Nuclear receptors are activated when certain substances bind to them, namely low molecular-weight compounds, hormones, drugs and nutrients. The receptors then bind to response elements on the DNA, resulting in changes in gene transcription, mRNA and protein levels. This eventually changes cell function. The PPARgamma receptors are important in the control of many aspects of metabolism and homeostasis, and are the focus of much current research. This increases glucose uptake and utilisation by skeletal muscle and adipose tissue, and reduces glucose release from the liver.
Metformin reduces hepatic glucose production and increases glucose utilisation by cells.
PPARgamma agonists reduce insulin resistance and help preserve beta-cell function. Even if ideal levels cannot be reached, it was shown that any improvement can help to reduce complications. Metformin should be the first-line drug of choice in the overweight, who account for 80 per cent of those with type 2 diabetes. If metformin and diet alone cannot maintain blood glucose control, other therapies may be required. Some people cannot tolerate metformin, and others may have contraindications or intercurrent illness requiring discontinuation.