Dissecting Long-Term Glucose Metabolism Identifies New Susceptibility Period for Metabolic Dysfunction in Aged Mice.

Anuradha Chauhan,Julio Vera,Markus Tiedge,Olaf Wolkenhauer,Heike Weiss,Saleh M Ibrahim,Franziska Koch

doi:10.1371/journal.pone.0140858

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.

Highlights

Metabolic disorders, like diabetes and obesity, are pathogenic outcomes of metabolic imbalance in glucose metabolism [1]
In order to understand this non-linear blood glucose dynamics, we further studied the effect of a 12 month long high-fat diet (HFD) administration on further key regulators of metabolism and subjected the data to mathematical modeling
The animals were kept in cohorts of 4 animals/cage and had access to food and water ad libitum. 16– 20 animals per strain and diet were continuously monitored for body weight and blood glucose. 8–11 animals per strain and diet were used for the leptin and insulin measurement

Summary

Introduction

Like diabetes and obesity, are pathogenic outcomes of metabolic imbalance in glucose metabolism [1]. Imbalance in glucose metabolism can arise from a complex set of factors including genetic predisposition, nutrient excess and the ability of the body to deal with nutrient excess. The body’s ability to deal with excess nutrients involves direct adjustments in energy intake and expenditure pathways, along with the modulation in mitochondrial capacity/efficiency to generate ATP [2]. Mitochondria house their own genome (mtDNA), which can accumulate point mutations in an age-dependent manner in humans [3]. The conplastic mouse strain B6-mtFVB, has a stable mutation in mtAtp gene, found in mitochondrial ATPsynthase complex.

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Conclusion