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The antidiabetic drug metformin blunts NETosis in vitro and reduces circulating NETosis biomarkers in vivo

Published on Jun 1, 2018in Acta Diabetologica2.996
· DOI :10.1007/s00592-018-1129-8
Lisa Menegazzo18
Estimated H-index: 18
(UNIPD: University of Padua),
Valentina Scattolini6
Estimated H-index: 6
(UNIPD: University of Padua)
+ 8 AuthorsGian Paolo Fadini47
Estimated H-index: 47
(UNIPD: University of Padua)
Abstract
Aims Diabetes is associated with an excess release of neutrophil extracellular traps (NETs) and an enhanced NETosis, a neutrophil cell death programme instrumental to anti-microbial defences, but also involved in tissue damage. We herein investigated whether the antidiabetic drug metformin protects against NETosis.
  • References (31)
  • Citations (8)
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References31
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#2Rinkoo Dalan (TTSH: Tan Tock Seng Hospital)H-Index: 11
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Neutrophil dysfunction is strongly linked to type 2 diabetes mellitus (T2DM) pathophysiology, but the prognostic potential of neutrophil biomarkers remains largely unexplored due to arduous leukocyte isolation methods. Herein, a novel integrated microdevice is reported for single-step neutrophil sorting and phenotyping (chemotaxis and formation of neutrophil extracellular traps (NETosis)) using small blood volumes (fingerprick). Untouched neutrophils are purified on-chip from whole blood directl...
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#1Graham Rena (Dund.: University of Dundee)H-Index: 21
#2Chim C. Lang (Dund.: University of Dundee)H-Index: 47
Although introduced for use as a diabetic medication in 1957, metformin remains the cornerstone of diabetic drug management in patients with type 2 diabetes mellitus (T2D). Its widespread use has largely been underpinned by the United Kingdom Prospective Diabetes Study that reported lower cardiovascular mortality and morbidity in patients treated with metformin in comparison with alternative glucose-lowering drugs, despite similar glycemic control. A recent meta-analysis suggests that the cardio...
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#1Borko Amulic (MPG: Max Planck Society)H-Index: 13
#2Sebastian Lorenz Knackstedt (MPG: Max Planck Society)H-Index: 1
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Summary Neutrophils are essential for immune defense and can respond to infection by releasing chromatin in the form of neutrophil extracellular traps (NETs). Here we show that NETs are induced by mitogens and accompanied by induction of cell-cycle markers, including phosphorylation of the retinoblastoma protein and lamins, nuclear envelope breakdown, and duplication of centrosomes. We identify cyclin-dependent kinases 4 and 6 (CDK4/6) as essential regulators of NETs and show that the response i...
28 CitationsSource
#1Flavia Agata Cimini (Sapienza University of Rome)H-Index: 7
#2Ilaria Barchetta (Sapienza University of Rome)H-Index: 12
Last. Maria Gisella Cavallo (Sapienza University of Rome)H-Index: 23
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Aims Interleukin-8 (IL-8) is a chemokine involved in systemic immunity, macrophages infiltration and activation in adipose tissue and may play a significant role in the pathogenesis of type 2 diabetes (T2D) and atherosclerosis. Aims of this study were to evaluate circulating IL-8 levels in adult patients with T2D in comparison with non-diabetic subjects and to describe clinical and biochemical correlates of IL-8 concentration.
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#1Leonardo Gomes Peixoto (UFU: Federal University of Uberlandia)H-Index: 7
#2Renata Roland Teixeira (UFU: Federal University of Uberlandia)H-Index: 10
Last. Foued Salmen Espindola (UFU: Federal University of Uberlandia)H-Index: 19
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Aims Inflammation induced by hyperglycemia triggers the toll-like receptor (TLR) pathway into cells. Our hypothesis was that metformin treatment attenuates the TLR signaling pathways triggered by inflammation in skeletal muscle of hypoinsulinemic/hyperglycemic STZ-induced rats. Thus, we examined TLR signaling under hypoinsulinemia and hyperglycemia conditions and its correlation with insulin resistance in muscle of diabetic rats treated with metformin.
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#1Elaine F. Kenny (MPG: Max Planck Society)H-Index: 3
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The immune system protects the body against microorganisms that can cause infections and diseases. Neutrophils are a type of immune cell that patrol the blood in search of germs. Once they encounter potentially harmful microbes, neutrophils eradicate them in different ways. One way to catch the germs is by using ‘neutrophil extracellular traps’, or NETs for short, to confine and kill the invaders. NETs are web-like structures made up of anti-microbial proteins and the neutrophil’s own DNA. The p...
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#1Na Wu (PRC: China Medical University (PRC))H-Index: 4
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Aims The purpose of this study was to investigate the mechanism of vascular endothelial cell apoptosis induced by acute blood glucose fluctuation.
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#1Gian Paolo Fadini (UNIPD: University of Padua)H-Index: 47
#2Benedetta Maria Bonora (UNIPD: University of Padua)H-Index: 10
Last. Angelo Avogaro (UNIPD: University of Padua)H-Index: 68
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Background Sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce glucose levels, body weight, and blood pressure, possibly resulting in cardiovascular protection. In phase III trials, SGLT2i were shown to increase HDL cholesterol. We aimed to evaluate whether the SGLT2i dapagliflozin affects HDL function in a randomized placebo-controlled trial.
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#1Agostina Carestia (New York Academy of Medicine)H-Index: 11
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Introduction and Objective Diabetes is characterized by chronic inflammation, endothelial dysfunction, increased risk of infections and early cardiovascular disease. By releasing neutrophil extracellular traps (NETs), neutrophils kill bacteria and exert pro-inflammatory and pro-thrombotic activities. Increased NETosis has been found in cross-sectional studies including treated type 2 diabetes mellitus (T2DM) patients. In this study, we determined whether the ability of neutrophils to form NETs d...
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#1Lianfeng WuH-Index: 5
#2Ben ZhouH-Index: 12
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Summary Metformin has utility in cancer prevention and treatment, though the mechanisms for these effects remain elusive. Through genetic screening in C. elegans , we uncover two metformin response elements: the nuclear pore complex (NPC) and acyl-CoA dehydrogenase family member-10 (ACAD10). We demonstrate that biguanides inhibit growth by inhibiting mitochondrial respiratory capacity, which restrains transit of the RagA-RagC GTPase heterodimer through the NPC. Nuclear exclusion renders RagC inc...
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Metformin is used for the treatment of type 2 diabetes mellitus and has shown therapeutic effects in preclinical models of other pathologies, such as cancer and autoimmune diseases. The antitumor activity of metformin is due, in part, to immunostimulatory effects. In the context of other pathologies, such as autoimmune or inflammatory diseases, metformin has immunosuppressive effects. There is evidence that the immunostimulatory effects of metformin are indirect. The immunosuppressive effects of...
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