| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Papers In Press, published online ahead of print March 17, 2004
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
Corresponding Author: SUZUKIR-INT{at}h.u-tokyo.ac.jp
We previously reported that insulin receptor substrate-2 (IRS-2)-deficient mice develop diabetes as a result of insulin resistance in the liver and failure of
J. Biol. Chem, 10.1074/jbc.M311956200
Submitted on October 31, 2003
Revised on March 1, 2004
Accepted on March 17, 2004
Both insulin signaling defects in the liver and obesity contribute to insulin resistance and cause diabetes in Irs2-/- mice
-cell hyperplasia. In this study we introduced the IRS-2 gene specifically into the liver of Irs2-/- mice with adenovirus vectors. Glucose tolerance tests revealed that the IRS-2 restoration in the liver ameliorated the hyperglycemia, but the improvement in hyperinsulinemia was only partial. Endogenous glucose production (EGP) and glucose utilization (Rd) were measured during hyperinsulinemic-euglycemic clamp studies: EGP was increased two-fold in the Irs2-/- mice, while Rd decreased by 50%. Restoration of IRS-2 in the liver suppressed EGP to a level similar to that in wild-type mice, but Rd remained decreased in the adeno-IRS-2-infected Irs2-/- mice. Irs2-/- mice also exhibit obesity and hyperleptinemia associated with impairment of hypothalamic PI 3-kinase activation. Continuous intracerebroventricular (ICV) leptin infusion or caloric restriction yielded Irs2-/- mice whose adiposity was comparable to that of Irs2+/+ mice, and both the hyperglycemia and the hyperinsulinemia of these mice improved with increased Rd, albeit partially. Finally, combination treatment consisting of adenovirus-mediated gene transfer of IRS-2 and continuous ICV leptin infusion completely reversed the hyperglycemia and hyperinsulinemia in Irs2-/- mice. EGP and Rd also became normal in these mice as well as in mice treated by caloric restriction plus adenoviral gene-transfer. We therefore concluded that a combination of increased EGP due to insulin signaling defects in the liver and reduced Rd due to obesity accounts for the systemic insulin resistance in Irs2-/- mice.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Wauman, A.-S. De Smet, D. Catteeuw, D. Belsham, and J. Tavernier Insulin Receptor Substrate 4 Couples the Leptin Receptor to Multiple Signaling Pathways Mol. Endocrinol., April 1, 2008; 22(4): 965 - 977. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Li, Y. Zhou, C. Carter-Su, M. G. Myers Jr., and L. Rui SH2B1 Enhances Leptin Signaling by Both Janus Kinase 2 Tyr813 Phosphorylation-Dependent and -Independent Mechanisms Mol. Endocrinol., September 1, 2007; 21(9): 2270 - 2281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Kim, Y. Kido, P. E. Scherer, M. F. White, and D. Accili Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2 Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1694 - E1701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kamei, K. Tobe, R. Suzuki, M. Ohsugi, T. Watanabe, N. Kubota, N. Ohtsuka-Kowatari, K. Kumagai, K. Sakamoto, M. Kobayashi, et al. Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissues Causes Macrophage Recruitment and Insulin Resistance J. Biol. Chem., September 8, 2006; 281(36): 26602 - 26614. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kubota, Y. Terauchi, T. Kubota, H. Kumagai, S. Itoh, H. Satoh, W. Yano, H. Ogata, K. Tokuyama, I. Takamoto, et al. Pioglitazone Ameliorates Insulin Resistance and Diabetes by Both Adiponectin-dependent and -independent Pathways J. Biol. Chem., March 31, 2006; 281(13): 8748 - 8755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fujimoto, N. Shimizu, K. Kunii, J.A. J. Martyn, K. Ueki, and M. Kaneki A Role for iNOS in Fasting Hyperglycemia and Impaired Insulin Signaling in the Liver of Obese Diabetic Mice Diabetes, May 1, 2005; 54(5): 1340 - 1348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Suzuki, K. Tobe, M. Aoyama, K. Sakamoto, M. Ohsugi, N. Kamei, S. Nemoto, A. Inoue, Y. Ito, S. Uchida, et al. Expression of DGAT2 in White Adipose Tissue Is Regulated by Central Leptin Action J. Biol. Chem., February 4, 2005; 280(5): 3331 - 3337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Duan, M. Li, and L. Rui SH2-B Promotes Insulin Receptor Substrate 1 (IRS1)- and IRS2-mediated Activation of the Phosphatidylinositol 3-Kinase Pathway in Response to Leptin J. Biol. Chem., October 15, 2004; 279(42): 43684 - 43691. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
