Peripheral cannabinoid CB1 receptor (CB1R) blockade reverses β-cell loss, hyperglycemia by reversing macrophage-induced activation of the NLRP3 inflammasome in a rat model of type 2 diabetes (T2DM).

Thursday, October 11, 2012 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center, Building 45	NIAAA	ENDOC-9

* FARE Award Winner

Authors

• T Jourdan
• G Godlewski
• R Cinar
• J Tam
• G Szanda
• A Bertola
• J Liu
• T Han
• B Mukhopadhyay
• C Ju
• G Kunos

Abstract

Inflammasomes are intracellular protein complexes that sense infection or tissue damage, leading to activation of caspase 1 and subsequent secretion of interleukin-1β and IL-18. The nucleotide binding domain, leucine-rich-family, pyrin domain-containing-3 (Nlrp3) inflammasome is a sensor of metabolic dysregulation, particularly obesity-induced inflammation, insulin resistance and T2DM. In the natural history of T2DM, insulin resistance progresses to β-cell failure and uncompensated hyperglycemia, a process replicated in the Zucker diabetic (ZDF) rat. Endocannabinoids are lipid mediators that contribute to obesity-induced insulin resistance via activation of peripheral CB1R, but their potential role in β-cell failure is unknown. We report that β-cell failure in adult ZDF rats is accompanied by the activation of the Nlrp3 inflammasome in pancreatic islets, which are heavily infiltrated by M1 macrophages and cytotoxic T cells. Chronic treatment with a novel, peripherally restricted CB1R antagonist (JD-5037) reverses inflammasome activation and inflammatory cell infiltration and restores glucose-induced insulin secretion by targeting macrophage action. Indeed, depletion of macrophages by clodronate-containing liposomes leads to a delay in the onset of T2DM in ZDF rats, replicating the effects of JD-5037. These findings implicate endocannabinoids acting via CB1R in inflammasome activation and β-cell failure in T2DM, and identify peripheral CB1R as a novel therapeutic target.

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