To tackle our first objective, we have engineered unique cellular imaging tools allowing us to trace these processes in space and time and to identify underlying molecular mechanisms. With these tools, we investigated insulin granule degradation in pancreatic β cell under overnutrition conditions. We observed that chronic exposure to elevated glucose and saturated fatty acids promoted insulin granule degradation. Indeed, using microscopy to track fluorescent markers of insulin granules and lysosomes, we highlighted an increased co-localization between insulin granules and lysosomes. These data were confirmed by electronic microscopy allowing us to evidence the accumulation of insulin granules in the degradation compartment.
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.
