Interaction between cytokines and inflammatory cells in islet dysfunction, insulin resistance and vascular disease

Abstract

Inflammation is an established pathogenic player in insulin resistance, islet demise, and atherosclerosis. The complex interactions between cytokines, immune cells, and affected tissues result in sustained inflammation in diabetes and atherosclerosis. 12- and 15-lipoxygenase (LO), such as 12/15LO, produces a variety of metabolites through peroxidation of fatty acids and potentially contributes to the complex molecular crosstalk at the site of inflammation. 12- and 15-LO pathways are frequently activated in tissues affected by diabetes and atherosclerosis including adipose tissue, islets, and the vasculature. Moreover, mice with whole body and tissue-specific knockout of 12/15-LO are protected against insulin resistance, hyperglycemia, and atherosclerosis supporting functional contribution of 12- and 15-LO pathways in diabetes and atherosclerosis. Recently it has emerged that there is a temporal regulation of the particular isoforms of 12- and 15-LO in human adipose tissue and islets during the development of type 1 and type 2 diabetes and obesity. Analyses of tissues affected by diabetes and atherosclerosis also implied the roles of interleukin (IL)-12 and NADPH oxidase 1 (NOX1) in islets and IL-17A in atherosclerosis. Future studies should aim to test the efficacy of inhibitions of these mediators for treatment of diabetes and atherosclerosis.

Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction

“…Studies have implicated inflammatory cytokines and immune cell infiltration leading to pathways, including oxidative and endoplasmic reticulum (ER) stress activation, that damage beta cell viability [4][5][6][7][8][9][10][11]. Despite advances, key therapeutic targets leading to new drug-based strategies to prevent the loss of functional beta cell mass have not been clearly identified [12].…”

“…12-Lipoxygenase is an oxygenase for arachidonic acid (AA) and other fatty acids, leading to proinflammatory lipids including 12-S-hydroperoxieicosatetraenoic acid (12-S-HPETE) and 12-S-hydroxyeicosatetraenoic acid (12-S-HETE) [14,15]. 12-Lipoxygenase is expressed in rodent and human islets [11,[15][16][17][18] and is upregulated under conditions of metabolic and cytokine stress. Direct addition of 12-S-HETE can impair beta cell function or can lead to loss of human beta cell viability [13,15,16,[19][20][21][22].…”

“…Direct addition of 12-S-HETE can impair beta cell function or can lead to loss of human beta cell viability [13,15,16,[19][20][21][22]. Recent evidence indicates that increased expression of 12-lipoxygenase in islets is a common feature of both rodent and human models of type 1 and type 2 diabetes [11,13,15,17,22]. Deletion of 12-lipoxygenase protects mice against hyperglycaemia induced with low dose streptozotocin.…”

“…Deletion of 12-lipoxygenase significantly inhibits the development of insulin resistance in mice fed a high-fat diet. Products of 12-lipoxygenase lead to ER stress, oxidative stress and generation of proinflammatory cytokines [11,13,14,26]. Very recent evidence has shown that 12-lipoxygenase can generate IL-12 production in the islet [23,27].…”

“…Local IL-12 production may propagate an immune inflammatory state that further induces beta cell damage [27]. In human islets obtained from donors with type 2 diabetes, 12-lipoxygenase is upregulated and is associated with early islet dysfunction and increased migration of CD45 + leucocytes [11]. Studies to date have not shown any adverse effects associated with a targeted genetic deletion of 12-lipoxygenase in rodent models.…”