Children with left-to-right shunt, with and without congestive heart failure, were found to have impaired glucose tolerance tests (GTT). In cyanotic children normal levels of glucose were found in association with abnormally high levels of insulin following oral GTT. Several possible mechanisms are proposed to explain the different glucose tolerance alterations: (1) Suppression of insulin release appeared to partially explain the low levels of insulin in congestive heart failure. This suppression may be related to the high levels of circulating norepinephrine found in these patients. (2) Excessive clearance of insulin by the lung may also be responsible for the reduced arterial insulin levels in patients with left-to-right shunt, and underclearance of insulin for the abnormally higher arterial insulin levels in patients with right-to-left shunts in whom a significant amount of venous blood has bypassed the lung. (3) Hypoxia of the pancreas and the liver in cyanotic patients and those with congestive heart failure may explain the reduction of insulin levels in the hepatic vein following i.v. glucose tolerance tests. An excess production of a glucagonlike gastrointestinal factor in cyanotic children may partially explain the abnormally high levels of insulin following oral GTT.