Hepatocyte-specific glucose-6-phosphatase deficiency disturbs platelet aggregation and decreases blood monocytes upon fasting-induced hypoglycemia
| Autor: | Bertien Dethmers-Ausema, Niels J. Kloosterhuis, Folkert Kuipers, Gilles Mithieux, Anouk M. La Rose, Martijn G S Rutten, Oliver Soehnlein, Joanne A Hoogerland, J Hendrik Nijland, Marit Westerterp, Fabienne Rajas, Maaike H. Oosterveer, Arthur Flohr Svendsen, Venetia Bazioti, Michaël V. Lukens, Martijn van Faassen, Anouk G. Groenen |
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| Přispěvatelé: | University of Groningen [Groningen], University Medical Center Groningen [Groningen] (UMCG), 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), Université de Lyon, Karolinska Institutet [Stockholm], University of Münster, Center for Liver, Digestive and Metabolic Diseases (CLDM), Translational Immunology Groningen (TRIGR), Di Carlo, Marie-Ange, Nutrition, diabète et cerveau (NUDICE), Westfälische Wilhelms-Universität Münster = University of Münster (WWU) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine INTESTINAL GLUCONEOGENESIS Platelet Aggregation Glycogen Storage Disease Type I INSULIN-INDUCED HYPOGLYCEMIA 0302 clinical medicine Medicine Glycogen storage disease Platelet Internal medicine Mice Knockout biology medicine.diagnostic_test Metabolic disorder GLUCOSE-METABOLISM VASCULAR-DISEASE Fasting 3. Good health 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1 platelets Female Original Article [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Glycogen storage disease type 1a monocytes Partial thromboplastin time STORAGE medicine.medical_specialty VON-WILLEBRAND-FACTOR BONE-MARROW Mice Transgenic 030209 endocrinology & metabolism Hypoglycemia 03 medical and health sciences Von Willebrand factor Animals [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Molecular Biology Glycemic ADP RECEPTORS business.industry corticosterone Ice Hypertriglyceridemia nutritional and metabolic diseases Cell Biology medicine.disease RC31-1245 DISEASE TYPE IA Disease Models Animal 030104 developmental biology Endocrinology hypoglycemia Hepatocytes biology.protein business |
| Zdroj: | Molecular metabolism Molecular metabolism, Elsevier, 2021, pp.101265. ⟨10.1016/j.molmet.2021.101265⟩ Molecular metabolism, 53:101265, 1-14. ELSEVIER SCIENCE BV Molecular Metabolism, Vol 53, Iss, Pp 101265-(2021) Molecular Metabolism |
| ISSN: | 2212-8778 |
| Popis: | Objective Glycogen storage disease type 1a (GSD Ia) is a rare inherited metabolic disorder caused by mutations in the glucose-6-phosphatase (G6PC1) gene. When untreated, GSD Ia leads to severe fasting-induced hypoglycemia. Although current intensive dietary management aims to prevent hypoglycemia, patients still experience hypoglycemic events. Poor glycemic control in GSD Ia is associated with hypertriglyceridemia, hepatocellular adenoma and carcinoma, and also with an increased bleeding tendency of unknown origin. Methods To evaluate the effect of glycemic control on leukocyte levels and coagulation in GSD Ia, we employed hepatocyte-specific G6pc1 deficient (L-G6pc−/−) mice under fed or fasted conditions, to match good or poor glycemic control in GSD Ia, respectively. Results We found that fasting-induced hypoglycemia in L-G6pc−/− mice decreased blood leukocytes, specifically proinflammatory Ly6Chi monocytes, compared to controls. Refeeding reversed this decrease. The decrease in Ly6Chi monocytes was accompanied by an increase in plasma corticosterone levels and was prevented by the glucocorticoid receptor antagonist mifepristone. Further, fasting-induced hypoglycemia in L-G6pc−/− mice prolonged bleeding time in the tail vein bleeding assay, with reversal by refeeding. This could not be explained by changes in coagulation factors V, VII, or VIII, or von Willebrand factor. While the prothrombin and activated partial thromboplastin time as well as total platelet counts were not affected by fasting-induced hypoglycemia in L-G6pc−/− mice, ADP-induced platelet aggregation was disturbed. Conclusions These studies reveal a relationship between fasting-induced hypoglycemia, decreased blood monocytes, and disturbed platelet aggregation in L-G6pc−/− mice. While disturbed platelet aggregation likely accounts for the bleeding phenotype in GSD Ia, elevated plasma corticosterone decreases the levels of proinflammatory monocytes. These studies highlight the necessity of maintaining good glycemic control in GSD Ia. Highlights • Fasting-induced hypoglycemia in hepatocyte-specific G6pc1 deficiency disturbs platelet aggregation. • Fasting-induced hypoglycemia in hepatocyte-specific G6pc1 deficiency decreases blood monocytes. • Fasting-induced hypoglycemia in hepatocyte-specific G6pc1 deficiency increases plasma corticosterone. |
| Databáze: | OpenAIRE |
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