Type 2 diabetes mellitus (T2DM) progresses from a state of insulin resistance with euglycemia and hyperinsulinemia to β-cell failure resulting in impaired insulin secretion and fasting hyperglycemia. The pathogenic role of inflammation in both stages of T2DM is increasingly recognized. Adipose tissue inflammation contributes to insulin resistance via proinflammatory cytokines such as TNFα and IL-6, and infiltration of proinflammatory cells into pancreatic islets of diabetic patients and animals may contribute to β-cell failure. Furthermore, the Nlrp3 (NOD-like receptor family, pyrin domain containing 3) inflammasome, a protein complex involved in the proteolytic activation of caspase-1 and interleukin-1β (IL-1β) secretion, has been implicated in the pathogenesis of diabetogenic insulitis (i.e. inflammation of pancreatic islets).
Endocannabinoids, the lipid ligands of G protein-coupled CB1 and CB2 receptors, produce a broad range of biological effects (reviewed in Pacher, P., et. al., Pharmacol Rev 58, 389-462 (2006)). CB1R (CB1 receptor) activation promotes food intake, increases lipogenesis in adipose tissue and liver, and induces insulin resistance and dyslipidemia, suggesting that an overactive endocannabinoid/CB1R system contributes to the development of visceral obesity and its complications. Accordingly, chronic CB1R/CB1R blockade reduced body weight and improved obesity-related insulin resistance, dyslipidemia and fatty liver both in rodent models of obesity and in overweight people with the metabolic syndrome. CB1R blockade also improved glycemic control as a monotherapy in drug-naive patients with T2DM. However, the therapeutic development of CB1R antagonist/inverse agonists has been halted due to adverse psychiatric effects.