Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice

Abstract

Background/Aims: Sepsis is a common disease that continues to increase in prevalence worldwide, and diabetes mellitus may make the situation worse. This study was designed to determine the role of Liver Kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in diabetic mice complicated with systemic endotoxemia. Methods: The effects of LKB1/AMPK signaling pathway activation on endotoxemia were investigated in streptozotocin induced diabetic mice (STZ-mice) and db/db diabetic mice. Primary peritoneal macrophages and human umbilical vein endothelial cells (HUVECs) monolayers were simultaneously stimulated by both high glucose and LPS and used as a model to investigate the potential molecular mechanisms in vitro. Results: After treatment with LPS, high glucose or both LPS and high glucose, phosphor-AMPK expression was decreased, and moreover, AMPK activation by metformin treatment alleviated the decrease in phosphor-AMPK expression in HUVECs and macrophages as well as in lung tissue. Furthermore, both LPS and high glucose co-treatment decreased LKB1 and phosphor-AMPK expression via enhanced oxidative stress response, and importantly, LKB1 overexpression mediated by adenovirus inhibited the decrease in phosphor-AMPK expression in macrophages and HUVECs. AMPK activation by metformin administration improved the survival of STZ-induced diabetic mice and db/db diabetic mice, which was associated with reduced lung endothelial hyperpermeability and systemic inflammatory response. Furthermore, the permeability of HUVECs monolayers induced by both high glucose and LPS stimulation was also alleviated by AMPK activation, which was partly via suppression of VE-cadherin phosphorylation. Conclusion: These data demonstrated that LKB1/AMPK signaling pathway activation improved the survival of diabetic mice complicated with endotoxemia. Thus, LKB1/AMPK signaling pathway may serve as a potentially useful therapeutic target for severe infection in diabetic patients.

Differential Regulation of LPS-Mediated VE-Cadherin Disruption in Human Endothelial Cells and the Underlying Signaling Pathways: A Mini Review

“…In previous studies, AMPK has been identified as an enzyme that regulates Sirt3 by promoting the expression of peroxisome-activator receptor coactivator-1α (PGC-1α) as well as oxidative stress in autophagy (Palacios et al, 2009;Giralt et al, 2011;Kahn et al, 2015;Pillai et al, 2015). This is in line with the study of Yang et al (2017) which also reported a notable decrease in liver kinase B (LKB1), followed by decreased phosphorylation of AMPK and its downstream kinase, namely acetyl coenzyme A carboxylase (Acc) at serine residue 79.…”

Endothelial function and dysfunction: Impact of metformin

“…Metformin (5mM for in vitro studies, and 400mg/kg bid for in vivo studies) decreases permeability in endothelial cells stimulated with high glucose and LPS as well as improving lung barrier integrity in both STZ-induced diabetic and db/db mice models; the mechanism is linked to the activation of the LKB1/AMPK pathway (Y. Yang, et al, 2017).…”

Short-term Effects of Metformin on Cardiac and Peripheral Blood Cells Following Cecal Ligation and Puncture-induced Sepsis

“…It is demonstrated that during sepsis, the inflammation leads to cellular signaling alteration, increase in LPO and ROS concentrations, neutrophil hyperactivity, and infiltration of MPO into different tissues and organs [22][23][24][25][26][27]. Several studies have reported that administration of metformin during sepsis can improve mitochondrial function, accelerate bacterial clearance, strengthen intracellular junctions, and alleviate edema and organ necrosis [28][29][30][31][32][33][34][35][36][37][38]. Besides, metformin administration can reduce the oxidative stress level in the blood, brain, and pancreas 9-72 hrs.…”