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J Biol Chem, Vol. 275, Issue 12, 8456-8460, March 24, 2000
From the Insulin resistance is a major factor in the
pathogenesis of type 2 diabetes and may be related to alterations in
fat metabolism. Fatless mice have been created using dominant-negative
protein (A-ZIP/F-1) targeted gene expression in the adipocyte and shown to develop diabetes. To understand the mechanism responsible for the
insulin resistance in these mice, we conducted
hyperinsulinemic-euglycemic clamps in awake fatless and wild type
littermates before the development of diabetes and examined insulin
action and signaling in muscle and liver. We found the fatless mice to
be severely insulin-resistant, which could be attributed to defects in
insulin action in muscle and liver. Both of these abnormalities were
associated with defects in insulin activation of insulin receptor
substrate-1 and -2-associated phosphatidylinositol 3-kinase activity
and a 2-fold increase in muscle and liver triglyceride content. We also
show that upon transplantation of fat tissue into these mice,
triglyceride content in muscle and liver returned to normal as does
insulin signaling and action. In conclusion, these results suggest that
the development of insulin resistance in type 2 diabetes may be due to
alterations in the partitioning of fat between the adipocyte and
muscle/liver leading to accumulation of triglyceride in the latter
tissues with subsequent impairment of insulin signaling and action.
Mechanism of Insulin Resistance in A-ZIP/F-1 Fatless Mice*
§,,
Howard Hughes Medical Institute and the
Department of Internal Medicine, Yale University School of Medicine,
New Haven, Connecticut 06536 and the ¶ Diabetes Branch, NIDDK,
National Institutes of Health, Bethesda, Maryland 20892
*
This study was supported by United States Public Health
Service Grants R01 DK-40936 and P30 DK-45735.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Investigator of the Howard Hughes Medical Institute. To whom
correspondence should be addressed: Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Ave., BCMM 254C, Box 9812, New Haven, CT 06536-8012. Tel.: 203-737-1115; Fax: 203-737-4059; E-mail: gerald. shulman{at}yale.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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A. Virkamaki, E. Korsheninnikova, A. Seppala-Lindroos, S. Vehkavaara, T. Goto, J. Halavaara, A.-M. Hakkinen, and H. Yki-Jarvinen Intramyocellular Lipid Is Associated With Resistance to In Vivo Insulin Actions on Glucose Uptake, Antilipolysis, and Early Insulin Signaling Pathways in Human Skeletal Muscle Diabetes, October 1, 2001; 50(10): 2337 - 2343. [Abstract] [Full Text]
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 H. Cho, J. Mu, J. K. Kim, J. L. Thorvaldsen, Q. Chu, E. B. Crenshaw III, K. H. Kaestner, M. S. Bartolomei, G. I. Shulman, and M. J. Birnbaum Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBbeta ) Science, June 1, 2001; 292(5522): 1728 - 1731. [Abstract] [Full Text] [PDF]
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K. Ebihara, Y. Ogawa, H. Masuzaki, M. Shintani, F. Miyanaga, M. Aizawa-Abe, T. Hayashi, K. Hosoda, G. Inoue, Y. Yoshimasa, et al. Transgenic Overexpression of Leptin Rescues Insulin Resistance and Diabetes in a Mouse Model of Lipoatrophic Diabetes Diabetes, June 1, 2001; 50(6): 1440 - 1448. [Abstract] [Full Text]
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J. K. Kim, J. J. Fillmore, Y. Chen, C. Yu, I. K. Moore, M. Pypaert, E. P. Lutz, Y. Kako, W. Velez-Carrasco, I. J. Goldberg, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance PNAS, May 30, 2001; (2001) 121164498. [Abstract] [Full Text] [PDF]
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J. M. Zabolotny, Y.-B. Kim, O. D. Peroni, J. K. Kim, M. A. Pani, O. Boss, L. D. Klaman, S. Kamatkar, G. I. Shulman, B. B. Kahn, et al. Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance PNAS, April 12, 2001; (2001) 71050398. [Abstract] [Full Text]
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R. H. UNGER and L. ORCI Diseases of liporegulation: new perspective on obesity and related disorders FASEB J, February 1, 2001; 15(2): 312 - 321. [Abstract] [Full Text] [PDF]
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S. F. Previs, D. J. Withers, J.-M. Ren, M. F. White, and G. I. Shulman Contrasting Effects of IRS-1 Versus IRS-2 Gene Disruption on Carbohydrate and Lipid Metabolism in Vivo J. Biol. Chem., December 8, 2000; 275(50): 38990 - 38994. [Abstract] [Full Text] [PDF]
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L. L. Listenberger, D. S. Ory, and J. E. Schaffer Palmitate-induced Apoptosis Can Occur through a Ceramide-independent Pathway J. Biol. Chem., April 27, 2001; 276(18): 14890 - 14895. [Abstract] [Full Text] [PDF]
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J. M. Zabolotny, Y.-B. Kim, O. D. Peroni, J. K. Kim, M. A. Pani, O. Boss, L. D. Klaman, S. Kamatkar, G. I. Shulman, B. B. Kahn, et al. Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance PNAS, April 24, 2001; 98(9): 5187 - 5192. [Abstract] [Full Text] [PDF]
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J. K. Kim, J. J. Fillmore, Y. Chen, C. Yu, I. K. Moore, M. Pypaert, E. P. Lutz, Y. Kako, W. Velez-Carrasco, I. J. Goldberg, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance PNAS, June 19, 2001; 98(13): 7522 - 7527. [Abstract] [Full Text] [PDF]
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S. Neschen, I. Moore, W. Regittnig, C. L. Yu, Y. Wang, M. Pypaert, K. F. Petersen, and G. I. Shulman Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content Am J Physiol Endocrinol Metab, February 1, 2002; 282(2): E395 - E401. [Abstract] [Full Text] [PDF]
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