Stress-Induced Protein Dermcidin Develops Diabetes Targeting GLUT4/Insulin via NO/cGMP Inhibition

Diabetes is highly prevalent in tobacco-consuming individuals, hypoxia-experiencing persons and post-menopausal women. The mechanism behind diabetes-associated vascular-disorders remains speculative. Dermcidin, an 11 kDa-protein plays a crucial role in acute myocardial infarction through the inhibition of nitric-oxide synthase. Therefore, dermcidin has been tested in the genesis of diabetes in human and rodentmodels under different physiological conditions. In these investigations blood levels of dermdicin significantly correlated with the diabetic condition in post-menopausal women, in tobacco consuming individuals and in hypoxic person indicating a common pathway. In mice, injection of dermcidin augmented the blood sugar level with a concomitant reduction of nitric-oxide levels. Dermcidin triggers the release of glucose from liver/muscle/kidney; and antagonizes the effects of insulin even more effectively than glucagon. Immunohistochemical studies showed that dermcidin inhibits GLUT-4 translocation and impairs nitric-oxide production. Here, we show that tobacco consumption or hypoxia might provoke hyperglycemia induced by dermcidin by concomitant down regulation of NO-signaling, GLUT4-function and insulin-sensitivity. Largest representative of haematopoetic cell, neutrophils show significantly increased glucose mediated insulin, GLUT-4 and GANOS expression which was missing in postmenopausal women due to the dermcidin effect. Bioinformatics study with protein networking (STRING) analysis suggests DCN role on soluble guanylate-cylase activity in higher primate. Our FRET-imaging studies demonstrate that DCD-induced NO deregulation impairs cGMP mediated cellular signaling. Molecular docking experiments (AUTODOC/PATCHDOC) decisively show high affinity binding of DCN to GLUT-4, insulin and its receptor (Ectodomain 1/2). Synergisms of these effects result in breakdown of glucose homeostasis machinery in individuals under wide variety of stressors. Funding Statement: The authors state: "No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Declaration of Interests: The authors declare: "None." Ethics Approval Statement: The protocols for both animal and human sample experiments were approved by the Institutional Review Board, Human & Animal Research Ethics Committee, Sinha Institute of Medical Science and Technology, Kolkata, India. The protocol strictly followed the Human ethics according to the 1964 Helsinki Declaration and National Institutes of Health, USA guidelines.