Systemic Oxidative Stress and Visceral Adipose Tissue Mediators of NLRP3 Inflammasome and Autophagy Are Reduced in Obese Type 2 Diabetic Patients Treated with Metformin.

Zaida Abad-Jiménez,Víctor M Víctor,Carlos Morillas,Milagros Rocha,Francesca Iannantuoni,Rubén Díaz-Rúa,Sandra López-Domènech,Dolores Periañez-Gómez,Segundo Ángel Gómez-Abril

doi:10.3390/antiox9090892

Abstract

Obesity is a low-grade inflammatory condition affecting a range of individuals, from metabolically healthy obese (MHO) subjects to type 2 diabetes (T2D) patients. Metformin has been shown to display anti-inflammatory properties, though the underlying molecular mechanisms are unclear. To study whether the effects of metformin are mediated by changes in the inflammasome complex and autophagy in visceral adipose tissue (VAT) of obese patients, a biopsy of VAT was obtained from a total of 68 obese patients undergoing gastric bypass surgery. The patients were clustered into two groups: MHO patients and T2D patients treated with metformin. Patients treated with metformin showed decreased levels of all analyzed serum pro-inflammatory markers (TNFα, IL6, IL1β and MCP1) and a downwards trend in IL18 levels associated with a lower production of oxidative stress markers in leukocytes (mitochondrial ROS and myeloperoxidase (MPO)). A reduction in protein levels of MCP1, NFκB, NLRP3, ASC, ATG5, Beclin1 and CHOP and an increase in p62 were also observed in the VAT of the diabetic group. This downregulation of both the NLRP3 inflammasome and autophagy in VAT may be associated with the improved inflammatory profile and leukocyte homeostasis seen in obese T2D patients treated with metformin with respect to MHO subjects and endorses the cardiometabolic protective effect of this drug.

Highlights

Obesity represents a risk factor for diverse clinical and metabolic disturbances, leading to increased mortality and shortened life expectancy
When we evaluated serum levels of cytokines released by the formation of the NLRP3 inflammasome complex, a significant decrease in serum interleukin 1β (IL1β) (Figure 2E, p < 0.05) and a downward trend in serum interleukin 18 (IL18) (Figure 2F, p = 0.146) were observed in diabetic patients treated with metformin with respect to metabolically healthy obese (MHO) subjects
We demonstrate that obese type 2 diabetes (T2D) patients treated with metformin display a more favorable immuno-inflammatory status than MHO subjects: namely, a reduction in leukocyte

Summary

Introduction

Obesity represents a risk factor for diverse clinical and metabolic disturbances, leading to increased mortality and shortened life expectancy. Antioxidants 2020, 9, 892 of metabolic abnormalities, including dyslipidemia, insulin resistance, hypertension and endothelial dysfunction [1,2]. These effects are exacerbated by the aberrant release of cytokines and adipokynes by the VAT [3], which contributes to systemic low-grade inflammation, increased cardiovascular risk and development of type 2 diabetes (T2D). Metformin displays anti-hyperglycemic properties, and improves endothelial function, lipid profile and hemostasis [4]. Emerging evidence suggests that metformin displays anti-inflammatory effects via direct and indirect targeting of tissue-resident immune cells in metabolic organs such as the liver, gastrointestinal tract and adipose tissue [8]

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