ELEVATED PROTEIN-TYROSINE-PHOSPHATASE ACTIVITY AND INCREASED MEMBRANEVISCOSITY ARE ASSOCIATED WITH IMPAIRED ACTIVATION OF THE INSULIN-RECEPTOR KINASE IN OLD RATS

Insulin resistance is very common in the elderly, and may be associate d with glucose intolerance or frank diabetes. In previous studies we d emonstrated that insulin resistance in old Wistar rats is associated w ith decreased autophosphorylation and activation of the hepatic insuli n receptor kinase (IRK) in vivo. We now show that this defect can be r eproduced in vitro, where the extent of insulin-induced activation of IRK in liver membranes of old rats was decreased by similar to 50% com pared with young controls. The defect could be largely abolished after solubilization of the membranes with Triton X-100. We also show that: (a) the viscosity of membranes from the old rats was significantly (P < 0.001, n = 4) higher (by 15%) compared with young controls; (b) inc ubation of plasma membranes from old animals with lecithin liposomes, which lowered their cholesterol levels, partially abolished the defect in IRK activation; and (c) Triton extracts of liver membranes prepare d from old rats did not interfere with the activation of IRK derived f rom young controls. Additionally, non-membrane components did contribu te to the development of this defect. We observed a significant (simil ar to 30%) (P < 0.001, n = 18) elevation of cytosolic protein tyrosine phosphatase (PTP) activity directed against the P subunit of the insu lin receptor in livers of old rats. No such elevation of PTP activity could be demonstrated with synthetic substrates. Our findings are cons istent with a model in which increased membrane viscosity as well as e nhancement of a cytosolic PTP activity both markedly inhibit the activ ation in vivo of the hepatic IRK in old animals.