Nutrient-dependent lysosomal functions in type 2 diabetes – LYSODIABETES

Proper nutrient sensing is crucial in multicellular organisms. In mammals upon feeding, the pancreatic ß cell mainly senses increasing glucose levels and secretes insulin that acts to induce anabolic pathways in different organs. Inversely, the ß cell decreases insulin secretion to suppress these anabolic reactions upon low glucose levels during fasting. While mechanisms linking glucose sensing to exocytosis of insulin granules have been widely investigated, relatively little is known about how nutrients impact on molecular events at the Trans-Golgi-Network (TGN) underlying insulin granule biogenesis and their cellular destination.
We have recently identified Protein Kinase D (PKD) at the TGN as a crucial nutrient-dependent gatekeeper in these processes. We have derived compelling data supporting a novel concept in which PKD-dependent signals at the TGN determine routing of newly-made insulin granules for secretion in presence or for lysosomal degradation in absence of nutrients. Lysosomal degradation of insulin granules (LDIG) results in activation of mTORC1 at lysosomes and suppression of macroautophagy (hereafter referred to as “autophagy”). Keeping autophagy high during fasting led to uncontrolled insulin release. Suppression of autophagy through LDIG is thus an optimal strategy to counteract insulin secretion during fasting, at the same time providing sufficient nutrients for ß cells to survive. However, we have recently obtained data providing evidence that deregulation of LDIG could be a hallmark of diabetic ß cells that may contribute to secretory dysfunction in type 2 diabetes (T2D).
Based on these findings, we wish to explore more fundamentally the role of lysosomes in ß cell function, opening a new research avenue going beyond our previous research activity. We also wish to extend experimental results into more physiological as well as translational aspects, opening a new national collaborative project involving the laboratory of Prof. François Pattou at the E.g.i.d. at the University of Lille and the laboratory of Prof. Catherine Postic at the “Institut Cochin” in Paris.
The objectives of the project are (1) to mechanistically explore LDIG in pancreatic ß cells, (2) to address how deregulation of LDIG affects progression of T2D, and (3) to provide a solid basis for LDIG to be considered as a valuable therapeutic target in T2D.
To tackle above objectives, we have engineered unique cellular imaging tools allowing us to trace these processes in space and time and to identify underlying molecular mechanisms using a cellular screening approach. These unbiased experiments will be combined with candidate approaches based on solid preliminary data using genetically manipulated cell lines, pancreatic islets as well as mouse models. Finally, we have developed strategies to implement our findings into a human disease context aiming at assessing their therapeutic potential. This comprehensive experimental approach will set the stage for a new concept explaining as to how ß cell function decompensates in response to obesity-related insulin resistance, which constitutes a major question in the field.
There is an emerging endeavour of the pharmaceutical industry to develop strategies targeting the ß cell that go beyond improving insulin secretion. This project will thus fortify our hypothesis that lysosomal insulin degradation contributes to ß cell failure in T2D. Moreover, it will determine whether pharmacological targeting of these processes in the ß cell will be beneficial in T2D.