The role of epinephrine in the acute caffeine-induced glucose intolerance in humans

This thesis examined the role of epinephrine in the acute caffeine-induced decrease in whole body insulin-mediated glucose disposal in humans. In Study 1, epinephrine was infused at a rate pre-determined to achieve a similar plasma epinephrine concentration known to accompany the ingestion of 5 mg/kg caffeine (0.6 nM). This level of epinephrine did not induce an independent reduction in whole body insulin-mediated glucose disposal suggesting that caffeine decreases glucose disposal via an epinephrine-independent mechanism. Furthermore, the role of the liver (i.e. hepatic endogenous glucose production) in the caffeine-induced reduction in glucose disposal was assessed and determined not to be a contributing factor in the caffeine effect. In Study 2, caffeine ingestion in persons with tetraplegia did not result in an impairment of glucose tolerance. This lack of effect could be partially attributed to the fact that caffeine ingestion did not result in a characteristic rise in plasma epinephrine concentrations within this population and suggests a role for epinephrine in caffeine's effects. To clarify the contrasting findings of Study 1 and 2, Study 3 assessed the effects of caffeine and epinephrine in concert on whole body glucose disposal. Although not fully additive the reduction in glucose disposal by the combined caffeine and epinephrine treatment was more pronounced than either treatment alone suggesting a closely related mechanism by which epinephrine and caffeine impair insulin action. Furthermore, despite a 50% lower epinephrine concentration during the caffeine trial, both caffeine and epinephrine independently resulted in similar reductions in whole body insulin-mediated glucose disposal (26 and 24% respectively) confirming the results of Study 1 that caffeine elicits epinephrine-independent effects on glucose metabolism. Taken together, these results suggest that while epinephrine is necessary to observe a caffeine-induced reduction in glucose tolerance, it does not account solely for all of the caffeine effect and other mechanism(s) must be involved. Due to the lack of a fully additive response when caffeine and epinephrine are administered simultaneously, it is likely the both epinephrine and the other mechanism (i.e. adenosine receptor antagonism) elicit their effects via closely related mechanisms which ultimately result in a decrease in skeletal muscle insulin-mediated glucose disposal.