Increased amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals

We have recently demonstrated that insulin activates farnesyltransferase (F Tase) and thereby increases the amounts of cellular farnesylated p21Ras in 3T3-L1 fibroblasts, adipocytes and vascular smooth muscle cells. We postula ted that hyperinsulinaemia might considerably increase the the cellular poo l of farnesylated p21Ras available for activation by other growth factors. To examine the role of in vivo hyperinsulinaemia in regulating farnesylated p21Ras, we measured the amounts of farnesylated p21Ras in tissues of hyper insulinaemic animals. Liver, aorta. and skeletal muscle of ob/ob mice, and mice made obese and hyperinsulinaemic by injection of gold-thioglucose cont ained greater amounts of farnesylated p21Ras than tissues of their lean nor moinsulinaemic counterparts. Similarly, farnesylated p21Ras was increased ( 67 vs 35 % in control animals, p < 0.01) in the livers of hyperinsulinaemic Zucker rats (fa/fa). Reduction of hyperinsulinaemia by exercise training ( 2 h/day for 7-8 weeks) resulted in decreases in the amounts of farnesylated p21Ras in these animals, increased farnesylated p21Ras in hyperinsulinaemi c animals reflected increasing increments in the activity of FTase in ob/ob mice (2-fold increase) and fa/fa Zucker rats (3.5-fold increase), while th e total amounts of Ras proteins remained unchanged. In contrast to insulin- resistant hyperinsulinaemic animals, denervated insulin-resistant rat soleu s muscle tin the presence of normoinsulinaemia) showed normal amounts of fa rnesylated p21Ras. In summary, these data confirm increased amounts of farn esylated p21Ras in tissues of hyperinsulinaemic animals.