Effect of the nicotine metabolite 5'-hydroxycotinine on glucose transport and glycogen synthase activity in rat skeletal muscle

Cigarette smoke contains many potentially harmful substances, including nicotine and nicotine metabolites, which are likely to contribute to altered glucose homeostasis. We determined the effects of nicotine and nicotine derivatives on glucose transport in skeletal muscle. Split rat soleus muscles were pre-incubated in the presence of nicotine (range 0.01–100 µg/ml) or nicotine metabolites including nicotine 1'-N-oxide, cotinine, trans-3'-hydroxycotinine, 5'-hydroxycotinine, γ-3-pyridyl-γ-oxo-butyric acid and nicotine iminium ion before measurement of 3-O-methylglucose transport rate and glycogen synthase activity. Nicotine (100 µg/ml) did not alter basal 3-O-methylglucose transport. Insulin-stimulated (0.6 nmol/l) glucose transport was unaltered following acute (50 min) exposure to nicotine (0.01–100 µg/ml). The nicotine metabolite 5'-hydroxycotinine increased basal glucose transport and glycogen synthase activity (up to 50%; P<0.05), with no effect on insulin-stimulated glucose transport and glycogen synthase activity. None of the other nicotine metabolites had any effect on basal or insulin-stimulated glucose transport. Acute exposure of skeletal muscle to the nicotine derivative 5'-hydroxycotinine appears to directly increase basal glucose transport and metabolism. Whether this leads to changes in whole-body glucose homeostasis in cigarette smokers requires further investigation.