scholarly journals Implication of glycogen synthase kinase 3 in diabetes-associated islet inflammation

2020 ◽  
Vol 244 (1) ◽  
pp. 133-148 ◽  
Author(s):  
Caterina Luana Pitasi ◽  
Junjun Liu ◽  
Blandine Gausserès ◽  
Gaëlle Pommier ◽  
Etienne Delangre ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Diabetic Rat ◽  
Gk Rats ◽  
Islet Inflammation ◽  
The Impact ◽  
Pro Inflammatory Cytokines

Islet inflammation is associated with defective β cell function and mass in type 2 diabetes (T2D). Glycogen synthase kinase 3 (GSK3) has been identified as an important regulator of inflammation in different diseased conditions. However, the role of GSK3 in islet inflammation in the context of diabetes remains unexplored. In this study, we investigated the direct implication of GSK3 in islet inflammation in vitro and tested the impact of GSK3 inhibition in vivo, on the reduction of islet inflammation, and the improvement of glucose metabolism in the Goto-Kakizaki (GK) rat, a spontaneous model of T2D. GK rats were chronically treated with infra-therapeutic doses of lithium, a widely used inhibitor of GSK3. We analyzed parameters of glucose homeostasis as well as islet inflammation and fibrosis in the endocrine pancreas. Ex vivo, we tested the impact of GSK3 inhibition on the autonomous inflammatory response of non-diabetic rat and human islets, exposed to a mix of pro-inflammatory cytokines to mimic an inflammatory environment. Treatment of young GK rats with lithium prevented the development of overt diabetes. Lithium treatment resulted in reduced expression of pro-inflammatory cytokines in the islets. It decreased islet fibrosis and partially restored the glucose-induced insulin secretion in GK rats. Studies in non-diabetic human and rat islets exposed to inflammatory environment revealed the direct implication of GSK3 in the islet autonomous inflammatory response. We show for the first time, the implication of GSK3 in islet inflammation and suggest this enzyme as a viable target to treat diabetes-associated inflammation.

scholarly journals Role of glycogen synthase kinase-3 beta in the inflammatory response caused by bacterial pathogens

2012 ◽  
Vol 9 (1) ◽  
pp. 23 ◽  
Author(s):  
Ricarda Cortés-Vieyra ◽  
Alejandro Bravo-Patiño ◽  
Juan J Valdez-Alarcón ◽  
Marcos Juárez ◽  
B Finlay ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Glycogen Synthase ◽  
Bacterial Pathogens ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

scholarly journals Glycogen Synthase Kinase-3 Regulates Production of Amyloid-βPeptides and Tau Phosphorylation in Diabetic Rat Brain

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Zhong-Sen Qu ◽  
Liang Li ◽  
Xiao-Jiang Sun ◽  
Yu-Wu Zhao ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Rat Brain ◽  
Glycogen Synthase ◽  
Selective Inhibition ◽  
Neurological Complications ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Diabetic Rat ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Amyloid Deposits

The pathogenesis of diabetic neurological complications is not fully understood. Diabetes mellitus (DM) and Alzheimer’s disease (AD) are characterized by amyloid deposits. Glycogen synthase kinase-3 (GSK-3) plays an important role in the pathogenesis of AD and DM. Here we tried to investigate the production of amyloid-βpeptides (Aβ) and phosphorylation of microtubule-associated protein tau in DM rats and elucidate the role of GSK-3 and Akt (protein kinase B, PKB) in these processes. Streptozotocin injection-induced DM rats displayed an increased GSK-3 activity, decreased activity and expression of Akt. And Aβ40 and Aβ42 were found overproduced and the microtubule-associated protein tau was hyperphosphorylated in the hippocampus. Furthermore, selective inhibition of GSK-3 by lithium could attenuate the conditions of Aβoverproduction and tau hyperphosphorylation. Taken together, our studies suggest that GSK-3 regulates both the production of Aβand the phosphorylation of tau in rat brain and may therefore contribute to DM caused AD-like neurological defects.

scholarly journals Glycogen Synthase Kinase-3: A Focal Point for Advancing Pathogenic Inflammation in Depression

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2270
Author(s):  
Ryan T. McCallum ◽  
Melissa L. Perreault
Keyword(s):  
Immune Response ◽  
Glycogen Synthase ◽  
Focal Point ◽  
T Cell Differentiation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Major Depressive ◽  
Wide Range ◽  
Excessive Secretion ◽  
Pro Inflammatory Cytokines

Increasing evidence indicates that the host immune response has a monumental role in the etiology of major depressive disorder (MDD), motivating the development of the inflammatory hypothesis of depression. Central to the involvement of chronic inflammation in MDD is a wide range of signaling deficits induced by the excessive secretion of pro-inflammatory cytokines and imbalanced T cell differentiation. Such signaling deficits include the glutamatergic, cholinergic, insulin, and neurotrophin systems, which work in concert to initiate and advance the neuropathology. Fundamental to the communication between such systems is the protein kinase glycogen synthase kinase-3 (GSK-3), a multifaceted protein critically linked to the etiology of MDD and an emerging target to treat pathogenic inflammation. Here, a consolidated overview of the widespread multi-system involvement of GSK-3 in contributing to the neuropathology of MDD will be discussed, with the feed-forward mechanistic links between all major neuronal signaling pathways highlighted.

scholarly journals Glycogen Synthase Kinase 3 Activation Is Important for Anthrax Edema Toxin-Induced Dendritic Cell Maturation and Anthrax Toxin Receptor 2 Expression in Macrophages

2011 ◽  
Vol 79 (8) ◽  
pp. 3302-3308 ◽  
Author(s):  
Jason L. Larabee ◽  
Francisco J. Maldonado-Arocho ◽  
Sergio Pacheco ◽  
Bryan France ◽  
Kevin DeGiusti ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Glycogen Synthase ◽  
Dominant Negative ◽  
Anthrax Toxin ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Cell Surface Expression ◽  
Luciferase Reporter ◽  
Edema Toxin ◽  
The Impact

ABSTRACTAnthrax edema toxin (ET) is one of two binary toxins produced byBacillus anthracisthat contributes to the virulence of this pathogen. ET is an adenylate cyclase that generates high levels of cyclic AMP (cAMP), causing alterations in multiple host cell signaling pathways. We previously demonstrated that ET increases cell surface expression of the anthrax toxin receptors (ANTXR) in monocyte-derived cells and promotes dendritic cell (DC) migration toward the lymph node-homing chemokine MIP-3β. In this work, we sought to determine if glycogen synthase kinase 3 (GSK-3) is important for ET-induced modulation of macrophage and DC function. We demonstrate that inhibition of GSK-3 dampens ET-induced maturation and migration processes of monocyte-derived dendritic cells (MDDCs). Additional studies reveal that the ET-induced expression of ANTXR in macrophages was decreased when GSK-3 activity was disrupted with chemical inhibitors or with small interfering RNA (siRNA) targeting GSK-3. Further examination of the ET induction of ANTXR revealed that a dominant negative form of CREB could block the ET induction of ANTXR, suggesting that CREB or a related family member was involved in the upregulation of ANTXR. Because CREB and GSK-3 activity appeared to be important for ET-induced ANTXR expression, the impact of GSK-3 on ET-induced CREB activity was examined in RAW 264.7 cells possessing a CRE-luciferase reporter. As with ANTXR expression, the ET induction of the CRE reporter was decreased by reducing GSK-3 activity. These studies not only provide insight into host pathways targeted by ET but also shed light on interactions between GSK-3 and CREB pathways in host immune cells.

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