Amylin and calcitonin gene-related peptide (CGRP) were each shown to stimulate endogenous glucose production in vivo in rats. Neither peptide had any effect on any of several measures of intermediary carbohydrate metabolism in isolated hepatocytes or isolated perfused liver in rats. The possibility exists that augmentation of endogenous glucose production was secondary to release of lactate from muscle into the plasma, thereby stimulating gluconeogenesis by increasing the availability of substrate. Results from hyperlactemic clamp preparations, which allowed for direct measurement of such an effect, suggested that there were additional mechanisms that accounted for amylin stimulation of endogenous glucose production in rats. There is no evidence that amylin increases endogenous glucose production in humans.