[Mechanisms of action of thiazolidinediones].
The recent discovery and marketing of a new class of antidiabetic drug improving insulin sensitivity, the thiazolidinediones (TZD), has opened interesting therapeutic perspectives. Those molecules correct hyperglycemia and hyperinsulinemia in several animal models of NIDDM. Clinical studies in human have confirmed that TZD lowered postprandial and postabsorptive glycemia and insulinemia. Glucose clamp studies have clearly shown an improvement of insulin-induced glucose utilization (in skeletal muscle). In contrast, the inhibition of glucose production in response to insulin was much less reproducible. TZD have also been used with success to treat insulin resistance in non-diabetic obeses, in glucose-intolerant prediabetic subjects and in patients with polycystic ovary syndrome (pcos). Nevertheless, TZD appears less efficient in human than in animal models. TZD bind to an isoform of a nuclear receptor, the PPARgamma (Peroxisome Proliferator Activated Receptor). PPAR gamma is a transcription factor which, after heterodimerization with the retinoid receptor (RXR), bind to specific response elements of a number of target genes and control their transcription. There is an excellent correlation between the hypoglycemic effects of TZD in vivo and their affinity for PPARgamma in vitro, but the site of action and the molecular mechanism of TZD still remain poorly known. In human, skeletal muscles are responsible for more than 80% of glucose uptake in response to insulin. Unfortunately, skeletal muscles contain limited amounts of PPAR gamma. How TZD with the principal site of action being adipose tissue, can improve glucose metabolism in skeletal muscle? One possibility is the following Another possibility is that chronic treatment with TZD induces PPAR gamma expression in skeletal muscles. Finally, TZD could have a direct effect on skeletal muscles, independently of PPARgamma.
Girard
J
J
Centre de Recherche sur l'Endocrinologie, Moleculaire et le developpement, UPR 524 CNRS, 9, rue Jules Hetzel, 92190 Meudon, France.
D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance; D018482:Muscle, Skeletal / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014157:Transcription Factors; D005947:Glucose