Dissecting long-term glucose metabolism identifies new susceptibility period for metabolic dysfunction in aged mice
Date
2015
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
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.
Description
CITATION: Chauhan, A., et al. 2015. Dissecting long-term glucose metabolism identifies new susceptibility period for metabolic dysfunction in aged mice. PLoS ONE, 10(11):1-16, doi:10.1371/journal.pone.0140858.
The original publication is available at http://journals.plos.org/plosone
The original publication is available at http://journals.plos.org/plosone
Keywords
Metabolism -- Disorders, Diabetes -- Nutritional aspects, Obesity, Nutritional disorders in old age, Glucose metabolism
Citation
Chauhan, A., et al. 2015. Dissecting long-term glucose metabolism identifies new susceptibility period for metabolic dysfunction in aged mice. PLoS ONE, 10(11):1-16, doi:10.1371/journal.pone.0140858