Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes

Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates... Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB 1 receptors (CB 1 Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB 1 R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB 1 R-deficient ( Cnr1 −/− ) or Nlrp3 −/− mice, with the endocannabinoid anandamide. Peripheral CB 1 R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB 1 R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB 1 R as a therapeutic target in T2DM. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Medicine Springer Journals

Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes

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Publisher
Springer Journals
Copyright
Copyright © 2013 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
ISSN
1078-8956
eISSN
1546-170X
D.O.I.
10.1038/nm.3265
Publisher site
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Abstract

Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB 1 receptors (CB 1 Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB 1 R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB 1 R-deficient ( Cnr1 −/− ) or Nlrp3 −/− mice, with the endocannabinoid anandamide. Peripheral CB 1 R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB 1 R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB 1 R as a therapeutic target in T2DM.

Journal

Nature MedicineSpringer Journals

Published: Aug 18, 2013

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