SULFONYLUREA THERAPY IMPROVES GLUCOSE DISPOSAL WITHOUT CHANGING SKELETAL-MUSCLE GLUT4 LEVELS IN NONINSULIN-DEPENDENT DIABETES-MELLITUS SUBJECTS - A LONGITUDINAL-STUDY

A major pathological feature of noninsulin-dependent diabetes (NIDDM) is defective insulin-stimulated glucose transport in skeletal muscle. When NIDDM subjects are assessed as a group, GLUT4 gene expression in skeletal muscle varies widely and is not different from that in contro ls. Thus, longitudinal studies are needed to assess whether changes in GLUT4 expression in muscle of NIDDM subjects could be responsible for changes in glucose disposal. The question is timely because recent st udies in transgenic mice show that increasing GLUT4 expression can inc rease insulin-stimulated glucose uptake in vivo and in vitro. Here we use a longitudinal design to investigate the effects of 8 weeks of the rapy with the sulfonylurea gliclazide on glycemic control, glucose tol erance, insulin-stimulated glucose disposal, and GLUT4 expression in m uscle of 10 obese NIDDM subjects. Subjects were on a weight-maintainin g diet. Gliclazide treatment results in increased serum C-peptide, dec reased hemoglobin-A(1c), decreased glucose excursion on glucose tolera nce test, and 35% increased insulin-stimulated glucose disposal. Glicl azide therapy is not associated with any change in DNA or protein cont ent per g muscle or any alteration in GLUT4 levels expressed either pe r mu g membrane protein or per DNA. In summary, the improvement in gly cemic control and glucose disposal in NIDDM subjects receiving gliclaz ide therapy cannot be explained by increased expression of GLUT4 in mu scle. Thus, therapeutic effects on insulin-stimulated glucose disposal can be achieved in NIDDM subjects without altering GLUT4 expression i n muscle.