Review
Effects of CB1 antagonist on the control of metabolic functions in obese type 2 diabetic patients

https://doi.org/10.1016/j.diabet.2007.02.001Get rights and content

Abstract

Clinical reports (RIO trials) have shown that chronic administration of a CB-cannabinoid receptor antagonist (rimonabant) provides improvements of disturbed metabolic parameters observed in overweight and obese patients with type 2 diabetes. The production of endocannabinoid and the expression of CB1-cannabinoid receptors are largely distributed in the different organs aside from the brain. It is now clearly established that endocannabinoids act both through orexigenic effects and peripheral metabolic effects in various tissues involved in the control of metabolism and energy expenditure (i.e. adipose tissue, liver, gastrointestinal tract, skeletal muscle and pancreas). This review will consider: i) the disturbances of glucose and lipid metabolisms in obese type 2 diabetics; ii) an overview of the pharmacological properties of rimonabant and iii) the various mechanisms involved in tissues and organs to explain the therapeutic efficacy of rimonabant. A special attention will be paid to its utilization in obese type 2 diabetics. The emerging concept of endocannabinoids acting as metabolic regulators is the more likely explanation of the success of rimonabant treatments in phase III studies.

Résumé

Effets d'un antagoniste des récepteurs CB1 sur les fonctions métaboliques des patients obèses diabétiques de type 2.

Diverses études cliniques (Études RIO) ont montré que l'administration d'un antagoniste des récepteurs des cannabinoïdes (rimonabant) améliorait divers paramètres métaboliques défavorables rencontrés chez des patients en surpoids ou des patients obèses atteints de diabète de type 2. En dehors du système nerveux, la production d'endocannabinoïdes et l'expression des récepteurs CB1 des cannabinoïdes ont été décrites dans de nombreux organes et tissus. Il est maintenant bien établi que les endocannabinoïdes agissaient à la fois par une action sur la prise alimentaire et plusieurs autres actions métaboliques dans les tissus impliqués dans le contrôle du métabolisme et de la dépense énergétique (i.e. tissu adipeux, foie, tractus gastro-intestinal, muscle squelettique et pancréas). Cette revue qui commence par une synthèse des perturbations du métabolisme glucidique et lipidique rencontrées chez les diabétiques de type 2, abordera les propriétés pharmacologiques du rimonabant et ses divers mécanismes d'action dans les tissus et organes qui sont susceptibles d'expliquer son efficacité thérapeutique. Une attention toute particulière sera dévolue à son utilisation chez l'obèse avec un diabète de type 2. Le concept émergent d'une action des endocannabinoïdes comme régulateurs métaboliques permet probablement d'expliquer le succès d'un traitement par le rimonabant dans les études de phase III rapportées à ce jour.

Introduction

The clinical importance of the endocannabinoid system in the control of energy status and metabolic equilibrium is supported by a number of clinical reports (RIO trials) showing that chronic administration of a CB-cannabinoid receptor antagonist (rimonabant) provides improvements of disturbed metabolic parameters observed in overweight and obese patients with type 2 diabetes (T2D) [1], [2], [3], [4], [5]. When compared with currently marketed antiobesity drugs, the weight loss (7.4 kg) observed after a 2-year administration of rimonabant (20 mg/day) in the RIO-North America Study is significant and there was no weight regain during the second year of treatment. An increase in plasma high-density lipoprotein (HDL)-C and a decrease in plasma triglyceride (TG) levels were also observed with rimonabant 20 mg/day relative to placebo. When administered to type 2 diabetic patients poorly controlled by metformin and/or sulfonylureas, in combination with diet and exercise, rimonabant promotes a reduction in body weight and in HbA1c levels, and an improvement of other cardiovascular and metabolic risk factors. A very important aspect of rimonabant action is that 50% of its metabolic effects are independent from the weight lost. This observation, combined with relevant preclinical data that will be summarized below, indicates that CB1 blockers can improve cardiovascular risk factors by a direct metabolic action.

