DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells

The increased availability of saturated lipids has been correlated with dev elopment of insulin resistance, although the basis for this impairment is n ot defined. This work examined the interaction of saturated and unsaturated fatty acids (FA) with insulin stimulation of glucose uptake and its relati on to the FA incorporation into different lipid pools in cultured human mus cle. It is shown that basal or insulin-stimulated 2-deoxy-glucose uptake wa s unaltered in cells preincubated with oleate, whereas basal glucose uptake was increased and insulin response was impaired in palmitate- and stearate -loaded cells. Analysis of the incorporation of FA into different lipid poo ls showed that palmitate, stearate, and oleate were similarly incorporated into phospholipids (PL) and did not modify the FA profile. In contrast, dif ferences were observed in the total incorporation of FA into triacylglyceri des (TAG): unsaturated FA were readily diverted toward TAG, whereas saturat ed FA could accumulate as diacylglycerol (DAG). Treatment with palmitate in creased the activity of membrane-associated protein kinase C, whereas oleat e had no effect. Mixture of palmitate with oleate diverted the saturated FA toward TAG and abolished its effect on glucose uptake. In conclusion, our data indicate that saturated FA-promoted changes in basal glucose uptake an d insulin response were not correlated to a modification of the FA profile in PL or TAG accumulation. In contrast, these changes were related to satur ated FA being accumulated as DAG and activating protein kinase C. Therefore , our results suggest that accumulation of DAG may be a molecular link betw een an increased availability of saturated FA and the induction of insulin resistance.