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Mol Metab. 2018 Apr;10:66-73. doi: 10.1016/j.molmet.2018.02.001. Epub 2018 Feb 7.

Evidence against a role for NLRP3-driven islet inflammation in db/db mice.

Author information

1
Cellular and Molecular Metabolism Laboratory, Baker Heart & Diabetes Institute, Melbourne, Australia. Electronic address: helene.kammoun@baker.edu.au.
2
Cellular and Molecular Metabolism Laboratory, Baker Heart & Diabetes Institute, Melbourne, Australia.
3
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia.
4
Division of Diabetes & Metabolism, Garvan Institute of Medical Research, Sydney, Australia.
5
Division of Diabetes & Metabolism, Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
6
Inflammation research, Trinity Biomedical Sciences Institute, Dublin, Ireland.
7
Cellular and Molecular Metabolism Laboratory, Baker Heart & Diabetes Institute, Melbourne, Australia; Division of Diabetes & Metabolism, Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia. Electronic address: m.febbraio@garvan.org.au.

Abstract

OBJECTIVES:

Type 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1β (IL-1β) have been implicated in pancreatic β cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic β cell death could allow for selective T2D treatment without compromising all IL-1β-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic β cell death, thereby preventing the onset of T2D.

METHODS:

Diabetic db/db mice were treated with MCC950 via drinking water for 8 weeks from 6 to 14 weeks of age, a period over which they developed pancreatic β cell failure. We assessed metabolic parameters such as body composition, glucose tolerance, or insulin secretion over the course of the intervention.

RESULTS:

MCC950 was a potent inhibitor of NLRP3-induced IL-1β in vitro and was detected at high levels in the plasma of treated db/db mice. Treatment of pre-diabetic db/db mice with MCC950, however, did not prevent pancreatic dysfunction and full onset of the T2D pathology. When examining the NLRP3 pathway in the pancreas of db/db mice, we could not detect an activation of this pathway nor increased levels of its target IL-1β.

CONCLUSIONS:

NLRP3 driven-pancreatic IL-1β inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D.

KEYWORDS:

Inflammasome; Interleukin-1β; MCC950; Type 2 diabetes; db/db mice

PMID:
29478918
PMCID:
PMC5985230
DOI:
10.1016/j.molmet.2018.02.001
[Indexed for MEDLINE]
Free PMC Article

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