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

Chauhan A, Weiss H, Koch F, Ibrahim SM, Vera J, Wolkenhauer O, Tiedge M - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Insulin and leptin strongly regulate the timing of blood glucose peak.Leptin (k5ml) and insulin (k5mi) mediated control of demand for food-intake via Ein (A2, B2). Blood glucose response to 100-fold change in k5ml and k5mi (dashed lines) compared to default blood glucose response (bold line). Arrow depicts the direction of fold-change increase in k5ml and k5mi (A1, B1,). Timing of the blood glucose peak is equally sensitive to fold change in respective leptin and insulin parameters that determine demand for food intake (A3, B3).
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pone.0140858.g004: Insulin and leptin strongly regulate the timing of blood glucose peak.Leptin (k5ml) and insulin (k5mi) mediated control of demand for food-intake via Ein (A2, B2). Blood glucose response to 100-fold change in k5ml and k5mi (dashed lines) compared to default blood glucose response (bold line). Arrow depicts the direction of fold-change increase in k5ml and k5mi (A1, B1,). Timing of the blood glucose peak is equally sensitive to fold change in respective leptin and insulin parameters that determine demand for food intake (A3, B3).

Mentions: In order to delineate the regulatory effects of insulin, leptin and body weight on the blood glucose dynamics, we performed a sensitivity analysis by systematically varying the model parameters over a 100-fold range (Figure C in S1 File). Both leptin (Fig 4A1) and insulin (Fig 4B1) were equally crucial in determining the overall blood glucose dynamics, when demand for food intake (k5ml, k5mi) (Fig 4A2 and 4B2) was varied. Timing of the early age blood glucose peak was strongly controlled by both leptin and insulin (Fig 4A3 and 4B3). However, leptin had a stronger impact on blood glucose dynamics at a later age (Fig 5A1), compared to insulin (Fig 5B1), when energy expenditure via leptin and insulin (k7l, k7i) (Fig 5A2 and 5B2) was varied in the same range. Amplitude of the blood glucose tail decreased more for leptin mediated energy expenditure with the fold change in respective parameter (Fig 5A3), compared to insulin mediated energy expenditure (Fig 5B3). Note that the simulations are performed for longer than 12 months of age.


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

Chauhan A, Weiss H, Koch F, Ibrahim SM, Vera J, Wolkenhauer O, Tiedge M - PLoS ONE (2015)

Insulin and leptin strongly regulate the timing of blood glucose peak.Leptin (k5ml) and insulin (k5mi) mediated control of demand for food-intake via Ein (A2, B2). Blood glucose response to 100-fold change in k5ml and k5mi (dashed lines) compared to default blood glucose response (bold line). Arrow depicts the direction of fold-change increase in k5ml and k5mi (A1, B1,). Timing of the blood glucose peak is equally sensitive to fold change in respective leptin and insulin parameters that determine demand for food intake (A3, B3).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4634931&req=5

pone.0140858.g004: Insulin and leptin strongly regulate the timing of blood glucose peak.Leptin (k5ml) and insulin (k5mi) mediated control of demand for food-intake via Ein (A2, B2). Blood glucose response to 100-fold change in k5ml and k5mi (dashed lines) compared to default blood glucose response (bold line). Arrow depicts the direction of fold-change increase in k5ml and k5mi (A1, B1,). Timing of the blood glucose peak is equally sensitive to fold change in respective leptin and insulin parameters that determine demand for food intake (A3, B3).
Mentions: In order to delineate the regulatory effects of insulin, leptin and body weight on the blood glucose dynamics, we performed a sensitivity analysis by systematically varying the model parameters over a 100-fold range (Figure C in S1 File). Both leptin (Fig 4A1) and insulin (Fig 4B1) were equally crucial in determining the overall blood glucose dynamics, when demand for food intake (k5ml, k5mi) (Fig 4A2 and 4B2) was varied. Timing of the early age blood glucose peak was strongly controlled by both leptin and insulin (Fig 4A3 and 4B3). However, leptin had a stronger impact on blood glucose dynamics at a later age (Fig 5A1), compared to insulin (Fig 5B1), when energy expenditure via leptin and insulin (k7l, k7i) (Fig 5A2 and 5B2) was varied in the same range. Amplitude of the blood glucose tail decreased more for leptin mediated energy expenditure with the fold change in respective parameter (Fig 5A3), compared to insulin mediated energy expenditure (Fig 5B3). Note that the simulations are performed for longer than 12 months of age.

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus