Excerpt
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors (subtypes so far identified: PPARγ, PPARα. and PPARδ) which act as transcription factors regulating a large number of genes involved in glucose and lipid metabolism [
1]. Agents that bind to and activate PPARs are in clinical use or development for the treatment of hyperglycaemia (PPARγ agonists), hypertriglyceridaemia (PPARα agonists) or both (dual and pan PPAR agonists). PPARγ agonists include both thiazolidinedione and non-thiazolidinedione compounds of varying specificity and affinity, and fibrates are typical PPARα agonists. Of the two thiazolidinediones currently on the market, rosiglitazone is a more specific and potent PPARγ agonist than pioglitazone, which also displays some PPARα agonist activity [
2]. Both agents enhance the sensitivity of glucose metabolism to insulin in patients with type 2 diabetes, thereby lowering plasma glucose concentrations within a few weeks of treatment. Studies with the euglycaemic–hyperinsulinaemic clamp have shown that both agents increase insulin-mediated glucose uptake at the whole-body level, and that this mostly reflects skeletal muscle glucose uptake [
3]. A recent study of rosiglitazone, which combined the clamp technique with
18F-deoxyglucose and positron-emitting tomography, also showed enhanced glucose uptake in both the visceral and subcutaneous adipose tissue of diabetic patients [
4]. Long-term use of both thiazolidinediones is associated with decreased abdominal visceral adipose tissue mass and weight gain due to an expansion of the subcutaneous fat mass [
3]. PPARγ expression is abundant in adipose tissue and scanty in skeletal muscle [
1], and the paradox that agents which target receptors mainly expressed in adipose tissue have their major effect upon the insulin sensitivity of skeletal muscle has required a lot of explanation. Many experts believe that the sequence of events starts with differentiation of pre-adipocytes into mature, small, insulin-sensitive adipocytes, which are more active in clearing NEFA from the circulation; the resulting decrease in plasma NEFA reduces competition with glucose for uptake by skeletal muscle, thereby enhancing insulin-mediated glucose uptake [
3]. However, this simple model lacks empirical support, given that the reduction of circulating NEFA by thiazolidinediones has been minimal or absent in several human studies. A report by Tan and colleagues in this issue of
Diabetologia [
5] sets forth to test, indeed to challenge, this paradigm. …