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Fluvastatin Causes NLRP3 Inflammasome-Mediated Adipose Insulin Resistance
- Source :
- Diabetes. 63:3742-3747
- Publication Year :
- 2014
- Publisher :
- American Diabetes Association, 2014.
-
Abstract
- Statins reduce lipid levels and are widely prescribed. Statins have been associated with an increased incidence of type 2 diabetes, but the mechanisms are unclear. Activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3)/caspase-1 inflammasome, promotes insulin resistance, a precursor of type 2 diabetes. We showed that four different statins increased interleukin-1β (IL-1β) secretion from macrophages, which is characteristic of NLRP3 inflammasome activation. This effect was dose dependent, absent in NLRP3−/− mice, and prevented by caspase-1 inhibition or the diabetes drug glyburide. Long-term fluvastatin treatment of obese mice impaired insulin-stimulated glucose uptake in adipose tissue. Fluvastatin-induced activation of the NLRP3/caspase-1 pathway was required for the development of insulin resistance in adipose tissue explants, an effect also prevented by glyburide. Fluvastatin impaired insulin signaling in lipopolysaccharide-primed 3T3-L1 adipocytes, an effect associated with increased caspase-1 activity, but not IL-1β secretion. Our results define an NLRP3/caspase-1–mediated mechanism of statin-induced insulin resistance in adipose tissue and adipocytes, which may be a contributing factor to statin-induced development of type 2 diabetes. These results warrant scrutiny of insulin sensitivity during statin use and suggest that combination therapies with glyburide, or other inhibitors of the NLRP3 inflammasome, may be effective in preventing the adverse effects of statins.
- Subjects :
- Male
medicine.medical_specialty
Indoles
Inflammasomes
Endocrinology, Diabetes and Metabolism
Glucose uptake
Interleukin-1beta
Adipose tissue
Type 2 diabetes
Fatty Acids, Monounsaturated
Mice
Insulin resistance
3T3-L1 Cells
Internal medicine
Diabetes mellitus
Glyburide
NLR Family, Pyrin Domain-Containing 3 Protein
Internal Medicine
medicine
Animals
Obesity
Fluvastatin
integumentary system
biology
business.industry
Macrophages
Caspase 1
Inflammasome
medicine.disease
Insulin receptor
Endocrinology
Adipose Tissue
biology.protein
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Insulin Resistance
Carrier Proteins
business
medicine.drug
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 63
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....c765e1a1756ff10ac1d0dd4f09b995de
- Full Text :
- https://doi.org/10.2337/db13-1398