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Bax Inhibitor 1 protects against pancreatic beta cell death and meta- bolic disorders

par Blanc, M.;Xiao, Peng ;Gilleron, J.;Janona, M;Lacas-Gervais, Sandra;Yvan-Charvet, L;Gual, P;Cardozo, Alessandra K ;Bailly Maître, Beatrice
Référence European Association for the Study of Diabetes, 58th, Stockholm, Sweden, 2022-09-19, Diabetologia, (vol. 65, p. 211) (ISSN: 0012-186X)
Publication Publié, 2022-09-19

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Résumé :

demand in secretory protein leads to Endoplasmic Reticulum (ER) stress in pancreatic β cell. In response to the ER stress, the Unfolded Protein Response (UPR) is mediated by three transmembrane proteins located in the ER: ATF6, PERK and IRE1α. Bax Inhibitor-1 (BI-1) is a negative regulator of inositol-requiring enzyme 1 (IRE1α), an UPR sensor endowed with kinase and endoribonuclease (RNase) activities. BI-1 can interact with IRE1α and restrains its RNase activity signalling. Taking advantage of BI-1 deficient mice, we observed that BI-1 deletion leads to a hyperglycaemic profile, with an aggravation of the phenotype under HFD challenge. We hypothesized that BI-1 deficiency could sensitize the pancreatic β cell death and favor the onset of type 2 diabetes. Materials and methods: Taking advantage of BI-1 deficient mice, we monitored systemic inflammation and pancreatic lipases levels in sera, glycemia and insulinemia. We performed GTT (Glucose Tolerance Test) /ITT (Insulin Test Tolerance) and GSIS (Glucose Stimulated Insulin Secretion) in fasted and fed conditions. From pancreatic sections and pancreatic islets isolated from WT and transgenic mice, we analysed pancreatic β cell death and ER stress markers by combining several approaches at structural (TEM: transmission electronic microscopy) and molecular & biochemical levels (H&E, TUNEL, MPO, qPCR and Western Blot). Statistical analyses were obtained by Mann-Whitney or Two-Way ANOVA (p-value < 0,05).Results: BI-1 deficient mice present a glucose intolerance and a poor insulin response in steady state and under an HFD, as revealed after performing GTT and an ITT. Serum insulin levels were statistically reduced in the BI-1 KO mice. When challenged with glucose (GSIS), BI-1 deficient mice secrete significantly less insulin than BI-1 WT mice. Increased levels of TNFα, IFNγ and pancreatic lipases were statistically observed in the serum of BI-1 KO mice compared to WT mice, indicating respectively significant inflammation and pancreatic injuries in BI- 1 KO mice. We observed less pancreatic islets in BI-1 KO corre- lating with significant increased β cell death and more infiltrated neutrophiles (MPO staining). Furthermore, BI-1 deficient mice present higher levels of inflammasome, and ER stress markers, especially IRE1α signaling in pancreatic β cells. Finally, the pharmacological inhibition of IRE1 RNase activity in HFD-BI-1 KO mice rescues pancreatic injuries, improves glucose homeosta- sis, and normalizes insulin levels.Conclusion: Our data suggests that BI-1 acts as a guardian of β cells homeostasis by counteracting IRE1α dependent-inflammation (inflam- masome) activation, -cell death and -metabolic disorders. We propose that normalizing BI-1 expression or pharmacologically targeting IRE1α could be effective in treating type 2 diabetes mellitus, but also in meta- bolic diseases associated with excessive ER stress.Supported by: This work was supported by ANR (2019), SFD (2020) and FRM (2022).Disclosure: M. Blanc: None.