TRANSGENIC MICE EXPRESSING THE HUMAN GLUT4 MUSCLE FAT FACILITATIVE GLUCOSE-TRANSPORTER PROTEIN EXHIBIT EFFICIENT GLYCEMIC CONTROL

To examine the physiological role of the GLUT4/muscle-fat specific fac ilitative glucose transporter in regulating glucose homeostasis, we ha ve generated transgenic mice expressing high levels of this protein in an appropriate tissue-specific manner. Examination of two independent founder lines demonstrated that high-level expression of GLUT4 protei n resulted in a marked reduction of fasting glucose levels (almost-equ al-to 70 mg/dl) compared to wild-type mice (almost-equal-to 130 mg/dl) . Surprisingly, 30 min following an oral glucose challenge the GLUT4 t ransgenic mice had only a slight elevation in plasma glucose levels (a lmost-equal-to 90 mg/dl), whereas wild-type mice displayed a typical 2 - to 3-fold increase (almost-equal-to 250-300 mg/dl). In parallel to t he changes in plasma glucose, insulin levels were almost-equal-to 2-fo ld lower in the transgenic mice compared to the wild-type mice. Furthe rmore, isolated adipocytes from the GLUT4 transgenic mice had increase d basal glucose uptake and subcellular fractionation indicated elevate d levels of cell surface-associated GLUT4 protein. Consistent with the se results, in situ immunocytochemical localization of GLUT4 protein i n adipocytes and cardiac myocytes indicated a marked increase in plasm a membrane-associated GLUT4 protein in the basal state. Taken together these data demonstrate that increased expression of the human GLUT4 g ene in vivo results in a constitutively high level of cell surface GLU T4 protein expression and more efficient metabolic control over fluctu ations in plasma glucose concentrations.