CONDITIONAL, TISSUE-SPECIFIC EXPRESSION OF Q205L G(ALPHA-I2) IN-VIVO MIMICS INSULIN ACTION

Deficiency of the G protein subunit G(alpha i2) that is known to media te the inhibitory control of adenylylcyclase impairs insulin action [1 1]. Using the promoter for the phosphoenolpyruvate carboxykinase gene, conditional, tissue-specific expression of the constitutively active mutant form (Q205L) of G(alpha i2) was achieved in mice harboring the transgene. Expression of Q205L G(alpha i2) was detected in liver and a dipose tissue of transgenic mice. Whereas the G(alpha i2) deficient mi ce displayed blunted glucose tolerance, the Q205L G(alpha i2) expressi ng mice displayed enhanced glucose tolerance. Hexose transport and the recruitment of GLUT4, but not GLUT1, transporters to the membrane wer e elevated in adipocytes from Q205L G(alpha i2) expressing mice in the absence of insulin. Additionally, hepatic glycogen synthase was found to be activated in Q205L G(alpha i2) expressing mice, in the absence of the administration of insulin. Serum insulin levels in transgenic m ice fasted overnight were equivalent to those of their control litterm ates. These data demonstrate that much as G(alpha i2) deficiency leads to insulin resistance, expression of Q205L constitutively active G(al pha i2) mimics insulin action in vivo, reflecting a permissive role of G(alpha i2) in signaling via this growth factor receptor tyrosine kin ase linked pathway.