Role of the endocannabinoid system in diabetes and diabetic complications

Abstract

Increasing evidence suggests that an overactive endocannabinoid system (ECS) may contribute to the development of diabetes by promoting energy intake and storage, impairing both glucose and lipid metabolism, by exerting pro-apoptotic effects in pancreatic beta cells and by facilitating inflammation in pancreatic islets. Furthermore, hyperglycaemia associated with diabetes has also been implicated in triggering perturbations of the ECS amplifying the pathological processes mentioned above, eventually culminating in a vicious circle. Compelling evidence from preclinical studies indicates that the ECS also influences diabetes-induced oxidative stress, inflammation, fibrosis and subsequent tissue injury in target organs for diabetic complications. In this review, we provide an update on the contribution of the ECS to the pathogenesis of diabetes and diabetic microvascular (retinopathy, nephropathy and neuropathy) and cardiovascular complications. The therapeutic potential of targeting the ECS is also discussed.

Linked articles: This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc.

Figure 1

Role of the ECS in the development of T2DM. Excess food intake and obesity enhance the ECS tone. A hyperactive ECS further contributes to visceral fat accumulation and obesity by reducing energy expenditure and by enhancing both food intake and lipogenesis. Therefore, the ECS is involved in the development of obesity‐dependent insulin resistance. Moreover, an overactive ECS has direct deleterious effects on insulin sensitivity independent of weight gain in peripheral organ of metabolism (liver, adipose tissue, skeletal muscle). Finally, the ECS indirectly contribute to beta cell failure through activation of the Nlrp3‐ASC inflammasome in infiltrating macrophages, resulting in beta cell apoptosis. Both insulin resistance and relative insulin deficiency lead to the development of T2DM.

Figure 2

Opposing effects of CB₁ receptor and CB₂ receptor in DN. The CB₁ receptor has deleterious pro‐oxidative and pro‐inflammatory effects, while opposing protective effects are induced by CB₂ receptor activation. In diabetes, hyperglycaemia and hypertension alter the balance between CB₁ receptor and CB₂ receptor signalling as CB₁ receptor expression is enhanced, while CB₂ receptor is down‐regulated. This imbalance favours oxidative stress, inflammatory and profibrotic processes and contributes to the development of proteinuria by enhancing nephrin loss and of renal function loss by exacerbating fibrogenesis in both the mesangium and tubulointerstitium.

Figure 3

Role of the EC‐CB₁ receptor signalling in diabetic cardiovascular complications. Hyperglycaemia and hyperlipidaemia associated with diabetes promotes increased ROS/RNS generation in endothelium, vascular smooth muscle and cardiomyocytes, induces stress signalling, profibrotic changes and cell death in the myocardial cells, as well as leads to activation and recruitment of inflammatory cells with consequent pro‐inflammatory response. Hyperglycaemia also directly or indirectly leads to enhanced EC‐CB₁ receptor signalling, which in turn amplifies these pathological processes facilitating tissue injury, cardiovascular dysfunction and eventually development of diabetic cardiovascular complications such as cardiomyopathy, nephropathy, retinopathy and enhanced atherosclerosis.