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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.

SUBMITTER: Chauhan A

PROVIDER: S-EPMC4634931 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPrevious clinical studies have shown that various measures of glucose metabolism are associated with a risk of chronic kidney disease in different populations, but results were not consistent. In this study we assessed measures of glucose metabolism and their association with kidney function in a population-based study.MethodsThe Netherlands Epidemiology of Obesity study is a population-based cohort study of middle-aged men and women. We categorized the study population according to glycaemic levels into normoglycaemia (reference group), pre-diabetes mellitus (pre-DM), known DM and newly diagnosed DM. Outcome variables were serum creatinine, estimated glomerular filtration rate (eGFR), glomerular hyperfiltration (defined as an eGFR >90th percentile; >102 mL/min/1.73 m2) and micro-albuminuria. We examined the association between measures of glucose metabolism [fasting glucose, haemoglobin A1c (HbA1c), fasting insulin, glucose area under the curve (AUC), insulin AUC, Homoeostatic Model Assessment of Insulin Resistance (HOMA-IR), HOMA of β-cell function (HOMA-B) and disposition index] and measures of kidney function.ResultsOf the total population (N = 6338), 55% of participants were classified as normoglycaemic (reference), 35% as pre-DM, 7% as DM and 4% as newly diagnosed DM. Compared with the reference group, diagnosed and newly diagnosed DMs were associated with a slightly higher trend in eGFR {+2.1 mL/min/1.73 m2 [95% confidence interval (CI) -0.2-4.4] and +2.7 mL/min/1.73 m2 [95% CI -0.3-5.7], respectively}. A 1% higher HbA1c was associated with increased odds of hyperfiltration [odds ratio (OR) 1.41 (95% CI 1.06-1.88)]. Higher levels of fasting plasma glucose, AUC glucose and HOMA-B were associated with hyperfiltration. Fasting insulin, AUC insulin and HOMA-IR were not associated with hyperfiltration. The OR of microalbuminuria was 1.21 (95% CI 1.04-1.42) per mmol/L higher fasting glucose concentrations.ConclusionsBoth fasting and post-prandial glucose and HOMA-B, but not measures of insulin resistance, were associated with glomerular hyperfiltration, while fasting glucose was also associated with microalbuminuria.

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

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