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Thiazolidinedione ligand dependent transactivation is responsible for the majority of anti-diabetic effects. The activated PPAR/RXR heterodimer binds to peroxisome proliferator hormone response elements upstream of target genes in complex with a number of coactivators such as nuclear receptor coactivator 1 and CREB binding protein, this causes upregulation of genes (for a full list see PPARγ):
It is in the thiazolidinedione (TZD) class and works by improving sensitivity of tissues to insulin. [3] Pioglitazone was patented in 1985, and came into medical use in 1999. [5] It is available as a generic medication. [3] In 2022, it was the 120th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
Drugs used in diabetes treat types of diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin , most GLP-1 receptor agonists ( liraglutide , exenatide , and others), and pramlintide , all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents.
PPARγ (gamma) is the main target of the drug class of thiazolidinediones (TZDs), used in diabetes mellitus and other diseases that feature insulin resistance. It is also mildly activated by certain NSAIDs (such as ibuprofen) and indoles, as well as from a number of natural compounds. Known inhibitors include the experimental agent GW-9662.
Useful thiazolidines include the drug pioglitazone, the antibiotic penicillin, and N-Methyl-2-thiazolidinethione, an accelerator for the vulcanization of chloroprene rubbers. [4] Thiazolidines functionalized with carbonyls at the 2 and 4 positions, the thiazolidinediones, are drugs used in the treatment of diabetes mellitus type 2.
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