It was shown that the liver is not the major site of removal of glucose after a carbohydrate meal in man. Fractional extractions varied from 5 to 10%. Alternative substrates for postprandial hepatic glycogen synthesis were therefore sought. It was demonstrated than, in man, about 60% of hepatic glycogen was formed from gluconeogenetic substrates. Since significant excursions occur only in plasma lactate after glucose loading, this was deemed the most likely substrate under these circumstances. By differential sampling across the liver and the gut in a conscious pig model, it was found that the liver takes up enough lactate (fractional extraction of 40-50%) to account for the gluconeogenetic production of glycogen. Forty percent of this arises from the gut. Muscle (as represented by the forearm in man) does not contribute lactate during glucose loading, suggesting that other tissues such as the skin are of importance. The gluconeogenetic process may be an important site for the obligatory tissue production of lactate.