PPARγ (Peroxisome Proliferator-Activated Receptor Gamma) agonists are a class of drugs that activate the PPARγ receptor, which is a nuclear receptor involved in the regulation of genes responsible for glucose and lipid metabolism, insulin sensitivity, and inflammation. The mechanism of action of PPARγ agonists primarily involves:
- Activation of PPARγ Receptors: PPARγ agonists, such as thiazolidinediones (e.g., pioglitazone, rosiglitazone), bind to PPARγ receptors in adipose tissue, muscle, and the liver. These receptors form heterodimers with the retinoid X receptor (RXR) and bind to specific regions on DNA called PPAR response elements (PPREs).
- Gene Regulation: Upon activation, PPARγ-RXR complexes modulate the transcription of various genes involved in glucose and lipid metabolism. This leads to increased expression of genes that promote glucose uptake and storage (such as the GLUT4 transporter) and reduced expression of genes involved in free fatty acid release.
- Improvement of Insulin Sensitivity: PPARγ agonists enhance insulin sensitivity in peripheral tissues by promoting adipocyte differentiation and increasing the storage of fatty acids in adipose tissue. This helps to lower circulating free fatty acids, which can improve insulin signaling in muscle and liver, leading to improved glucose uptake and utilization.
- Anti-inflammatory Effects: PPARγ activation can reduce the production of pro-inflammatory cytokines and suppress inflammation, particularly in adipose tissue. This anti-inflammatory effect further contributes to the improvement in insulin sensitivity and metabolic health.
- Lipid Metabolism: PPARγ agonists also influence lipid metabolism by promoting the storage of lipids in adipose tissue rather than in muscle or liver, reducing lipotoxicity and improving metabolic function.
Overall, PPARγ agonists are used primarily for the treatment of type 2 diabetes due to their ability to improve insulin sensitivity, lower blood glucose levels, and affect lipid metabolism. However, they are associated with side effects like weight gain and fluid retention.
Pioglitazone is a PPAR gamma agonist used in blood sugar control. It can be given in dosages of 15-30 mg after meals. 15 mg of pioglitazone lowers about 50 mg/dl of fasting sugar and 30 mg/dl of post prandial sugar, i.e. 15 mg of pioglitazone is equivalent to 500 mg of metformin.
Pioglitazone can lead to water retention in the body, thus aggravating congestive heart failure. It can also cause hypoglycemia.
Pioglitazone is preferred in thin patients who do not tolerate Metformin well and are losing weight.