Controlling insulin resistance through modulation of interplay between mediators of cellular senescence: A mathematical study

Obesity, metabolic syndrome and premature ageing form a hugely researched and discussed area of interest these days. In the pathology of this cluster of conditions, adipose tissue is gaining attention as a major playground for interplay between metabolic stress, inflammation and accelerated ageing, and not merely being an energy storage tank. Drastic elevation in the levels of reactive oxygen species, due to lipid overload and excessive lipolysis, causes genotoxic damage such as shortening of telomeres (an indicator of accelerated cell ageing), increased mRNA and protein expression for p53, p21, TNF-, IL-6 (interleukin 6), impaired insulin mediated glucose uptake, and decreased TERT mRNA expression. The increase of p53 in adipocytes is deleterious, since elevated p53 results in pre-mature ageing of fat tissues which secrete pro-inflammatory cytokines thereby contributing to insulin resistance. But inhibition of p53 as a therapeutic target, as suggested by many previous studies, could result in developing high risks of cancer. The association between hyperlipidemic/hyperglycaemic stress, premature growth arrest and insulin resistance, thus, forms an interesting premise for searching targets and designing interventions for therapy of metabolic syndrome, type 2 diabetes mellitus etc. We developed a mathematical study involving a 5D ODE model, which revealed crucial parametric conditions governing p53 dynamics in the case of metabolic stress-induced cellular senescence, and shed light on potential strategies to reduce pro-inflammatory cytokine levels which exacerbate insulin resistance through premature cellular ageing.\n\nHighlightsO_LIp53 oscillations signify DNA repair, and persistent stress causes prolonged surge in p53 levels inducing cellular senescence.\nC_LIO_LIp53-induced cellular senescence promotes inflammation and enhances progression of insulin resistance.\nC_LIO_LIRegulation of Mdmx and Akt can be a strategy to rejuvenate ageing cells through management of IL-6 dynamics.\nC_LI