Abstracts

Speaker 1
Francesca Siclari
 – Center for Investigation and Research on Sleep, CHUV, Lausanne, Switzerland
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Speaker
 2
Carlos Guillén Viejo
– Department of Biochemistry and Molecular Biology, Complutense University of Madrid, Spain
Hyperactivation of MTORC1, aging and pancreatic β cells

Type 2 diabetes mellitus (T2DM) is a very complex disease and it is considered epidemic in the world. Insulin resistance and pancreatic β cell dysfunction are considered to be the main contributors for the development to T2DM. As a consequence, β-cells compensate increasing its number and/or size in order to secrete more insulin and amylin. As the disease progresses, pancreatic β cells are overwhelmed and fails in their capacity to compensate insulin resistance. In addition, it is usually associated with other metabolic diseases such as hyperlipidemia, obesity and the metabolic syndrome. During the progression to T2DM there is a chronic activation of MTORC1 signaling pathway, which induces aging and acts as an endogenous inhibitor of autophagy. MTORC1 controls cell proliferation, cell growth as well as metabolism in a variety of cell types through a complex signaling network. Recent data indicate that autophagy pathway protects from human amylin-induced proteotoxicity. TSC2 is an essential component in the control of MTORC1 and it is regulated by multiple posttranslational modifications. Autophagy represents a protective mechanism for different cell types, including pancreatic β cells, and potentiates β cell survival across the progression to T2DM. Then, chronic overactivation of MTORC1 signaling pathway in β islets from prediabetics patients, make these cells more prone to trigger apoptosis upon several cellular stressors and allowing the progression from pre-diabetes to type 2 diabetes status. In fact, we have observed that overexpressed human amylin (hIAPP) induce the formation of amylin aggregates that accumulate in cytoplasm of insulinoma β cells, increasing ER stress, impairing autophagy, and inducing an unbalance in the mitochondrial dynamics with an inhibited mitophagy. The elimination of the harmful and toxic amylin plaques it is a critical point. Degradative pathways are interconnected with secretory pathways, which could facilitate exportation of protein aggregates and organelles to other tissues. The formation of exosomes represents a novel pathway of intercellular communication that may potentially be used as detoxifying mechanism to eliminate toxic amylin beta-sheet aggregates. The delivery of those exosomes through the blood brain barrier into brain structures and cells may cause neurodegeneration and potentiate that process in neurodegenerative diseases such as Alzheimer’s disease. As conclusion, firstly, a chronic hyperactivation of mTORC1 signaling pathway in β islets from prediabetic patients leads to on one hand to the expansion of the pancreatic beta cell mass and, on the other to the inhibition of autophagy as protective mechanism of beta cells against the attack of several stressors, making these cells more prone to trigger apoptosis. Thus, the maintenance of a functional autophagy it is an essential component to protect and prolong pancreatic β cell life span precluding chronic hyperglycemia. And secondly, exosomes could be a vehicle to carry on these toxic products to other cell types such as hippocampal cells, accelerating neurodegenerative processes, and establishing a possible etiopathological link between T2DM and neurodegenerative diseases.


Speaker 3
Wendy Russell – The Rowett Institute, University of Aberdeen, UK
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Speaker 4 – Start-up

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Speaker 5
Jonathan Cooper – Division of Biomedical Engineering, University of Glasgow, UK
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