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Lipid mediators and biomarkers associated with type 1 diabetes development.

ABSTRACT: Type 1 diabetes (T1D) is a consequence of autoimmune ? cell destruction, but the role of lipids in this process is unknown. We previously reported that activation of Ca2+-independent phospholipase A2? (iPLA2?) modulates polarization of macrophages (M?). Hydrolysis of the sn-2 substituent of glycerophospholipids by iPLA2? can lead to the generation of oxidized lipids (eicosanoids), pro- and antiinflammatory, which can initiate and amplify immune responses triggering ? cell death. As M? are early triggers of immune responses in islets, we examined the impact of iPLA2?-derived lipids (iDLs) in spontaneous-T1D prone nonobese diabetic mice (NOD), in the context of M? production and plasma abundances of eicosanoids and sphingolipids. We find that (a) M?NOD exhibit a proinflammatory lipid landscape during the prediabetic phase; (b) early inhibition or genetic reduction of iPLA2? reduces production of select proinflammatory lipids, promotes antiinflammatory M? phenotype, and reduces T1D incidence; (c) such lipid changes are reflected in NOD plasma during the prediabetic phase and at T1D onset; and (d) importantly, similar lipid signatures are evidenced in plasma of human subjects at high risk for developing T1D. These findings suggest that iDLs contribute to T1D onset and identify select lipids that could be targeted for therapeutics and, in conjunction with autoantibodies, serve as early biomarkers of pre-T1D.

SUBMITTER: Nelson AJ

PROVIDER: S-EPMC7455134 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Lipid mediators and biomarkers associated with type 1 diabetes development.

Nelson Alexander J AJ Stephenson Daniel J DJ Bone Robert N RN Cardona Christopher L CL Park Margaret A MA Tusing Ying G YG Lei Xiaoyong X Kokotos George G Graves Christina L CL Mathews Clayton E CE Kramer Joanna J Hessner Martin J MJ Chalfant Charles E CE Ramanadham Sasanka S

JCI insight 20200820 16

Type 1 diabetes (T1D) is a consequence of autoimmune β cell destruction, but the role of lipids in this process is unknown. We previously reported that activation of Ca2+-independent phospholipase A2β (iPLA2β) modulates polarization of macrophages (MΦ). Hydrolysis of the sn-2 substituent of glycerophospholipids by iPLA2β can lead to the generation of oxidized lipids (eicosanoids), pro- and antiinflammatory, which can initiate and amplify immune responses triggering β cell death. As MΦ are early ...[more]

PMID: 32814707

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Project description:Diabetes and its associated chronic complications present a healthcare challenge on a global scale. Despite improvements in the management of chronic complications of the micro-/macro-vasculature, their growing prevalence and incidence highlights the scale of the problem. It is currently estimated that diabetes affects 425 million people globally and it is anticipated that this figure will rise by 2025 to 700 million people. The vascular complications of diabetes including diabetes-associated atherosclerosis and kidney disease present a particular challenge. Diabetes is the leading cause of end stage renal disease, reflecting fibrosis leading to organ failure. Moreover, diabetes associated states of inflammation, neo-vascularization, apoptosis and hypercoagulability contribute to also exacerbate atherosclerosis, from the metabolic syndrome to advanced disease, plaque rupture and coronary thrombosis. Current therapeutic interventions focus on regulating blood glucose, glomerular and peripheral hypertension and can at best slow the progression of diabetes complications. Recently advanced knowledge of the pathogenesis underlying diabetes and associated complications revealed common mechanisms, including the inflammatory response, insulin resistance and hyperglycemia. The major role that inflammation plays in many chronic diseases has led to the development of new strategies aiming to promote the restoration of homeostasis through the "resolution of inflammation." These strategies aim to mimic the spontaneous activities of the 'specialized pro-resolving mediators' (SPMs), including endogenous molecules and their synthetic mimetics. This review aims to discuss the effect of SPMs [with particular attention to lipoxins (LXs) and resolvins (Rvs)] on inflammatory responses in a series of experimental models, as well as evidence from human studies, in the context of cardio- and reno-vascular diabetic complications, with a brief mention to diabetic retinopathy (DR). These data collectively support the hypothesis that endogenously generated SPMs or synthetic mimetics of their activities may represent lead molecules in a new discipline, namely the 'resolution pharmacology,' offering hope for new therapeutic strategies to prevent and treat, specifically, diabetes-associated atherosclerosis, nephropathy and retinopathy.

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Lipid mediators and biomarkers associated with type 1 diabetes development.

Publications

Lipid mediators and biomarkers associated with type 1 diabetes development.

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