Joan Mir-Coll1,2, Jordi Duran1,3, Felipe Slebe1,3, Mar García-Rocha1, Ramon Gomis2,3,4,5, Rosa Gasa6,7, Joan J Guinovart8,9,10. 1. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain. 2. Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain. 3. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain. 4. Department of Medicine, University of Barcelona, Barcelona, Spain. 5. Department of Endocrinology and Nutrition, Hospital Clinic of Barcelona, Barcelona, Spain. 6. Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Rosselló 149-153, 08036, Barcelona, Spain. rgasa@clinic.ub.es. 7. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain, . rgasa@clinic.ub.es. 8. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain. guinovart@irbbarcelona.org. 9. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain, . guinovart@irbbarcelona.org. 10. Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain. guinovart@irbbarcelona.org.
Abstract
AIMS/HYPOTHESIS: 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/ INTERPRETATION: 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.
AIMS/HYPOTHESIS: Glycogen accumulation occurs in beta cells of diabeticpatients 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/ INTERPRETATION: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: M García-Rocha; A Roca; N De La Iglesia; O Baba; J M Fernández-Novell; J C Ferrer; J J Guinovart Journal: Biochem J Date: 2001-07-01 Impact factor: 3.857
Authors: Raimond B G Ravelli; Ruby D Kalicharan; M Cristina Avramut; Klaas A Sjollema; Joachim W Pronk; Freark Dijk; Abraham J Koster; Jeroen T J Visser; Frank G A Faas; Ben N G Giepmans Journal: Sci Rep Date: 2013 Impact factor: 4.379
Authors: Lilla Nagy; Judit Márton; András Vida; Gréta Kis; Éva Bokor; Sándor Kun; Mónika Gönczi; Tibor Docsa; Attila Tóth; Miklós Antal; Pál Gergely; Balázs Csóka; Pal Pacher; László Somsák; Péter Bai Journal: Br J Pharmacol Date: 2017-06-18 Impact factor: 8.739