Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia
| العنوان: | Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia |
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| المؤلفون: | Arend Heerschap, Terry G J Derks, Theo H. van Dijk, Maud Soty, Elodie Mutel, Maaike H. Oosterveer, Andreas Boss, Gilles Mithieux, Dirk-Jan Reijngoud, Brenda S. Hijmans, Henk Wolters, Albert K. Groen, Fabienne Rajas |
| المساهمون: | University Medical Center Groningen [Groningen] (UMCG), Radboud University Medical Center [Nijmegen], Nutrition, diabète et cerveau, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Di Carlo, Marie-Ange, Nutrition, diabète et cerveau (NUDICE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM) |
| المصدر: | Hepatology Hepatology, Wiley-Blackwell, 2017, 66 (6), pp.2042-2054. ⟨10.1002/hep.29389⟩ Hepatology, 66, 2042-2054 Hepatology, 2017, 66 (6), pp.2042-2054. ⟨10.1002/hep.29389⟩ Hepatology, 66, 6, pp. 2042-2054 Hepatology, 66(6), 2042-2054. Wiley |
| بيانات النشر: | HAL CCSD, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Glycerol, Male, 0301 basic medicine, medicine.medical_specialty, COMPENSATED CIRRHOSIS, PORTAL-HYPERTENSION, Glycogen Storage Disease Type I, Sudden death, Glycogen debranching enzyme, Mice, 03 medical and health sciences, Glycogen phosphorylase, chemistry.chemical_compound, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], Glycogen branching enzyme, medicine, Animals, Glycogen storage disease, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Glycogen synthase, VARICES, ELASTOGRAPHY, Hepatology, biology, Glycogen, Glucokinase, Galactose, alpha-Glucosidases, STIFFNESS, PLATELET COUNT, medicine.disease, Disease Models, Animal, Glucose, 030104 developmental biology, Endocrinology, chemistry, Glucose-6-Phosphatase, Hepatocytes, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], CHRONIC LIVER-DISEASES, LOW-RISK, 030217 neurology & neurosurgery |
| الوصف: | It is a long-standing enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production despite the loss of glucose-6-phosphatase activity. Insight into the source of residual endogenous glucose production is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated glucose-6-phosphatase–independent endogenous glucose production in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6pc–/– mice) and performed real-time analysis of hepatic glucose fluxes and glycogen metabolism in L-G6pc–/– mice using state-of-the-art stable isotope methodologies. Here we show that G6pc-deficient hepatocytes are capable of producing glucose. In vivo analysis of hepatic glucose metabolism revealed that the hepatic glucokinase flux was decreased by 95% in L-G6pc–/– mice. It also showed increased glycogen phosphorylase flux in L-G6pc–/– mice, which is coupled to the release of free glucose through glycogen debranching. Although the ex vivo activities of debranching enzyme and lysosomal acid maltase, two major hepatic α-glucosidases, were unaltered in L-G6pc−/− mice, pharmacological inhibition of α-glucosidase activity almost completely abolished residual glucose production by G6pc-deficient hepatocytes.Conclusion: Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that α-glucosidase activity, i.e. glycogen debranching and/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L-G6pc-/- mice furthermore limits the phosphorylation of free glucose synthesized by G6pc-deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in G6pc-deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 0270-9139 1527-3350 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c1b0bbcba44010d1bd9e79f945c55c91 https://www.hal.inserm.fr/inserm-02339628 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c1b0bbcba44010d1bd9e79f945c55c91 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 02709139 15273350 |
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