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      Catabolic and anabolic faces of insulin resistance and their disorders: a new insight into circadian control of metabolic disorders leading to diabetes


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          Maintenance of glucose homeostasis during circadian behavioral cycles is critical. The processes controlling the switch between predominant lipolysis/fatty oxidation during fasting and predominant lipid storage/glucose oxidation following feeding are determined principally by insulin. Chronic elevated threshold of insulin resistance (IR) is a key pathological feature of obesity, Type 2 diabetes, sepsis and cancer cachexia; however, a temporal reduced threshold of IR is widely met in fasting/hibernation, pregnancy, antibacterial immunity, exercise and stress. Paradoxically, some of these cases are associated with catabolic metabolism, whereas others are related to anabolic pathways. This article considers the possible causes of circadian disorders in glucose and lipid metabolism that act as a driving force for obesity-promoted development of Type 2 diabetes. This is intended to provide improved insight into the pathogenesis of chronic circadian disorders that increase the risk of diabetes, and consider new targets for its metabolic and drug correction.

          Lay abstract:

          Insulin resistance (IR) is a common adaptive mechanism, acting under opposite anabolic and catabolic conditions. However, chronic IR is a key pathological feature of obesity, Type 2 diabetes and cancer cachexia, whereas a temporal IR is widely seen in fasting, pregnancy, exercise and stress. Therefore, it is important to understand when this transient IR-mechanism shifts to chronic IR-associated diseases. What factors result in the switch between the anabolic and catabolic conditions and what defect(s) in this switch is associated with chronic IR induction? The present opinion article aimed to address these questions to the metabolic changes typical for circadian regulation in lean, obese and diabetic patients.

          Graphical abstract: Early circadian IR disorders caused by overweight and obesity are associated with increased risk for diabetes via formation of a vicious cycle between lipid anabolic and catabolic programs thus distorting insulin and lipid levels in day/night period.

          Most cited references34

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          The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta.

          NF-kappaB comprises a family of cellular transcription factors that are involved in the inducible expression of a variety of cellular genes that regulate the inflammatory response. NF-kappaB is sequestered in the cytoplasm by inhibitory proteins, I(kappa)B, which are phosphorylated by a cellular kinase complex known as IKK. IKK is made up of two kinases, IKK-alpha and IKK-beta, which phosphorylate I(kappa)B, leading to its degradation and translocation of NF-kappaB to the nucleus. IKK kinase activity is stimulated when cells are exposed to the cytokine TNF-alpha or by overexpression of the cellular kinases MEKK1 and NIK. Here we demonstrate that the anti-inflammatory agents aspirin and sodium salicylate specifically inhibit IKK-beta activity in vitro and in vivo. The mechanism of aspirin and sodium salicylate inhibition is due to binding of these agents to IKK-beta to reduce ATP binding. Our results indicate that the anti-inflammatory properties of aspirin and salicylate are mediated in part by their specific inhibition of IKK-beta, thereby preventing activation by NF-kappaB of genes involved in the pathogenesis of the inflammatory response.
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            Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis.

            Metabolism and immunity are inextricably linked both to each other and to organism-wide function, allowing mammals to adapt to changes in their internal and external environments. In the modern context of obesogenic diets and lifestyles, however, these adaptive responses can have deleterious consequences. In this Review, we discuss the pleiotropic actions of inflammation and insulin resistance in metabolic homeostasis and disease. An appreciation of the adaptive context in which these responses arose is useful for understanding their pathogenic actions in disease.
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              Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans.

              Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show--by using two 8-d laboratory protocols--in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers.

                Author and article information

                Future Sci OA
                Future Sci OA
                Future Science OA
                Future Science Ltd (London, UK )
                August 2017
                26 June 2017
                : 3
                : 3
                : FSO201
                [1 ]Institute of Theoretical & Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
                Author notes
                *Author for correspondence: P.Schwartsburd@ 123456rambler.ru
                © 2017 Future Science Ltd

                This work is licensed under a Creative Commons Attribution 4.0 License

                : 25 January 2017
                : 23 March 2017
                Special Report

                circadian disorders,inflammation,insulin resistance,obesity,metabolism,type 2 diabetes


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