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Science 16 May 2003:
Vol. 300. no. 5622, pp. 1140 - 1142
DOI: 10.1126/science.1082889
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Reports

Mitochondrial Dysfunction in the Elderly: Possible Role in Insulin Resistance

Kitt Falk Petersen,1 Douglas Befroy,1,7 Sylvie Dufour,1,7 James Dziura,1 Charlotte Ariyan,3 Douglas L. Rothman,4 Loretta DiPietro,5,6 Gary W. Cline,1 Gerald I. Shulman1,2,7*

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes in the elderly. To investigate how insulin resistance arises, we studied healthy, lean, elderly and young participants matched for lean body mass and fat mass. Elderly study participants were markedly insulin-resistant as compared with young controls, and this resistance was attributable to reduced insulin-stimulated muscle glucose metabolism. These changes were associated with increased fat accumulation in muscle and liver tissue assessed by 1Hnuclear magnetic resonance (NMR) spectroscopy, and with a ~40% reduction in mitochondrial oxidative and phosphorylation activity, as assessed by in vivo 13C/31P NMR spectroscopy. These data support the hypothesis that an age-associated decline in mitochondrial function contributes to insulin resistance in the elderly.

1 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
2 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
3 Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA.
4 Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
5 Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520, USA.
6 John B. Pierce Laboratory, Yale University School of Medicine, New Haven, CT 06520, USA.
7 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.

* To whom correspondence should be addressed. E-mail: gerald.shulman{at}yale.edu

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Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo.
C. E. Amara, E. G. Shankland, S. A. Jubrias, D. J. Marcinek, M. J. Kushmerick, and K. E. Conley (2007)
PNAS 104, 1057-1062
   Abstract »    Full Text »    PDF »
An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations.
K. C. Kregel and H. J. Zhang (2007)
Am J Physiol Regulatory Integrative Comp Physiol 292, R18-R36
   Abstract »    Full Text »    PDF »
PGC-1{alpha}: a key regulator of energy metabolism.
H. Liang and W. F. Ward (2006)
Advan Physiol Educ 30, 145-151
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Skeletal Muscle Mitochondrial Functions, Mitochondrial DNA Copy Numbers, and Gene Transcript Profiles in Type 2 Diabetic and Nondiabetic Subjects at Equal Levels of Low or High Insulin and Euglycemia.
Y. W. Asmann, C. S. Stump, K. R. Short, J. M. Coenen-Schimke, Z. Guo, M. L. Bigelow, and K. S. Nair (2006)
Diabetes 55, 3309-3319
   Abstract »    Full Text »    PDF »
Molecular Mechanisms of Insulin Resistance in Humans and Their Potential Links With Mitochondrial Dysfunction.
K. Morino, K. F. Petersen, and G. I. Shulman (2006)
Diabetes 55, S9-S15
   Abstract »    Full Text »    PDF »
Interleukin-6 Regulation of AMP-Activated Protein Kinase: Potential Role in the Systemic Response to Exercise and Prevention of the Metabolic Syndrome.
N. B. Ruderman, C. Keller, A.-M. Richard, A. K. Saha, Z. Luo, X. Xiang, M. Giralt, V. B. Ritov, E. V. Menshikova, D. E. Kelley, et al. (2006)
Diabetes 55, S48-S54
   Abstract »    Full Text »    PDF »
Hepatic Gene Expression Profile of Lipid Metabolism in Rats: Impact of Caloric Restriction and Growth Hormone/Insulin-Like Growth Factor-1 Suppression.
Y. Higami, T. Tsuchiya, T. Chiba, H. Yamaza, I. Muraoka, M. Hirose, T. Komatsu, and I. Shimokawa (2006)
J. Gerontol. A Biol. Sci. Med. Sci. 61, 1099-1110
   Abstract »    Full Text »    PDF »
Overexpression of Peroxisome Proliferator-Activated Receptor {gamma} Co-Activator-1{alpha} Leads to Muscle Atrophy with Depletion of ATP.
S. Miura, E. Tomitsuka, Y. Kamei, T. Yamazaki, Y. Kai, M. Tamura, K. Kita, I. Nishino, and O. Ezaki (2006)
Am. J. Pathol. 169, 1129-1139
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The underappreciated role of muscle in health and disease..
R. R Wolfe (2006)
Am. J. Clinical Nutrition 84, 475-482
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PGC-1{beta} Down-Regulation Is Associated With Reduced ERR{alpha} Activity and MCAD Expression in Skeletal Muscle of Senescence-Accelerated Mice..
R. Rodriguez-Calvo, M. Jove, T. Coll, A. Camins, R. M. Sanchez, M. Alegret, M. Merlos, M. Pallas, J. C. Laguna, and M. Vazquez-Carrera (2006)
J. Gerontol. A Biol. Sci. Med. Sci. 61, 773-780
   Abstract »    Full Text »    PDF »
Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85{alpha}: The Two Sides of a Coin..
B. Draznin (2006)
Diabetes 55, 2392-2397
   Abstract »    Full Text »    PDF »
Tough love: left out in the cold, but not abandoned, by UCP3.
G. W. Cline (2006)
J Appl Physiol 101, 12-13
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Third Annual World Congress on the Insulin Resistance Syndrome: Mediators, antecedents, and measurement.
Z. T. Bloomgarden (2006)
Diabetes Care 29, 1700-1706
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The role of AMP-activated protein kinase in mitochondrial biogenesis.
R. M. Reznick and G. I. Shulman (2006)
J. Physiol. 574, 33-39
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Type 2 Diabetes Increases the Risk for Uric Acid Stones.
M. Daudon, O. Traxer, P. Conort, B. Lacour, and P. Jungers (2006)
J. Am. Soc. Nephrol. 17, 2026-2033
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Effects of exercise on mitochondrial content and function in aging human skeletal muscle..
E. V. Menshikova, V. B. Ritov, L. Fairfull, R. E. Ferrell, D. E. Kelley, and B. H. Goodpaster (2006)
J. Gerontol. A Biol. Sci. Med. Sci. 61, 534-540
   Abstract »    Full Text »    PDF »
Downregulation of Electron Transport Chain Genes in Visceral Adipose Tissue in Type 2 Diabetes Independent of Obesity and Possibly Involving Tumor Necrosis Factor-{alpha}.
I. Dahlman, M. Forsgren, A. Sjogren, E. A. Nordstrom, M. Kaaman, E. Naslund, A. Attersand, and P. Arner (2006)
Diabetes 55, 1792-1799
   Abstract »    Full Text »    PDF »
Minireview: Implication of Mitochondria in Insulin Secretion and Action.
A. Wiederkehr and C. B. Wollheim (2006)
Endocrinology 147, 2643-2649
   Abstract »    Full Text »    PDF »


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