How pioglitazone affects glucose and lipid metabolism

The two primary perturbations resulting in hyperglycaemia in type 2 diabete s are insulin resistance and insulin deficiency. Insulin resistance occurs in peripheral organs (muscle and fat) leading to decreased glucose uptake a nd utilisation and in liver leading to increased hepatic glucose production . Thiazolidinediones, synthetic ligands for peroxisome proliferator-activat ed receptor gamma (PPAR gamma) can modulate the expression of genes influen cing carbohydrate and lipid metabolism. Pioglitazone, a recently introduced thiazolidinedione, improves glycaemic control and lipid profiles in people with type 2 diabetes. Some of the possible mechanisms of improving glycaem ic control include increases in glucose transporters 1 and 4, enhancement o f insulin signalling, decrease in tumour necrosis factor-alpha, reduction o f plasma free fatty acid, and decrease in phosphoenolpyruvate carboxykinase . Together, these can increase glucose uptake and utilisation in the periph eral organs and decrease gluconeogenesis in the liver. Possible mechanisms resulting in more desirable lipid profiles include an increase in phosphodi esterase 3B, resulting in reduced intracellular lipolysis in adipocytes, an d an increase in lipoprotein lipase resulting in enhanced clearance of trig lyceride-rich lipoproteins. In brief, pioglitazone reduces hepatic and peri pheral insulin resistance.