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Deficiency of Cbl-b gene causes glucose intolerance and peripheral insulin resistance in mice.  J. Goto,1 K. Hirasaka,1 H. Kiyoi,1 K. Hisada,1 H. Furochi,1 Y. Onishi,1 K. Ishidoh,2 Gu H.,4 N. Yasui,3 S. Takeda,5 K. Kishi,1 and T. Nikawa.1  1Department of Nutrition, The University of Tokushima School of Medicine, Tokushima; 2The Institute for Health Sciences, Tokushima Bunri University, Tokushima; 3Department of Orthopaedics, The University of Tokushima School of Medicine, Tokushima, Japan; 4Department of Microbiology, Columbia University, New York, NY, USA; 5National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

 c-Cbl plays an important role in whole-body fuel homeostasis by regulating insulin action.  In the present study, we examined the role of Cbl-b, another member of the Cbl family, in insulin action.  In elder Cbl-b-deficient mice (more than 20 weeks old), glucose intolerance and peripheral insulin resistance occurred, while the fasting blood glucose level was not changed.  Serum insulin concentration in elder Cbl-b-deficient mice was also higher than that in wild-type mice of the same age during fasting or after glucose injection.  Deficiency of Cbl-b gene significantly decreased the uptake of 2-deoxyglucose into the white adipose tissue, but not into the skeletal muscle.  In white adipose tissue of elder Cbl-b-deficient mice, insulin-stimulated phosphorylation of c-Cbl was significantly inhibited, whereas phosphorylation of Akt-1 by insulin stimulation occurred at the normal level.  To confirm the role of Cbl-b in insulin signaling finally, we overexpressed Cbl-b in CHO-IR-APS-CAP cells, which contained high amounts of insulin receptor, c-Cbl, APS and CAP, but not Cbl-b.  Overexpression of Cbl-b protein significantly increased the interaction with c-Cbl and its phosphorylation, leading to the increased glucose uptake into the cells.  Our present study suggests that Cbl-b plays an important role in insulin-stimulated glucose uptake in white adipose tissue, but not in skeletal muscle.  Thereby, deficiency of Cbl-b is considered to show characteristics of type II diabetes, such as glucose intolerance and insulin resistance.