CARDIAC AND ADIPOSE-TISSUE ABNORMALITIES BUT NOT DIABETES IN MICE DEFICIENT IN GLUT4

THE insulin-sensitive glucose transporter, GLUT4, is the most abundant facilitative glucose transporter in muscle and adipose tissue, the ma jor sites for postprandial glucose disposal, To assess the role of GLU T4 in glucose homeostasis, we have disrupted the murine GLUT4 gene. Be cause GLUT4 has been shown to be dysregulated in pathological states s uch as diabetes and obesity, it was expected that genetic ablation of GLUT4 would result in abnormal glucose homeostasis, The mice deficient in GLUT4 (GLUT4-null) are growth-retarded and exhibit decreased longe vity associated with cardiac hypertrophy and severely reduced adipose tissue deposits, Blood glucose levels in female GLUT4-null mice are no t significantly elevated in either the fasting or fed state; in contra st, male GLUT4-null mice have moderately reduced glycaemias in the fas ted state and increased glycaemias in the fed state, However, both fem ale and male GLUT4-null mice exhibit postprandial hyperinsulinaemia, i ndicating possible insulin resistance. Increased expression of other g lucose transporters is observed in the liver (GLUT2) and heart (GLUT1) but not skeletal muscle. Oral glucose tolerance tests show that both female and male GLUT4-null mice clear glucose as efficiently as contro ls, but insulin tolerance tests indicate that these mice are less sens itive to insulin action, The GLUT4-null mice demonstrate that function al GLUT4 protein is not required for maintaining nearly normal glycaem ia but that GLUT4 is absolutely essential for sustained growth, normal cellular glucose and fat metabolism, and expected longevity.