Methylxanthines and human health: epidemiological and experimental evidence.

When considering methylxanthines and human health, it must be recognized that in many countries most caffeine is consumed as coffee. This is further confounded by the fact that coffee contains many bioactive substances in addition to caffeine; it is rich in phenols (quinides, chlorogenic acid, and lactones) and also has diterpenes (fatty acid esters), potassium, niacin, magnesium, and the vitamin B(3) precursor trigonelline. There is a paradox as consumption of either caffeine or caffeinated coffee results in a marked insulin resistance and yet habitual coffee consumption has repeatedly been reported to markedly reduce the risk for type 2 diabetes. There is strong evidence that caffeine reduces insulin sensitivity in skeletal muscle and this may be due to a combination of direct antagonism of A(1) receptors and indirectly β-adrenergic stimulation as a result of increased sympathetic activity. Caffeine may also induce reduced hepatic glucose output. With the exception of bone mineral, there is little evidence that caffeine impacts negatively on other health issues. Coffee does not increase the risk of cardiovascular diseases or cancers and there is some evidence suggesting a positive relationship for the former and for some cancers, particularly hepatic cancer.