Endocrine and exocrine pancreas pathologies crosstalk: Insulin regulates the unfolded protein response in pancreatic exocrine acinar cells

Exocrine pancreas insufficiency is common in diabetic mellitus (DM) patients. Cellular stress is a prerequisite in the development of pancreatic pathologies such as acute pancreatitis (AP). The molecular mechanisms underlying exocrine pancreatic ER-stress in DM are largely unknown. We studied the effects of insulin and glucose (related to DM) alone and in combination with cerulein (CER)-induced stress (mimicking AP) on ER-stress unfolded protein response (UPR) in pancreatic acinar cells. Exocrine pancreas cells (AR42J) were exposed to high glucose (Glu, 25 mM) and insulin (Ins, 100 nM) levels with or without CER (10 nM). ER-stress UPR activation was analyzed at the transcript, protein, immunocytochemistry, western blotting, quantitative RT-PCR and XBP1 splicing, including; XBP1, sXBP1, ATF6, cleaved ATF6, IRE1-p, CHOP, Caspase-12 and Bax. Exocrine acinar cells exposed to high Ins or Ins+Glu concentrations (but not Glu alone) exhibited ER-stress UPR, demonstrated by significant increase of transcript and protein levels of downstream markers in the ATF6 and IRE1 transduction arms, including: sXBP1, cleaved ATF6, XBP1, CHOP, IRE1-p and caspase-12. UPR activation resulted in IRE1-p aggregation and nuclear trans-localization of cleaved activated ATF6 and sXBP1. Ins further aggravated UPR when cells were co-challenged with CER-induced stress, exacerbating the effects of CER alone. High Ins levels, typical to type-2-DM, activate the ER-stress UPR in pancreatic acinar cells, through the ATF6 and IRE1 pathways. This effect of Ins in naïve acinar cells further augments CER-induced UPR. Our data highlight molecular pathways through which DM enhances exocrine pancreas pathologies.