Central role of the adipocyte in the insulin-sensitising and cardiovascular risk modifying actions of the thiazolidinediones.

Insulin resistance is a key metabolic defect in type 2 diabetes that is exacerbated by obesity, especially if the excess adiposity is located intra-abdominally/centrally. Insulin resistance underpins many metabolic abnormalities-collectively known as the insulin resistance syndrome-that accelerate the development of cardiovascular disease. Thiazolidinedione anti-diabetic agents improve glycaemic control by activating the nuclear receptor peroxisome proliferator activated receptor-gamma (PPARgamma). This receptor is highly expressed in adipose tissues. In insulin resistant fat depots, thiazolidinediones increase pre-adipocyte differentiation and oppose the actions of pro-inflammatory cytokines such as tumour necrosis factor-alpha. The metabolic consequences are enhanced insulin signalling, resulting in increased glucose uptake and lipid storage coupled with reduced release of free fatty acids (FFA) into the circulation. Metabolic effects of PPARgamma activation are depot specific-in people with type 2 diabetes central fat mass is reduced and subcutaneous depots are increased. Thiazolidinediones increase insulin sensitivity in liver and skeletal muscle as well as in fat, but they do not express high levels of PPARgamma, suggesting that improvement in insulin action is indirect. Reduced FFA availability from adipose tissues to liver and skeletal muscle is a pivotal component of the insulin-sensitising mechanism in these latter two tissues. Adipocytes secrete multiple proteins that may both regulate insulin signalling and impact on abnormalities of the insulin resistance syndrome--this may explain the link between central obesity and cardiovascular disease. Of these proteins, low plasma adiponectin is associated with insulin resistance and atherosclerosis--thiazolidinediones increase adipocyte adiponectin production. Like FFA, adiponectin is probably an important signalling molecule regulating insulin sensitivity in muscle and liver. Adipocyte production of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, and angiotensin II secretion are partially corrected by PPARgamma activation. The favourable modification of adipocyte-derived cardiovascular risk factors by thiazolidinediones suggests that these agents may reduce cardiovascular disease as well as provide durable glycaemic control in type 2 diabetes.