slets of Langerhans is biphasic; the first and better understood phase is completely lost in diabetic patients while the second is severely impaired. The first phase is largely dependent on ATP sensitive potassium channels (K_ATP). In normal individuals, glucose is rapidly taken up by the beta cells and metabolized. The resulting increase in ATP concentration triggers closure of K_ATP channels leading to membrane depolarization and opening of voltage-gated calcium channels. The increase in calcium concentration induces fusion of the insulin-granules with the plasma membrane and SNARE-mediated insulin exocytosis. Insulin binding to its receptor sets in motion the insulin pathway which in turn, activates downstream signaling pathways to regulate glucose transport, insulin expression and a range of other gene expression and cellular events. Nateglinide and repaglinide are two drugs used as blockers of the (K_ATP) channels to promote insulin secretion and lower blood glucose levels in T2D patients. The drugs are loosely categorized as members of the meglitinide family by virtue of functional rather than structural relationships. Meglitinide is the non-sulfonylurea portion of glibenclamide molecule - the regulatory subunits of K_ATP channel are receptors for sulfonylureas. Repaglinide is the benzoic acid derivative of meglitinide; nateglinide is a D-phenylalanine derivative. The drugs have similar pharmacodynamic profiles with some differences in the interaction with and the effect upon the K_ATP channels. In humans, they share common pharmacokinetic characteristics but they appear to be substrates for distinct members of the cytochrome P450 superfamily of phase I metabolizing enzymes. There are 51 families of the cytochrome P450 superfamily. Families 1 to 3, responsible for the metabolism of most drugs and many xenobiotics, have low substrate specificity and have not been well preserved during evolution. The drugs appear to be metabolized in a species-specific manner. Polymorphisms in some of the genes can affect the metabolism of drugs in patients carrying the defective alleles. The drugs have been administered alone as well as in combination with other drugs and appear to be safe for patients with renal impairment. [Click here to browse drug pathways listed by categories at PharmGKB; anti-diabetic pathways are under ‘Alimentary Tract and Metabolism’]...(less)