title: Dissecting Long-Term Glucose Metabolism Identifies New Susceptibility Period for Metabolic Dysfunction in Aged Mice.
abstract: Metabolic disorders, like diabetes and obesity, are pathogenic outcomes of imbalance in glucose metabolism. Nutrient excess and mitochondrial imbalance are implicated in dysfunctional glucose metabolism with age. We used conplastic mouse strains with defined mitochondrial DNA (mtDNA) mutations on a common nuclear genomic background, and administered a high-fat diet up to 18 months of age. The conplastic mouse strain B6-mtFVB, with a mutation in the mt-Atp8 gene, conferred β-cell dysfunction and impaired glucose tolerance after high-fat diet. To our surprise, despite of this functional deficit, blood glucose levels adapted to perturbations with age. Blood glucose levels were particularly sensitive to perturbations at the early age of 3 to 6 months. Overall the dynamics consisted of a peak between 3-6 months followed by adaptation by 12 months of age. With the help of mathematical modeling we delineate how body weight, insulin and leptin regulate this non-linear blood glucose dynamics. The model predicted a second rise in glucose between 15 and 21 months, which could be experimentally confirmed as a secondary peak. We therefore hypothesize that these two peaks correspond to two sensitive periods of life, where perturbations to the basal metabolism can mark the system for vulnerability to pathologies at later age. Further mathematical modeling may perspectively allow the design of targeted periods for therapeutic interventions and could predict effects on weight loss and insulin levels under conditions of pre-diabetic obesity.
authors.affiliation: Department of Systems Biology and Bioinformatics, Institute of Computer Science, University of Rostock, Rostock, Germany. Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Chauhan
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Weiss
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Koch
authors.affiliation: Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
authors.affiliation: Department of Systems Biology and Bioinformatics, Institute of Computer Science, University of Rostock, Rostock, Germany. Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Julio
authors.initials: J
authors.lastname: Vera
authors.affiliation: Department of Systems Biology and Bioinformatics, Institute of Computer Science, University of Rostock, Rostock, Germany. Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Olaf
authors.initials: O
authors.lastname: Wolkenhauer
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, University of Rostock, Rostock, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Tiedge
mesh_terms: D000222:Adaptation, Physiological; D000367:Age Factors; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D004198:Disease Susceptibility / Q000378:metabolism / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D008659:Metabolic Diseases / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological
chemical_list: D005947:Glucose