Periodic Reporting for period 1 - INSULYSOSOME (The role of CD63 in lysosomal degradation of insulin granules in pancreatic beta cells in T2D diabetes)
Período documentado: 2018-11-01 hasta 2020-10-31
To maintain blood glucose at a normal level, the pancreatic β cell harbors an exemplary nutrient sensing machinery that is coupled to secretion of insulin. The pancreatic β cell mainly senses increasing glucose levels and secretes insulin that acts to promote the energy storage in different organs. Inversely, the β cell decreases insulin secretion to make available stored energy upon low glucose levels during fasting. Overnutrition conditions in combination with physical inactivity may trigger obesity and insulin resistance. To meet high insulin demands encountered in obese people, the pancreatic β cell will enhance its insulin secretory capacity. However, these compensatory mechanisms will eventually be overwhelmed culminating in β cell failure and full-blown type 2 diabetes (T2D).
While huge research efforts have been intended to unravel and target molecular mechanisms behind T2D, the picture is still far from being complete. While mechanisms linking glucose sensing to release of insulin have been widely investigated, little is known about how nutrients impact on insulin granule generation and their destination in the cell. Hence, novel research insights leading to therapeutic approaches are highly demanded to prevent enormous health costs and negative consequences of our modern lifestyle.
We have recently discovered a novel concept in which the newly-made insulin granules can be routed either for secretion in presence or for degradation in absence of nutrients. Moreover, we have discovered that routing insulin granules for degradation could be a hallmark of diabetic ß cells that may contribute to secretory dysfunction in T2D. Based on these findings, we have explored more fundamentally the role insulin granule degradation in ß cell function. It is essential to understand the molecular mechanisms behind the degradation of insulin in pancreatic ß cells and to address how this deregulation can promote progression of T2D.
Enhanced degradation of cellular components can counteract energy depletion caused by shortage of environmental nutrients through a process called autophagy. Interestingly, our laboratory has recently discovered that β cells employ a very distinct and so far unknown mechanism to adapt to nutrient depletion. Indeed, β cells induce insulin granule degradation independent of autophagy upon nutrient withdrawal. We thus next asked whether nutrient stress imposed by overnutrition treatment evoked similar effects. Our data indicated that degradation of insulin granules was likely to contribute to suppression of autophagy in overnutrition conditions for β cells. Hence, we propose that enhancement of insulin granule degradation leads to compromised autophagy accelerating β cell failure and T2D.
To confirm our findings in vivo, we decided to study insulin granule degradation in mice subjected to a metabolic stress by feeding animals a high-fat diet (HFD) or in a genetic model of T2D mouse. Interestingly, we observed the same increase of insulin granule degradation and the same inhibition of autophagy in mouse and human pancreatic β cells.
Our findings provide strong evidence for increased insulin granule degradation in diabetic β cells. Through a collaboration with an industrial partner, we have generated a compound with the potential to prevent degradation of insulin granules. We confirmed that the compound enhanced insulin content and autophagy in the β cells. Strikingly, a two-week treatment of obese mice prior β cell failure retarded diabetic progression.
Taken together, our data demonstrate that the nutrient sensing machinery in β cells controls targeting of insulin granules towards secretion or degradation. Nutrient stress-imposed deregulation favours triggering of insulin granule degradation and suppression of autophagy. This mechanism may contribute to insulin loss, reduced secretory capacity and to decreased autophagy, hallmarks of β cell dysfunction in T2D.
The work has been presented at numerous meetings including for example at the EMBO workshop “Lysosome and Metabolism” in 2018 in Naples or at the EASD meeting in Berlin in 2018 and was finally published in Nature Communications in 2019.
Existing treatments do not succeed in restoring a normal blood glucose in the long term, since β-cell function declines over time. Moreover, there is presently no single drug able to reverse all aspects of the disease. In addition, most of these medications have been shown to lose effectiveness with long-term use. We are convinced that the novelty of these results that have been obtained and the therapeutic potential could help to prevent the enormous health costs and negative consequences of modern lifestyle.