Mechanisms and clinical effects of thiazolidinediones.
Studies of pioglitazone, troglitazone, BRL 49653 and other thiazolidinediones in preclinical animal models of non-insulin dependent diabetes mellitus (NIDDM) and obesity led to the observation that these compounds were effective in reducing hyperglycaemia and hyperlipidaemia. In these models, animals treated with thiazolidinediones had notable improvements in blood glucose levels, hepatic glucose output, peripheral insulin resistance, and serum lipid levels. Mechanistic studies indicate that thiazolidinediones act at many intracellular sites and can influence several processes to increase cell sensitivity to insulin. These include influence on insulin receptor kinase activity, control of insulin receptor phosphorylation, change in number of insulin receptors, quantity and activity of GLUT-4, modulation of tumour necrosis factor (TNF) activity, activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and alteration of hepatic glucose metabolism. Available data on pioglitazone and troglitazone from clinical studies support the efficacy and safety of this class of compounds in reducing hyperglycaemia, hypertriglyceridaemia and insulin resistance associated with NIDDM. Currently, only troglitazone is approved for use in the United States and only in combination with insulin. This new pharmacological class of drugs has great promise for the treatment of NIDDM and also as a valuable research tool to further the understanding of the mechanisms that underlie NIDDM and insulin resistance syndrome.
Takeda America, Inc., 101 Carnegie Center, Suite 207, Princeton, NJ 08540, USA.
S L
SL
Grossman
J
J
Lessem