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- W2489743034 endingPage "158" @default.
- W2489743034 startingPage "99" @default.
- W2489743034 abstract "The discovery 30 years ago that inflammatory cytokines cause a concentration, activity, and time-dependent bimodal response in pancreatic β-cell function and viability has been a game-changer in the fields of research directed at understanding inflammatory regulation of β-cell function and survival and the causes of β-cell failure and destruction in diabetes. Having until then been confined to the use of pathophysiologically irrelevant β-cell toxic chemicals as a model of β-cell death, researchers could now mimic endocrine and paracrine effects of the cytokine response in vitro by titrating concentrations in the low to the high picomolar-femtomolar range and vary exposure time for up to 14-16h to reproduce the acute regulatory effects of systemic inflammation on β-cell secretory responses, with a shift to inhibition at high picomolar concentrations or more than 16h of exposure to illustrate adverse effects of local, chronic islet inflammation. Since then, numerous studies have clarified how these bimodal responses depend on discrete signaling pathways. Most interest has been devoted to the proapoptotic response dependent upon mainly nuclear factor κ B and mitogen-activated protein kinase activation, leading to gene expressional changes, endoplasmic reticulum stress, and triggering of mitochondrial dysfunction. Preclinical studies have shown preventive effects of cytokine antagonism in animal models of diabetes, and clinical trials demonstrating proof of concept are emerging. The full clinical potential of anticytokine therapies has yet to be shown by testing the incremental effects of appropriate dosing, timing, and combinations of treatments. Due to the considerable translational importance of enhancing the precision, specificity, and safety of antiinflammatory treatments of diabetes, we review here the cellular, preclinical, and clinical evidence of which of the death pathways recently proposed in the Nomenclature Committee on Cell Death 2012 Recommendations are activated by inflammatory cytokines in the pancreatic β-cell to guide the identification of antidiabetic targets. Although there are still scarce human data, the cellular and preclinical studies point to the caspase-dependent intrinsic apoptosis pathway as the prime effector of inflammatory β-cell apoptosis." @default.
- W2489743034 created "2016-08-23" @default.
- W2489743034 creator A5005408832 @default.
- W2489743034 creator A5010404114 @default.
- W2489743034 creator A5060488381 @default.
- W2489743034 creator A5089362378 @default.
- W2489743034 date "2016-01-01" @default.
- W2489743034 modified "2023-10-14" @default.
- W2489743034 title "Cytokines and Pancreatic β-Cell Apoptosis" @default.
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