GLP-1R is downregulated in beta cells of NOD mice and T1D patients
Recino, A.; Barkan, K.; Schmidt-Christensen, A.; Nilsson, J.; Holmes, N.; Howie, D.; Holmberg, D.; Larsson, P.; Flodstrom-Tullberg, M.; Laraia, L.; Spring, D. R.; Hecksher-Sorensen, J.; Cooke, A.; Ladds, G.; Wallberg, M.
Show abstract
Glucagon-like peptide 1 (GLP-1) is produced by L cells in the small intestine in response to ingested glucose and increases insulin release from pancreatic beta cells by activation of its cognate receptor (GLP-1R). Stimulation of this receptor also contributes to increased beta cell survival and regeneration. We have found that pancreatic beta cells from Non Obese Diabetic (NOD) mice express significantly lower levels of GLP-1R than C57BL/6 mice, leaving the NOD beta cells with an impaired response to GLP-1 stimulation. The lower expression appears to be caused by accelerated degradation of GLP-1R in the beta cells, a process that can be reversed by inhibiting trafficking to the lysosome. Importantly, our results appear to translate to the human disease since we also observed significantly lower expression of the GLP-1R in pancreatic islets from donors with type 1 diabetes. These results suggest that beta cell physiology may play a role in susceptibility to autoimmune inflammation.
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