Withdrawal
British Journal of Pharmacology(2022)
Abstract
BACKGROUND AND PURPOSE Diabetes is common in tobacco-consuming individuals, hypoxia-encountering people, and post-menopausal women. The mechanism behind diabetes-associated vascular-dysfunction remains speculative. Dermcidin (DCD), an 11 kDa-protein plays a detrimental role in acute myocardial-infarction through the impairment of endothelial-nitric-oxide-synthase (eNOS). EXPERIMENTAL APPROACH DCD mediated genesis of diabetes has been manifested in human and rodent-models under various stress-conditions. Here, plasma levels of DCD have been significantly correlated with the diabetic-conditions in postmenopausal-women, in tobacco-consuming individuals and in hypoxia indicating a common pathway. In mice, DCD infusion augmented the blood glucose with a concomitant reduction of nitric oxide levels. DCD triggers the release of glucose from the liver/muscle/kidney and antagonizes the effects of insulin. This has been demonstrated by the glucose tolerance and insulin tolerance test. Herein our studies showed that DCD inhibited GLUT-4 and impaired NO production. KEY RESULTS We showed that tobacco consumption or hypoxia might provoke DCD-induced hyperglycemia by down-regulation of NO-signaling, GLUT4-function, and insulin sensitivity. Tobacco-induced DCD up-regulation has been shown in RT-PCR and qPCR results and DCD-induced lower insulin-sensitivity has been shown by Western-blot. The insulin, GLUT-4, and GANOS expression were missing in postmenopausal women due to DCD. Our FRET-imaging studies demonstrate that DCD-induced NO deregulation impairs cGMP-mediated cellular-signaling. CONCLUSIONS & IMPLICATIONS Molecular-docking experiments (AUTODOCK/PATCHDOCK) decisively showed high-affinity binding of DCD to GLUT-4, insulin, and its receptor (Ectodomain1/2). Synergism of all these effects resulted in the breakdown of glucose homeostasis-machinery i.e. insulin-resistance, and further dermcidin induced NO/cGMP down-regulation in individuals under a variety of stressors.
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