Islet amyloid polypeptide (IAPP), a novel peptide isolated from islet amyloid deposits in patients with insulinoma and non-insulin-dependent diabetes mellitus (NIDDM), has been reported to be cosecreted with insulin from pancreatic β cells and to inhibit glucose uptake and glycogen synthesis in muscle tissue in vitro. We investigated the effects of the synthesized, rat-amidated form of IAPP on hepatic glucose output, and IAPP extraction, using an in situ flow-through perfusion system in rats to elucidate the actions of IAPP on the liver. The IAPP (10 −8 mol/L) alone had no effects on the hepatic glucose release. Infusion of 6 × 10 −11 mol/L glucagon alone resulted in an expected elevation in glucose production ( 30.0 ± 1.7 μmol 35 min g liver ). Insulin (3 × 10 −10 mol/L) submaximally decreased the glucagon-stimulated glucose production to 73% ( from 30.0 ± 1.7 to 22.0 ± 1.4 μmol 35 min g liver ; n = 7, P < .01). A simultaneous infusion of 10 −8 mol/L IAPP did not influence the glucagon-stimulated glucose production ( 27.6 ± 1.2 μmol 35 min g liver ) or the insulin-dependent inhibition of glucagon-stimulated glucose production ( 22.6 ± 1.3 μmol 35 min g liver ). IAPP extraction by the liver in a single passage was minimal, in contrast to approximately 50% hepatic insulin extraction. These results indicate that IAPP does not play any important role in modulating glycogen metabolism in the liver.