[MESH]|Polymerase Chain Reaction[MESH]|Weight Gain/drug effects[MESH] |
