Pharmacological treatment of insulin resistance in obesity

To discuss new pharmacological possibilities for acting on the lipid metabolism abnormalities relating obesity, insulin resistance and arterial disease.

Obesity is frequently associated with excess caloric fat dietary intake, especially in the form of fatty acids. An increased flux of fatty acids into muscle, liver and pancreas is probably a major cause of insulin resistance and possibly of pancreatic secretory disturbances. Liver exposure to fatty acid overload may also be the main reason for the atherogenic lipoprotein profile of insulin resistance and type 2 diabetes, which is characterised by prolonged post-prandial hypertriglyceridemia, high levels of large very low-density lipoproteins (VLDL) and small, dense low-density lipoproteins (LDL), and a reduced number of apoAl-containing high-density lipoproteins (HDL). This lipoprotein profile may be the main contributor to the high prevalence of arterial disease in patients with type 2 diabetes. The treatment of type 2 diabetes and insulin resistance in obese or non-obese subjects should therefore aim at normalising fatty acid fluxes because this can be expected to enhance insulin action and ameliorate the atherogenic lipoprotein abnormalities. The discovery of peroxisome proliferator-activated receptors (PPARs) and the elucidation of their function as master controllers of the genes involved in fatty acid metabolism have facilitated the development of potent modulating substances. Promising results have been obtained with the current generation of PPAR gamma ligands, but undesirable effects have also been reported.

New knowledge concerning the structure and function of PPAR gamma and PPAR alpha is being used to develop non-TZD modulators with combined PPAR alpha and gamma actions in animal studies. This new generation of substances may offer a more balanced spectrum of activity that may be better suited for the treatment of the insulin resistance and type 2 diabetes frequently associated with obesity.