INSULIN-INDUCED ACTIVATION OF GLYCEROL-3-PHOSPHATE ACYLTRANSFERASE BYA CHIRO-INOSITOL-CONTAINING INSULIN MEDIATOR IS DEFECTIVE IN ADIPOCYTES OF INSULIN-RESISTANT, TYPE-II DIABETIC, GOTO-KAKIZAKI RATS

Type II diabetic Goto-Kakizaki (GK) rats were insulin-resistant in eug lycemic-hyperinsulinemic damp studies. We therefore examined insulin s ignaling systems in control Wistar and diabetic GK rats. Glycerol-3-ph osphate acyltransferase (G3PAT), which is activated by headgroup media tors released from glycosyl-phosphatidylinositol (GPI), was activated by insulin in intact and cell-free adipocyte preparations of control, but not diabetic, rats. A specific chiro-inositol-containing inositol phosphoglycan (IPG) mediator, prepared from beef liver, bypassed this defect and comparably activated G3PAT in cell-free adipocyte preparati ons of both diabetic GK and control rats. A myo inositol-containing IP G mediator did not activate G3PAT. Relative to control adipocytes, lab eling of GPI by [H-3]glucosamine was diminished by 50% and insulin fai led to stimulate GPI hydrolysis in GK adipocytes. In contrast to GPI-d ependent G3PAT activation, insulin-stimulated hexose transport was int act in adipocytes and soleus and gastrocnemius muscles of the GK rat, as was insulin-induced activation of mitogen-activated protein kinase and protein kinase C. We conclude that (i) chiro-inositol-containing I PG mediator activates G3PAT during insulin action, (ii) diabetic GK ra ts have a defect in synthesizing or releasing functional chiro-inosito l-containing IPG, and (iii) defective IPG-regulated intracellular gluc ose metabolism contributes importantly to insulin resistance in diabet ic GK rats.