Mitochondrial fitness and insulin sensitivity in humans

Mitochondrial fitness and insulin sensitivity in humans Human mitochondria can be studied either in biopsies or by measuring flux through ATP synthase and phosphocreatine recovery using magnetic resonance spectroscopy. Myocellular ATP production (flux through ATP synthase (fATP)) increases by up to 90% during 8 h of insulin stimulation. Fasting mitochondrial function is 14–40% lower than in controls in the presence of insulin resistance, as seen in those with type 2 diabetes, their insulin-resistant relatives or the obese. Insulin-stimulated fATP is abolished in insulin-resistant relatives and patients with type 2 diabetes, and patients frequently show decreased mitochondrial size/density. Age, fat mass, physical activity, plasma NEFA and glucose all correlate negatively with mitochondrial function, but it is for methodological reasons difficult to determine whether reduced mitochondrial content or function account for reduced ATP production in insulin resistance. Experimental plasma NEFA elevation appears to inhibit mitochondrial function by interfering with the metabolic actions of insulin, which might explain impaired mitochondrial function in obesity. Alternatively, primary mitochondrial abnormalities, as seen in those with inherited risk of type 2 diabetes, could decrease lipid oxidation, thereby raising circulating and intracellular NEFA levels. In type 2 diabetes, chronic hyperglycaemia and dyslipidaemia could first diminish the function, and subsequently reduce the size or density of mitochondria via oxidative stress and apoptosis. Many questions remain unsolved, including (1) which mechanisms regulate mitochondrial adaptation to nutrient overload; (2) what factors control the expression of genes encoding mitochondrial proteins and other signals involved in mitochondrial biogenesis; (3) which geno/phenotypes are associated with both insulin resistance and mitochondrial abnormalities; and (4) which are the most promising targets for improving mitochondrial fitness in insulin resistance? http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diabetologia Springer Journals

Mitochondrial fitness and insulin sensitivity in humans

Diabetologia, Volume 51 (12) – Dec 1, 2008

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Publisher
Springer Journals
Copyright
Copyright © 2008 by Springer-Verlag
Subject
Medicine & Public Health; Human Physiology ; Metabolic Diseases ; Internal Medicine
ISSN
0012-186X
eISSN
1432-0428
DOI
10.1007/s00125-008-1153-2
Publisher site
See Article on Publisher Site

Abstract

Human mitochondria can be studied either in biopsies or by measuring flux through ATP synthase and phosphocreatine recovery using magnetic resonance spectroscopy. Myocellular ATP production (flux through ATP synthase (fATP)) increases by up to 90% during 8 h of insulin stimulation. Fasting mitochondrial function is 14–40% lower than in controls in the presence of insulin resistance, as seen in those with type 2 diabetes, their insulin-resistant relatives or the obese. Insulin-stimulated fATP is abolished in insulin-resistant relatives and patients with type 2 diabetes, and patients frequently show decreased mitochondrial size/density. Age, fat mass, physical activity, plasma NEFA and glucose all correlate negatively with mitochondrial function, but it is for methodological reasons difficult to determine whether reduced mitochondrial content or function account for reduced ATP production in insulin resistance. Experimental plasma NEFA elevation appears to inhibit mitochondrial function by interfering with the metabolic actions of insulin, which might explain impaired mitochondrial function in obesity. Alternatively, primary mitochondrial abnormalities, as seen in those with inherited risk of type 2 diabetes, could decrease lipid oxidation, thereby raising circulating and intracellular NEFA levels. In type 2 diabetes, chronic hyperglycaemia and dyslipidaemia could first diminish the function, and subsequently reduce the size or density of mitochondria via oxidative stress and apoptosis. Many questions remain unsolved, including (1) which mechanisms regulate mitochondrial adaptation to nutrient overload; (2) what factors control the expression of genes encoding mitochondrial proteins and other signals involved in mitochondrial biogenesis; (3) which geno/phenotypes are associated with both insulin resistance and mitochondrial abnormalities; and (4) which are the most promising targets for improving mitochondrial fitness in insulin resistance?

Journal

DiabetologiaSpringer Journals

Published: Dec 1, 2008

References

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