The production of endocannabinoids and the expression of CB1-cannabinoid receptors are largely distributed in the different organs out off the brain It is now clearly established that endocannabinoids act both through orexigenic effects and peripheral metabolic effects in various tissues involved in the control of metabolism and energy expenditure (i.e. adipose tissue, liver, gastrointestinal tract, skeletal muscle, endothelial cells and pancreas) (Fig. 1). The first results revealing the impact of cannabinoids on energy homeostasis and weight control originate from investigations performed on chronic marijuana smokers under clinically-controlled conditions. Consumption of marijuana, in addition to its behavioral effects, mediated by central mechanisms, and assessed by a transient and positive impact on calorie intake, was postulated to influence energy metabolism in the long-term. A continuous weight gain of the patients involved in the protocol was observed, although appetite stimulation and caloric intake leveled rapidly [6]. The existence of independent effects between the cannabinoid control of appetite and the peripheral actions controlling the energy status was postulated. More recently, experiments in rats fed a standard high carbohydrate diet [7] or in mice submitted to an obesity-promoting high fat diet [8] and treated chronically with the selective CB1-receptor antagonist, rimonabant, also supported the idea that factors other than food intake regulation were involved in the weight-reducing effects of CB1 antagonists. In fact, the metabolic action of rimonabant does not entirely result from weight loss and 50% of effects independent of weight loss result from changes in metabolism. The reducing effect on food intake was limited to the first week of administration of rimonabant while decrease in body weight was maintained over the entire period of treatment (5 weeks) [8]. The effect of chronic treatment with rimonabant was also studied in mice with established obesity (5-month high fat diet). The impact on food intake was transient whilst a sustained decrease in body weight associated with improvements in serum biochemical parameters and lipid profiles (i.e. decrease in leptin, insulin, glucose, TGs and low-density lipoprotein (LDL)-cholesterol levels) was observed [9]. The administration of another CB1 antagonist (AM-251) to diet-induced obese mice, has now confirmed all the results obtained with rimonabant [10]. Therefore, despite the waning of the anorectic effects, rimonabant, leads to a significant and sustained reduction in body weight that was not explained by food-intake regulation only. The lack of CB1-receptor in mutant KO mice (CB–/– mice) causes hypophagia and body fat reduction as well as resistance to high fat diet. Pair-fed older wild-type mice are heavier than the CB–/– mice. These results suggest that putative peripheral metabolic factors may be the cause of the lean phenotype [11], [12]. Moreover, studies in obese rodents and obese patients suggest that endocannabinoid formation is enhanced in obesity, perhaps because endocannabinoid degradation is decreased [5]. CB-1 receptor mediated effects in the major tissues involved in the regulation of metabolism are summarized in Fig. 1.

This review will be organized as follows: i) disturbances of glucose and lipid metabolisms in obese type 2 diabetics; ii) overview of the pharmacological properties of rimonabant and iii) the mechanisms of the therapeutic efficacy of rimonabant with a special attention to its utilization in obese type 2 diabetics.

Section snippets

Disturbances of glucose and lipid metabolisms in obese type 2 diabetics

T2D is associated with a two to four increased risk of cardiovascular disease [13]. Much of this increased risk derives from a typical dyslipidemia that is part of insulin resistance and that is exacerbated by insulin deficiency (development of overt hyperglycemia).

Pharmacological properties of rimonabant

Rimonabant (SR141716), (N-piperidino-5-(4-chlorophenyl)-1-(2-4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide) belongs to the family of 1.5-diarylpyrazoles. It is a potent and selective antagonist of CB1-cannabinoid receptors which prevents the occurrence of different in vitro and in vivo CB1-receptor mediated events [44]. In vitro, rimonabant displayed nanomolar affinity for the rodent and human CB1-receptor while metabolites of rimonabant have no affinity for CB1-receptors. In vivo,

Mechanisms explaining the therapeutic efficacy of rimonabant

Rimonabant suppresses CB1-receptor mediated effects in a number of target organs involved in the control of lipid and energy storage, for example in adipose tissue and liver. Rimonabant also suppresses CB1-mediated effects in the gastrointestinal tract, skeletal muscle and pancreatic β-cells. The mechanisms by which rimonabant exerted its metabolic effects have been mainly explored in rodents. Studies performed in human tissues are scarce.

Conclusions

Rimonabant is the first of a new class of selective cannabinoid receptor-1 (CB-1) antagonists used for the treatment of obesity and metabolic disorders. In several randomized, double-blind clinical trials in overweight or obese adults with or without T2D, orally administered rimonabant, once-daily, improved lipid and glucose metabolism parameters and regulated food intake and energy balance. A significantly greater proportion of rimonabant recipients achieved a clinically significant weight

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