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Science 21 January 2005:
Vol. 307. no. 5708, pp. 384 - 387
DOI: 10.1126/science.1104343
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Mitochondrial Dysfunction and Type 2 Diabetes

Bradford B. Lowell1 and Gerald I. Shulman2

Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic ß cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.

1 Department of Medicine, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Harvard Medical School, Boston, MA 02215, USA. E-mail: blowell{at}bidmc.harvard.edu
2 Howard Hughes Medical Institute, Department of Internal Medicine and Department of Cellular and Molecular Physiology, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06536, USA. E-mail: gerald.shulman{at}yale.edu

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Advan Physiol Educ 30, 145-151
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Estrogen-related receptor {alpha} as a therapeutic target in cancer.
R A Stein and D P McDonnell (2006)
Endocr. Relat. Cancer 13, S25-S32
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Hyperinsulinemia, Impaired Glucose Tolerance, and Diabetes Mellitus in Survivors of Childhood Cancer: Prevalence and Risk Factors.
K. A. Neville, R. J. Cohn, K. S. Steinbeck, K. Johnston, and J. L. Walker (2006)
J. Clin. Endocrinol. Metab. 91, 4401-4407
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The HADHSC Gene Encoding Short-Chain L-3-Hydroxyacyl-CoA Dehydrogenase (SCHAD) and Type 2 Diabetes Susceptibility: The DAMAGE Study.
E. C. van Hove, T. Hansen, J. M. Dekker, E. Reiling, G. Nijpels, T. Jorgensen, K. Borch-Johnsen, Y. H. Hamid, R. J. Heine, O. Pedersen, et al. (2006)
Diabetes 55, 3193-3196
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Effects of Type II diabetes on capillary hemodynamics in skeletal muscle.
D. J. Padilla, P. McDonough, B. J. Behnke, Y. Kano, K. S. Hageman, T. I. Musch, and D. C. Poole (2006)
Am J Physiol Heart Circ Physiol 291, H2439-H2444
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Common Single Nucleotide Polymorphisms in TCF7L2 Are Reproducibly Associated With Type 2 Diabetes and Reduce the Insulin Response to Glucose in Nondiabetic Individuals..
R. Saxena, L. Gianniny, N. P. Burtt, V. Lyssenko, C. Giuducci, M. Sjogren, J. C. Florez, P. Almgren, B. Isomaa, M. Orho-Melander, et al. (2006)
Diabetes 55, 2890-2895
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PGC-1{alpha} and PGC-1beta have both similar and distinct effects on myofiber switching toward an oxidative phenotype.
O. H. Mortensen, L. Frandsen, P. Schjerling, E. Nishimura, and N. Grunnet (2006)
Am J Physiol Endocrinol Metab 291, E807-E816
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Maternal nutrient restriction affects properties of skeletal muscle in offspring.
M. J. Zhu, S. P. Ford, W. J. Means, B. W. Hess, P. W. Nathanielsz, and M. Du (2006)
J. Physiol. 575, 241-250
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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
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Exercise training and calorie restriction increase SREBP-1 expression and intramuscular triglyceride in skeletal muscle.
K. J. Nadeau, L. B. Ehlers, L. E. Aguirre, R. L. Moore, K. N. Jew, H. K. Ortmeyer, B. C. Hansen, J. E. B. Reusch, and B. Draznin (2006)
Am J Physiol Endocrinol Metab 291, E90-E98
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Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes.
N. Tiffin, E. Adie, F. Turner, H. G. Brunner, M. A. van Driel, M. Oti, N. Lopez-Bigas, C. Ouzounis, C. Perez-Iratxeta, M. A. Andrade-Navarro, et al. (2006)
Nucleic Acids Res. 34, 3067-3081
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Apoptosis Signal-Regulating Kinase 1 Mediates Cellular Senescence Induced by High Glucose in Endothelial Cells.
T. Yokoi, K. Fukuo, O. Yasuda, M. Hotta, J. Miyazaki, Y. Takemura, H. Kawamoto, H. Ichijo, and T. Ogihara (2006)
Diabetes 55, 1660-1665
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Minireview: Implication of Mitochondria in Insulin Secretion and Action.
A. Wiederkehr and C. B. Wollheim (2006)
Endocrinology 147, 2643-2649
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Insulin resistance and microalbuminuria: a cross-sectional, case-control study of 158 patients with type 2 diabetes and different degrees of urinary albumin excretion..
A. I. Parvanova, R. Trevisan, I. P. Iliev, B. D. Dimitrov, M. Vedovato, A. Tiengo, G. Remuzzi, and P. Ruggenenti (2006)
Diabetes 55, 1456-1462
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Diet-Genotype Interactions in the Development of the Obese, Insulin-Resistant Phenotype of C57BL/6J Mice Lacking Melanocortin-3 or -4 Receptors.
G. M. Sutton, J. L. Trevaskis, M. W. Hulver, R. P. McMillan, N. J. Markward, M. J. Babin, E. A. Meyer, and A. A. Butler (2006)
Endocrinology 147, 2183-2196
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Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms.
J.-a Kim, M. Montagnani, K. K. Koh, and M. J. Quon (2006)
Circulation 113, 1888-1904
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Attenuation of progression of insulin resistance in patients with coronary artery disease by bezafibrate..
A. Tenenbaum, E. Z. Fisman, V. Boyko, M. Benderly, D. Tanne, M. Haim, Z. Matas, M. Motro, and S. Behar (2006)
Arch Intern Med 166, 737-741
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Protection of INS-1 Cells From Free Fatty Acid-Induced Apoptosis by Targeting hOGG1 to Mitochondria..
L. I. Rachek, N. P. Thornley, V. I. Grishko, S. P. LeDoux, and G. L. Wilson (2006)
Diabetes 55, 1022-1028
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CREB activation induced by mitochondrial dysfunction triggers triglyceride accumulation in 3T3-L1 preadipocytes.
S. Vankoningsloo, A. De Pauw, A. Houbion, S. Tejerina, C. Demazy, F. de Longueville, V. Bertholet, P. Renard, J. Remacle, P. Holvoet, et al. (2006)
J. Cell Sci. 119, 1266-1282
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AMPK: A Key Sensor of Fuel and Energy Status in Skeletal Muscle.
D. G. Hardie and K. Sakamoto (2006)
Physiology 21, 48-60
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Increased Lipid Availability Impairs Insulin-Stimulated ATP Synthesis in Human Skeletal Muscle.
A. Brehm, M. Krssak, A. I. Schmid, P. Nowotny, W. Waldhausl, and M. Roden (2006)
Diabetes 55, 136-140
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