Altérations du couplage stimulation-sécrétion dans les cellules β-pancréatiques exposées à l'hyperglycémie chronique
(2011)
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- Authors
- Supervisors
- Jonas, Jean-Christophe
- Abstract
- (en) Chronic exposure of pancreatic β-cells to supraphysiological glucose concentrations leads to an important reduction of their insulin secretory competence. This reduction has been classically attributed to a reduction of the β-cell insulin content and of their ability to increase their metabolic level and cytosolic calcium concentration ([Ca2+]c) in response to a glucose rise. This apparent desensitization to glucose can be due to oxidative stress, increased expression of the mitochondrial uncoupling protein, UCP-2 or apoptosis. However, other studies have shown that β-cells previously exposed to hyperglycemia are, in contrast, more sensitive to glucose. During my PhD, I confirmed that 1 week culture of pancreatic islets at 30 instead of 10 mM glucose increases the expression of UCP-2 and haeme oxygenase 1, an indicator of oxidative stress. These changes in islet gene expression are combined to a moderate increase in apoptosis, a reduction in insulin content, and an increased glucose sensitivity of key stimulus-coupling events like metabolism acceleration, calcium influx and insulin secretion (both triggering and amplifying pathways). This hypersensitization can be attributed to glycogen accumulation in pancreatic β-cells previously exposed to 30 mM glucose. This increase in glucose sensitivity is characterized by a clear increase in insulin secretion in the presence of low glucose concentrations and a clear reduction of the maximal glucose-induced insulin secretion with only little stimulation of insulin secretion within the physiological range of glucose concentrations. Moreover, in contrast with normal islets in which glucose stimulation is followed by an increase in [Ca2+]c measured by microfluorimetry techniques, in islets exposed to supraphysiological glucose concentration, glucose stimulation seemed to have no effects on [Ca2+]c. All these functional alterations are completely reversible after a further week of culture in the presence of 10 mM glucose. Finally, these alterations are differents from those induced by low doses of H2O2 and they are not prevented by two antioxidants which completely reverse the alterations induced by H2O2. These results suggest that β-cell dysfunction induced by one week culture in high glucose does not result from an increase in oxidative stress and/or UCP-2 overexpression. In conclusion, we suggest that restoring the triggering pathway, in particular the amplitude of calcium influx is an interesting and a challenging way to treat islets chronically exposed to hyperglycemia.
- Affiliations
Citations
Khaldi, M. (2011). Altérations du couplage stimulation-sécrétion dans les cellules β-pancréatiques exposées à l’hyperglycémie chronique. https://hdl.handle.net/2078.5/154918