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Antioxid Redox Signal. 2018 Sep 10;29(8):749-791. doi: 10.1089/ars.2017.7313. Epub 2018 Jan 30.

Mitochondria, the NLRP3 Inflammasome, and Sirtuins in Type 2 Diabetes: New Therapeutic Targets.

Author information

1
1 Service of Endocrinology and Nutrition, University Hospital Doctor Peset , Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain .
2
2 Department of Pharmacology, University of Valencia , Valencia, Spain .
3
4 CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED de Enfermedades Hepáticas y Digestivas (CIBERehd) , Madrid, Spain .
4
3 Department of General Surgery, Hospital University "Virgen del Rocío"/IBiS/CSIC/University of Seville , Seville, Spain .
5
5 Department of Physiology, University of Valencia , Valencia, Spain .

Abstract

SIGNIFICANCE:

Type 2 diabetes mellitus and hyperglycemia can lead to the development of comorbidities such as atherosclerosis and microvascular/macrovascular complications. Both type 2 diabetes and its complications are related to mitochondrial dysfunction and oxidative stress. Type 2 diabetes is also a chronic inflammatory condition that leads to inflammasome activation and the release of proinflammatory mediators, including interleukins (ILs) IL-1β and IL-18. Moreover, sirtuins are energetic sensors that respond to metabolic load, which highlights their relevance in metabolic diseases, such as type 2 diabetes. Recent Advances: Over the past decade, great progress has been made in clarifying the signaling events regulated by mitochondria, inflammasomes, and sirtuins. Nod-like receptor family pyrin domain containing 3 (NLRP3) is the best characterized inflammasome, and the generation of oxidant species seems to be critical for its activation. NLRP3 inflammasome activation and altered sirtuin levels have been observed in type 2 diabetes. Critical Issue: Despite increasing evidence of the relationship between the NLRP3 inflammasome, mitochondrial dysfunction, and oxidative stress and of their participation in type 2 diabetes physiopathology, therapeutic strategies to combat type 2 diabetes that target NLRP3 inflammasome and sirtuins are yet to be consolidated.

FUTURE DIRECTIONS:

In this review article, we attempt to provide an overview of the existing literature concerning the crosstalk between mitochondrial impairment and the inflammasome, with particular attention to cellular and mitochondrial redox metabolism and the potential role of the NLRP3 inflammasome and sirtuins in the pathogenesis of type 2 diabetes. In addition, we discuss potential targets for therapeutic intervention based on these molecular interactions. Antioxid. Redox Signal. 29, 749-791.

KEYWORDS:

NLRP3; inflammasome; mitochondria; oxidative stress; sirtuins; type 2 diabetes

PMID:
29256638
DOI:
10.1089/ars.2017.7313

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