Back to Search
Start Over
Glucose metabolism during fasting is altered in experimental porphobilinogen deaminase deficiency.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2016 Apr 01; Vol. 25 (7), pp. 1318-27. Date of Electronic Publication: 2016 Jan 21. - Publication Year :
- 2016
-
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.<br /> (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Cerebral Cortex metabolism
Fasting blood
Gene Expression
Gene Transfer Techniques
Genetic Therapy
Glucagon blood
Homeostasis
Insulin blood
Male
Mice
Mice, Knockout
Porphyria, Acute Intermittent blood
Porphyria, Acute Intermittent therapy
Disease Models, Animal
Fasting metabolism
Glucose metabolism
Hydroxymethylbilane Synthase genetics
Liver metabolism
Porphyria, Acute Intermittent metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 25
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 26908609
- Full Text :
- https://doi.org/10.1093/hmg/ddw013