Muscle insulin resistance may not be a primary etiological factor in the genetically obese fa/fa rat

It is not known whether hyperinsulinemia of the genetically obese fa/fa rat occurs before insulin resistance and abnormal glucose handling or vice versa. Therefore, it was decided to study, as a function of age, the evolution of the insulin-stimulated glucose uptake measuring the in vitro uptake of its analog, 2-deoxy-D-glucose (2DG), by diaphragm. The expression of the insulin-sensitive glucose transporter (GLUT 4) mRNA and protein were also investigated in muscles. The maximum increase over baseline in 2DG uptake in response to increasing insulin concentrations in the medium was upward shifted in diaphragm from preweaned 21-day-old preobese rats relative to that in lean controls (increased responsiveness). By 31 days of age the maximum increase over baseline diaphragm 2DG uptake in response to insulin was similar in young lean and obese rats. At 70 days of age, the 2DG uptake muscle dose response to insulin was significantly downward shifted, i.e. clearly insulin resistant (decreased responsiveness). Muscle (diaphragm and extensor digitorum longus) expression of GLUT 4 mRNA and protein revealed no intergroup difference at any of the ages studied. Hyperinsulinemia was moderate in preobese animals and progressively increased with the duration of the obesity syndrome. Based on the observation that diaphragm glucose uptake of 21-day-old preobese rats was overresponsive to insulin, normoinsulin responsive at 31 days, and insulin resistant at a later time, it is concluded that muscle insulin resistance is not a primary etiological defect, but must be secondary to other pathological alterations, the nature of which remains to be elucidated.