Pharmacological regulation of hepatic glucose production.
The discovery of antidiabetic agents that inhibit hepatic glucose production is a popular and potentially fruitful research area for the pharmaceutical research community. Metformin, a marketed agent with this mechanism of action, is widely used for the treatment of type 2 diabetes, however, more efficacious agents are sought. A number of promising proteins are being targeted for modulation by new compounds, including the glucagon receptor, glycogen phosphorylase, glucocorticoid receptor, 11 beta-hydroxysteroid dehydrogenase-1, fructose-1,6-bisphosphatase, carnitine palmitoyltransferase-1, glycogen synthase kinase-3, glucose-6-phosphate T1 translocase and the A2B receptor. Compounds designed to work against these targets are at the early clinical or preclinical phase of study. Glucagon receptor antagonists, glycogen phosphorylase inhibitors, 11 beta-hydroxysteroid dehydrogenase-1 inhibitors, carnitine palmitoyltransferase-1 inhibitors and fructose-1,6-bisphosphatase inhibitors are, or have been, clinically evaluated. Preclinical studies against the other targets have yielded compounds that demonstrate efficacy in diabetic animal models and clinical activity will continue.
Link
James T
JT
Abbott Laboratories, 100 Abbott Park Road, IL 60064-6098, USA. james.link@abbott.com
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000096:biosynthesis*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008112:Liver Glycogen / Q000096:biosynthesis; D008687:Metformin / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D008112:Liver Glycogen; D058915:Purinergic P1 Receptor Antagonists; D018027:Receptors, Glucagon; D011965:Receptors, Glucocorticoid; D008687:Metformin; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002334:Carnitine O-Palmitoyltransferase; D024981:Glycogen Phosphorylase; D038362:Glycogen Synthase Kinase 3; D006597:Fructose-Bisphosphatase; D005947:Glucose