Bax Inhibitor 1 protein protects against metabolic disorders and programmed cell death in pancreatic β cells
Obesity is a major public health problem worldwide. In France, more than 50% of the population is overweight or obese. Obesity is accompanied by diseases namely type 2 diabetes (T2D). The prevalence of T2D increases, correlating with the worldwide increases of obesity. Insulin resistance in peripheral tissues (liver, muscle, adipose tissue) and a progressive loss of pancreatic β cells contribute to the development of type 2 diabetes. Pancreatic β cells have an Endoplasmic Reticulum (ER) highly developed to respond effectively to rapid fluctuations in blood sugar, consequences of the daily nutrient intake. In this context, the increased insulin synthesis by pancreatic β cells can lead to an accumulation of misfolded proteins, including insulin itself, within the ER, activating a molecular signalling pathway called the Unfolded Protein Response (UPR).
Studies have shown that during obesity, chronic activation of the UPR contributes to the development of insulin resistance and pancreatic β cell death through apoptosis, via molecular mechanisms that still need to be better characterized. The UPR is mediated by three transmembrane proteins: PERK, ATF6 and IRE1α. We were particularly interested in IRE1α, a unique protein in the evolution, by its double enzymatic activity: a serine/threonine kinase activity and an endoribonuclease (RNase) activity. We were able to characterize its dialogue with the anti-apoptotic protein: Bax Inhibitor 1 (BI-1), also anchored in the ER membrane and able to inhibit IRE1α’s RNase activity. We took advantage of BI-1 deficient mice (BI-1 KO mice) in our studies. Our results show that BI-1 KO mice develop basal hyperglycaemia with age as well as glucose intolerance, compared to wild-type BI-1 mice. This phenotype is aggravated during a 3-month high fat diet. BI-1 KO mice show a decrease in insulinemia, and in insulin secretion in response to glucose injection, in vivo. Our analyses show a significant increase in serum levels of pancreatic lipases, correlating with increased cell death by apoptosis within pancreatic islets, an increase in circulating levels of pro-inflammatory cytokines and neutrophils infiltration within pancreatic islets. By combining biochemical and genetic analyses, this study highlights a link between pancreatic β cell death and an overwhelmed IRE1α’s RNase, in BI-1 KO mice. Indeed, isolated pancreatic islets from BI-1 KO mice are more sensitive to ER stress induced cell death, induced by specific chemical activators of ER stress and exhibit a significant increase in gene expression levels and proteins associated with IRE1α’s RNase activity, such as XBP1 and CHOP, ex vivo. Finally, treatments with specific pharmacological inhibitor of IRE1α’s RNase activity normalizes hyperglycaemia, insulin levels and pancreatic lipase levels in serum.
In conclusion, the BI-1-IRE1α tandem plays a crucial role during the development of T2D. Normalizing the expression of BI-1 protein or targeting IRE1α’s RNase activity appear to be promising therapeutic targets for T2DM.
Type 2 Diabetes, Pancreatic β cells, Unfolded Protein Response, IRE1α, BI-1, Apoptosis, Inflammation, Inflammasome, Metabolic disorders.
Prof. Alessandra CARDOZO, DR, Université Libre de Bruxelles
Dr. Jean-Sébastien ANNICOTTE, CR, Université de Lille - Institut Pasteur
Dr. Serge MANIE, DR, Université de Lyon - CRCL
Dr. Fabienne FOUFELLE, DR, Sorbonne Université - CRC
Dr. Sandrine MARCHETTI, CR, Université Côte d’Azur - C3M
Dr. Christophe GIRARD, CR, Université Côte d’Azur - C3M
Dr. Béatrice BAILLY-MAITRE, CR, Université Côte d’Azur - C3M