Via practica S4/2007

BLOCKADE OF ENDOCANNABINOID EC1-RECEPTORS AND ITS EFFECT ON THE CARDIOMETABOLIC RISK

Insulin resistance and abdominal obesity are basic pathogenetic mechanism in the development of the metabolic syndrome whose further features are impaired glycemia or diabetes, dyslipidemia and increased blood pressure. In addition, the metabolic syndrome is associated with proinflammatory and procoagulation states, as well as with endothelial dysfunction. The subjects with metabolic syndrome have at least twice increased risk for the development of cardiovascular disease. The relationship between insulin resistance and obesity is complex. Genetically determined insulin resistance leads with abnormal caloric intake to the development of intraabdominal adiposity and obesity. On the other hand, the adipose tissue contributes to the impairment of insulin resistance by release of free fatty acids and different adipocytokines, mainly interleukin 6 and TNF-α. The endocannabinoid system (ECS) plays an important role on the different levels in the food intake and metabolism. The stimulation of this system in the central nervouse system leads to an increased food intake. It is also suspected that ECS plays a role in signalling of satiety from the gastrointestinal tract. Its activation leads to the development of insulin restistance in fat tissue, liver and muscle. The studies with rimonabant, a selective EC1-receptor blocker, have shown its beneficial effect on body weight and waist circumference reduction, improvement of glycemic control in diabetic patients, improvement of atherogenic dyslipidemia, as well as a slight decrease of blood pressure. These effects were only partially dependent on weight reduction and were probably also dependent on direct improvement of insulin resistance, which was confirmed by increased insulin sensitivity assessed by HOMA method and adiponectin level. Reduction of the parameter of subclinical inflammation – CRP – was also observed. Based on the above-mentioned reasons the blockade of endocannabinoid EC1-receptors seems to be a promising therapeutic approach in the treatment of patients with type 2 diabetes or metabolic syndrome, which might lead to a total cardiometabolic risk reduction.

Keywords: insulin resistance, abdominal obesity, metabolic syndrome, type 2 diabetes mellitus, endocannabinoid system, rimonabant.