Insulin Secretagogue: D-Phenylalanine Derivative

INSULIN SECRETAGOGUE: D-PHENYLALANINE DERIVATIVE

Nateglinide, aD-phenylalanine derivative, is the latest insulinsecretagogue to become clinically available. Nateglinide stimulates very rapid and transient release of insulin from beta cells through closure of the ATP-sensitive K⁺ channel. It also partially restores initial insulin release in response to an intravenous glucose toler-ance test. This may be a significant advantage of the drug because type 2 diabetes is associated with loss of this initial insulin response. The restoration of more normal insulin secretion may suppress glucagon release early in the meal and result in less endogenous or hepatic glucose production. Nateglinide may have a special role in the treatment of individuals with isolated post-prandial hyperglycemia, but it has minimal effect on overnight or fasting glucose levels. Nateglinide is efficacious when given alone or in combination with nonsecretagogue oral agents (such as met-formin). In contrast to other insulin secretagogues, dose titration is not required.

Nateglinide is ingested just before meals. It is absorbed within 20 minutes after oral administration with a time to peak concen-tration of less than 1 hour and is metabolized in the liver by CYP2C9 and CYP3A4 with a half-life of about 1 hour. The over-all duration of action is about 4 hours. Nateglinide amplifies the insulin secretory response to a glucose load, but it has a markedly diminished effect in the presence of normoglycemia. The incidence of hypoglycemia with nateglinide may be the lowest of all the secretagogues, and nateglinide has the advantage of being safe in those with very reduced renal function.