title: Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis.
abstract: OBJECTIVE
  Glycogen accumulation occurs in beta cells of diabetic patients and has been proposed to partly mediate glucotoxicity-induced beta cell dysfunction. However, the role of glycogen metabolism in beta cell function and its contribution to diabetes pathophysiology remain poorly understood. We investigated the function of beta cell glycogen by studying glucose homeostasis in mice with (1) defective glycogen synthesis in the pancreas; and (2) excessive glycogen accumulation in beta cells.
  
  
  METHODS
  Conditional deletion of the Gys1 gene and overexpression of protein targeting to glycogen (PTG) was accomplished by Cre-lox recombination using pancreas-specific Cre lines. Glucose homeostasis was assessed by determining fasting glycaemia, insulinaemia and glucose tolerance. Beta cell mass was determined by morphometry. Glycogen was detected histologically by periodic acid-Schiff's reagent staining. Isolated islets were used for the determination of glycogen and insulin content, insulin secretion, immunoblots and gene expression assays.
  
  
  RESULTS
  Gys1 knockout (Gys1 (KO)) mice did not exhibit differences in glucose tolerance or basal glycaemia and insulinaemia relative to controls. Insulin secretion and gene expression in isolated islets was also indistinguishable between Gys1 (KO) and controls. Conversely, despite effective glycogen overaccumulation in islets, mice with PTG overexpression (PTG(OE)) presented similar glucose tolerance to controls. However, under fasting conditions they exhibited lower glycaemia and higher insulinaemia. Importantly, neither young nor aged PTG(OE) mice showed differences in beta cell mass relative to age-matched controls. Finally, a high-fat diet did not reveal a beta cell-autonomous phenotype in either model.
  
  
  CONCLUSIONS
  Glycogen metabolism is not required for the maintenance of beta cell function. Glycogen accumulation in beta cells alone is not sufficient to trigger the dysfunction or loss of these cells, or progression to diabetes.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.|Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Mir-Coll
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Duran
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Slebe
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: García-Rocha
authors.affiliation: Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.|Department of Medicine, University of Barcelona, Barcelona, Spain.|Department of Endocrinology and Nutrition, Hospital Clinic of Barcelona, Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
authors.affiliation: Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain. rgasa@clinic.ub.es.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain, . rgasa@clinic.ub.es.
authors.forename: Rosa
authors.initials: R
authors.lastname: Gasa
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain. guinovart@irbbarcelona.org.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain, . guinovart@irbbarcelona.org.|Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain. guinovart@irbbarcelona.org.
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Guinovart
mesh_terms: D000818:Animals; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism* / Q000502:physiology; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D007328:Insulin; D006003:Glycogen; D006006:Glycogen Synthase; D005947:Glucose
keywords: Beta cell; Diabetes; Glucotoxicity; Glycogen; Glycogen synthase; Insulin secretion; Pancreatic islets
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