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Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes
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Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes
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Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes
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Journal Article
Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes
2013
Overview
George Kunos and his colleagues show in a rat model that endocannabinoid activation of the Nlrp3 inflammasome in macrophages results in death of pancreatic beta cells, and thus development of type 2 diabetes mellitus. These results suggest that preventing this process might be a therapeutic option for diabetes in the clinic.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ Arachidonic Acids - pharmacology
/ Cannabinoid Receptor Agonists - pharmacology
/ Carrier Proteins - metabolism
/ Diabetes
/ Diabetes Mellitus, Type 2 - metabolism
/ Endocannabinoids - pharmacology
/ Humans
/ Insulin-Secreting Cells - drug effects
/ Insulin-Secreting Cells - metabolism
/ Islets of Langerhans - cytology
/ Islets of Langerhans - metabolism
/ Male
/ Mice
/ NLR Family, Pyrin Domain-Containing 3 Protein
/ Obesity
/ Pancreas
/ Polyunsaturated Alkamides - pharmacology
/ Rats
/ Rodents
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