title: Glucose metabolism during fasting is altered in experimental porphobilinogen deaminase deficiency.
abstract: Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks when hepatic heme synthesis is activated by endogenous or environmental factors including fasting. While the molecular mechanisms underlying the nutritional regulation of hepatic heme synthesis have been described, glucose homeostasis during fasting is poorly understood in porphyria. Our study aimed to analyse glucose homeostasis and hepatic carbohydrate metabolism during fasting in PBGD-deficient mice. To determine the contribution of hepatic PBGD deficiency to carbohydrate metabolism, AIP mice injected with a PBGD-liver gene delivery vector were included. After a 14 h fasting period, serum and liver metabolomics analyses showed that wild-type mice stimulated hepatic glycogen degradation to maintain glucose homeostasis while AIP livers activated gluconeogenesis and ketogenesis due to their inability to use stored glycogen. The serum of fasted AIP mice showed increased concentrations of insulin and reduced glucagon levels. Specific over-expression of the PBGD protein in the liver tended to normalize circulating insulin and glucagon levels, stimulated hepatic glycogen catabolism and blocked ketone body production. Reduced glucose uptake was observed in the primary somatosensorial brain cortex of fasted AIP mice, which could be reversed by PBGD-liver gene delivery. In conclusion, AIP mice showed a different response to fasting as measured by altered carbohydrate metabolism in the liver and modified glucose consumption in the brain cortex. Glucose homeostasis in fasted AIP mice was efficiently normalized after restoration of PBGD gene expression in the liver.
authors.affiliation: MicroPET Research Unit, CIMA-CUN, University of Navarra, Pamplona, Spain, Nuclear Medicine Department, Clínica Universidad de Navarra, Pamplona, Spain, Instituto de Investigación Sanitaria de Navarra (idiSNA), Pamplona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Collantes
authors.affiliation: Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Irantzu
authors.initials: I
authors.lastname: Serrano-Mendioroz
authors.affiliation: Medicina y Cirugía Experimental, Hospital General Universitario Gregorio Marañón, CIBERSAM, Madrid, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Benito
authors.affiliation: MicroPET Research Unit, CIMA-CUN, University of Navarra, Pamplona, Spain, Movement Disorders Lab, Neuroscience Area, Centre for Applied Medical Research (CIMA), University of Navarra, Navarra, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Molinet-Dronda
authors.affiliation: Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Delgado
authors.affiliation: CIBERDEM-IISSPV-Centre for Omic Sciences (COS), Universitat Rovira i Virgili, Avinguda Universitat 3, Reus 43204, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Vinaixa
authors.affiliation: Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sampedro
authors.affiliation: Research Center, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Enríquez de Salamanca
authors.affiliation: Nuclear Medicine Department, Clínica Universidad de Navarra, Pamplona, Spain, Instituto de Investigación Sanitaria de Navarra (idiSNA), Pamplona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Prieto
authors.affiliation: Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense, Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pozo
authors.affiliation: MicroPET Research Unit, CIMA-CUN, University of Navarra, Pamplona, Spain, Nuclear Medicine Department, Clínica Universidad de Navarra, Pamplona, Spain, Instituto de Investigación Sanitaria de Navarra (idiSNA), Pamplona, Spain.
authors.forename: Iván
authors.initials: I
authors.lastname: Peñuelas
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (idiSNA), Pamplona, Spain, Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain, Proteomics and Bioinformatics Laboratory, CIMA, University of Navarra, PRB2-ProteoRed-ISCIII, Pamplona, Spain, CIBERehd, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain and.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
authors.affiliation: Health Science Department, Public University of Navarra (UPNA), Pamplona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Barajas
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (idiSNA), Pamplona, Spain, Hepatology Area, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain, CIBERehd, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain and afontanellas@unav.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fontanellas
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D005215:Fasting / Q000097:blood / Q000378:metabolism*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D011163:Hydroxymethylbilane Synthase / Q000235:genetics*; D007328:Insulin / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017118:Porphyria, Acute Intermittent / Q000097:blood / Q000378:metabolism* / Q000628:therapy
chemical_list: D007328:Insulin; D005934:Glucagon; D011163:Hydroxymethylbilane Synthase; D005947:Glucose