Dual acting and pan-PPAR activators as potential anti-diabetic therapies

Abstract

The thiazolidinedione PPAR-γ activator drugs rosiglitazone and pioglitazone suppress insulin resistance in type 2 diabetic patients. They lock lipids into adipose tissue triglyceride stores, thereby preventing lipid metabolites from causing insulin resistance in liver and skeletal muscle and β-cell failure. They also reduce the secretion of inflammatory cytokines such as TNFɑ and increase the plasma level of adiponectin, which increases insulin sensitivity in liver and skeletal muscle. However, they have only a modest effect on dyslipidaemia, and they increase fat mass and plasma volume. Fibrate PPAR-ɑ activator drugs decrease plasma triglycerides and increase HDL-cholesterol levels. PPAR-δ activators increase the capacity for fat oxidation in skeletal muscle. Clinical experiencewith bezafibrate, which activates PPAR-δ and -ɑ, and studies on the PPAR-ɑ/δ activator tetradecylthioacetic acid, the PPAR-δ activatorGW501516, and combinations of the PPAR-ɑ activator fenofibrate with rosiglitazone or pioglitazone have encouraged attempts to develop single molecules that activate two or all three PPARs.Most effort has focussed on dual PPAR-ɑ/γ activators. These reduce both hyperglycaemia and dyslipidaemia, but their development has been terminated by issues such as increased weight gain, oedema, plasma creatinine and myocardial infarction or stroke. In addition, the FDA has stated that many PPAR ligands submitted to it have caused increased numbers of tumours in carcinogenicity studies. Rather than aiming for full potent agonists, it may be best to identify subtypeselective partial agonists or compounds that selectively activate PPAR signalling pathways and use these in combination. Nutrients or modified lipids that are lowaffinity agonists may also have potential.