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      Purinergic P2X 7 receptors regulate secretion of interleukin-1 receptor antagonist and beta cell function and survival

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          Abstract

          Aims/hypothesis

          In obesity, beta cells activate compensatory mechanisms to adapt to the higher insulin demand. Interleukin-1 receptor antagonist (IL-1Ra) prevents obesity-induced hyperglycaemia and is a potent target for the treatment of diabetes, but the mechanisms of its secretion and regulation in obesity are unknown. In the present study, we hypothesise the regulation of IL-1Ra secretion by purinergic P2X 7 receptors in islets.

          Methods

          Production and regulation of P2X 7 were studied in pancreatic sections from lean and obese diabetic patients, non-diabetic controls and in isolated islets. IL-1Ra, IL-1β and insulin secretion, glucose tolerance and beta cell mass were studied in P2x7 (also known as P2Rx7)-knockout mice.

          Results

          P2X 7 levels were elevated in beta cells of obese patients, but downregulated in patients with type 2 diabetes mellitus. Elevated glucose and non-esterified fatty acids rapidly activated P2X 7 and IL-1Ra secretion in human islets, and this was inhibited by P2X 7 blockade. In line with our results in vitro, P2x7-knockout mice had a lower capacity to secrete IL-1Ra. They exhibited severe and rapid hyperglycaemia, glucose intolerance and impaired beta cell function in response to a high-fat/high-sucrose diet, were unable to compensate by increasing their beta cell mass in response to the diet and showed increased beta cell apoptosis.

          Conclusions/interpretation

          Our study shows a tight correlation of P2X 7 activation, IL-1Ra secretion and regulation of beta cell mass and function. The increase in P2X 7 production is one mechanism that may explain how beta cells compensate by adapting to the higher insulin demand. Disturbances within that system may result in the progression of diabetes.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00125-009-1349-0) contains supplementary material, which is available to authorised users.

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          Most cited references38

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          Diet-induced type II diabetes in C57BL/6J mice.

          We investigated the effects of diet-induced obesity on glucose metabolism in two strains of mice, C57BL/6J and A/J. Twenty animals from each strain received ad libitum exposure to a high-fat high-simple-carbohydrate diet or standard Purina Rodent Chow for 6 mo. Exposure to the high-fat, high-simple-carbohydrate, low-fiber diet produced obesity in both A/J and C57BL/6J mice. Whereas obesity was associated with only moderate glucose intolerance and insulin resistance in A/J mice, obese C57BL/6J mice showed clear-cut diabetes with fasting blood glucose levels of greater than 240 mg/dl and blood insulin levels of greater than 150 microU/ml. C57BL/6J mice showed larger glycemic responses to stress and epinephrine in the lean state than AJ mice, and these responses were exaggerated by obesity. These data suggest that the C57BL/6J mouse carries a genetic predisposition to develop non-insulin-dependent (type II) diabetes. Furthermore, altered glycemic response to adrenergic stimulation may be a biologic marker for this genetic predisposition to develop type II diabetes.
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            Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets.

            In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic beta cells, causing impaired insulin secretion. IL-1beta is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1beta inhibits beta cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-kappaB. Recently, we have shown that increased glucose concentrations also induce Fas expression and beta cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1beta may mediate the deleterious effects of high glucose on human beta cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1beta, followed by NF-kappaB activation, Fas upregulation, DNA fragmentation, and impaired beta cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. beta cells themselves were identified as the islet cellular source of glucose-induced IL-1beta. In vivo, IL-1beta-producing beta cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1beta was induced in beta cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented beta cell expression of IL-1beta. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1beta/NF-kappaB pathway as a target to preserve beta cell mass and function in this condition.
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              Rapid secretion of interleukin-1beta by microvesicle shedding.

              The proinflammatory cytokine interleukin-1beta (IL-1beta) is a secreted protein that lacks a signal peptide and does not follow currently known pathways of secretion. Its efficient release from activated immune cells requires a secondary stimulus such as extracellular ATP acting on P2X(7) receptors. We show that human THP-1 monocytes shed microvesicles from their plasma membrane within 2-5 s of activation of P2X(7) receptors. Two minutes after such stimulation, the released microvesicles contained bioactive IL-1beta, which only later appeared in the vesicle-free supernatant. We conclude that microvesicle shedding is a major secretory pathway for rapid IL-1beta release from activated monocytes and may represent a more general mechanism for secretion of similar leaderless secretory proteins.
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                Author and article information

                Contributors
                kmaedler@uni-bremen.de
                Journal
                Diabetologia
                Diabetologia
                Springer-Verlag (Berlin/Heidelberg )
                0012-186X
                1432-0428
                25 April 2009
                August 2009
                : 52
                : 8
                : 1579-1588
                Affiliations
                [1 ]Department of Medicine, Larry L. Hillblom Islet Research Center, UCLA, Los Angeles, CA USA
                [2 ]Centre for Biomolecular Interactions Bremen, University of Bremen, NW2, Box 33 04 40, 28334 Bremen, Germany
                [3 ]Division of Transplantation, University of Illinois at Chicago, Chicago, IL USA
                Article
                1349
                10.1007/s00125-009-1349-0
                2709906
                19396427
                0ca8e5fc-ec5d-4f6b-9334-f80133d4af99
                © The Author(s) 2009
                History
                : 19 January 2009
                : 3 March 2009
                Categories
                Article
                Custom metadata
                © Springer-Verlag 2009

                Endocrinology & Diabetes
                islets,obesity,purinergic receptor p2x7,interleukin-1 receptor antagonist,diabetes

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