Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.11.247452v1?rss=1 Authors: Aggarwal, R., Peng, Z., Zeng, N., Silva, J., He, L., Chen, J., Debebe, A., Stiles, E., Chen, C.-Y., Stiles, B. L. Abstract: High circulating lipids occurring in obese individuals and insulin resistant patients are considered a contributing factor to Type 2 Diabetes (T2D). Exposure to high lipids initially causes the beta-cells to expand in population. Long-term exposure to high lipids however is associated with failure of beta-cells and the development of T2D. To prevent the failure of beta-cells and development of Type 2 Diabetes, this study focuses on understanding the molecular mechanisms that underlie this biphasic response of beta-cells to lipid exposure. Using palmitic acid (PA) in cultured beta-cells and islets, we demonstrated that chronic exposure to lipids leads to reduced viability and inhibition of cell cycle progression concurrent with downregulation of a pro-growth/survival kinase AKT, independent of glucose. This AKT downregulation by PA treatment is correlated with a consistent induction of mTOR/S6K activity concurrent with AKT downregulation. Inhibiting mTOR activity restores AKT activity and allows beta-cells to gain proliferation capacity that are lost after high fat diet exposure. In summary, we elucidated a novel mechanism for which lipid exposure may cause the dipole effects on beta-cell growth, where mTOR acts as a lipid sensor. These mechanisms can be novel targets for future therapeutic developments. Copy rights belong to original authors. Visit the link for more info