Eicosanoids, β-cell function, and diabetes

Abstract

Arachidonic acid (AA) is metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes into eicosanoids, which are involved in diverse diseases, including type 1 and type 2 diabetes. During the last 30 years, evidence has been accumulated that suggests important functions for eicosanoids in the control of pancreatic β-cell function and destruction. AA metabolites of the COX pathway, especially prostaglandin E₂ (PGE₂), appear to be significant factors to β-cell dysfunction and destruction, participating in the pathogenesis of diabetes and its complications. Several elegant studies have contributed to the sorting out of the importance of 12-LOX eicosanoids in cytokine-mediated inflammation in pancreatic β cells. The role of CYP eicosanoids in diabetes is yet to be explored. A recent publication has demonstrated that stabilizing the levels of epoxyeicosatrienoic acids (EETs), CYP eicosanoids, by inhibiting or deleting soluble epoxide hydrolase (sEH) improves β-cell function and reduces β-cell apoptosis in diabetes. In this review we summarize recent findings implicating these eicosanoid pathways in diabetes and its complications. We also discuss the development of animal models with targeted gene deletion and specific enzymatic inhibitors in each pathway to identify potential targets for the treatment of diabetes and its complications.

Introduction

Between 2000 and 2010, the number of people with diabetes has more than doubled, from 121 to 285 million. That number is expected to grow to 438 million by 2030 [1]. Currently, 23.4 million Americans have diabetes (American Diabetes Association, National Diabetes Fact Sheet, 2007). The Center for Disease Control (CDC) estimates that the current cost of diabetes is $174 billion annually in the U.S.

Diabetes, which is characterized by hyperglycemia, is divided into type 1 (T1DM) and type 2 diabetes mellitus (T2DM). T1DM is characterized by autoimmune destruction of β cells [2], [3]. Ultimately, circulating insulin concentrations are negligible or completely absent in patients with T1DM [4]. Obesity, which affects one in three Americans, is a serious health problem because it is often associated with T2DM [5], [6], which occurs because of insufficient generation of insulin and/or the inability of peripheral tissues, including skeletal muscle and adipose tissue, to respond to insulin efficiently. The development of T2DM is firmly associated with insulin resistance, a physiological condition in which insulin becomes less effective at lowering blood glucose [5], [6]. Diabetes shortens the life span as a consequence of cardiovascular disorders, including heart attack, hypertension, and stroke [7], [8]. Accordingly, diabetes-associated complications result in major expense for families and impose a major societal economic burden.

Since pancreatic β-cell dysfunction and destruction are the key events in the onset and progression of diabetes [2], [3], [9], [10], this review will focus on how arachidonic acid (AA)-derived lipid mediators affect insulin secretion and β-cell destruction as well as the role of these eicosanoids in diabetes. AA is a polyunsaturated fatty acid, which is esterified at the sn-2 position of the glycerol backbone of membrane phospholipids or other complex lipids [11]. AA is released from phospholipids by the action of phospholipase A₂ (PLA₂), which specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing AA and lysophospholipids.

As shown in Fig. 1, AA is modified by three major pathways, including cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP), into biologically active eicosanoids (eicosa, Greek for 20, refers to 20 carbon fatty acids) [11], [12], [13], [14]. The products of these pathways act as paracrine and autocrine factors and contribute significantly to the regulation of inflammation [13], [15], renal function [16], [17], and vascular function [18], [19]. Since novel receptors and metabolites of COX and LOX pathways are well defined, these two eicosanoid pathways are important therapeutic targets for inflammatory and cardiovascular diseases [13]. This review aims to provide important information related to brief background of biochemistry and function of eicosanoids, regulation of β-cell function by eicosanoids, regulation of β-cell destruction by eicosanoids, and the involvement of eicosanoids in diabetes.