Type 2 diabetes mellitus, a global epidemic, is largely attributed to
metabolic syndrome and its clustering of cardiovascular risk factors including
abdominal obesity,
dyslipidemia,
hypertension and
hyperglycemia. The two primary approaches to optimally control risk factors associated with
metabolic syndrome are lifestyle changes and medications. Although many pharmacological targets have been identified, clinical management of cardiovascular risk factors associated with
metabolic syndrome and
type 2 diabetes is still dismal. Recent evidence suggests premises of the
peroxisome proliferator-activated receptor (
PPAR)
ligands in the combat against
type 2 diabetes and
metabolic syndrome including
obesity and
insulin resistance. Three subtypes of the
PPAR nuclear
fatty acid receptors have been identified: alpha, beta/delta and gamma.
PPARalpha is believed to participate in
fatty acid uptake (beta- and omega-oxidation) mainly in the liver and heart.
PPARbeta/delta is involved in
fatty acid oxidation in muscle.
PPARgamma is highly expressed in fat to facilitate
glucose and
lipid uptake, stimulate
glucose oxidation, decrease
free fatty acid level and ameliorate
insulin resistance. Synthetic
ligands for
PPARalpha and gamma such as
fibric acid and
thiazolidinediones have been used in patients with
type 2 diabetes and pre-diabetic
insulin resistance with significantly improved HbA(1c) and
glucose levels. In addition, nonhypoglycemic effects may be elicited by
PPAR agonists or dual agonists including improved lipid metabolism, blood pressure control and endothelial function, as well as suppressed
atherosclerotic plaque formation and coagulation. However, issues of safety and clinical indication remain undetermined for use of
PPAR agonists for the incidence of
heart disease in
metabolic syndrome and
type 2 diabetes.