Mathematical modeling of trypsin activation in acinar cell environment

s / Pancreatology 13 (2013) e1–e94 e79 Background: Endocrine insufficiency in chronic pancreatitis (CP) is believed to be a late manifestation occurring as a result of b cell apoptosis. It is now shown that significant b cell dysfunction exists even in early CP in the absence of clinical diabetes. Our earlier studies suggested that in CP, IFN-g is the predominant cytokine in pancreas responsible for b cell dysfunction. In this study we investigated the source of pancreatic IFN-g and its effect on b cell function and apoptosis. Methods: Pancreatic tissues were obtained from CP patients with and without diabetes (study group) and those undergoing surgery for non pancreatic malignancy (control). IFN-g producing T-helper cells were enumerated in pancreatic tissues and circulation on Flow cytometry and confirmed by immunoflorescence. Islets were sorted for b cells; markers of apoptosis and GSIR were evaluated from controls, CP patients and control islets exposed to IFN-g. Islet proteins from controls, CP patients and control islets exposed to IFN-g were probed on western blots for signal pathway intermediates of insulin gene transcription. Results: IFN-g producing T-helper cell subsets (Th1, Th17) were significantly higher (p<0.01) in circulation and in pancreatic tissues from CP patients as compared to controls. b cells from non-diabetic CP patients showed minimal apoptosis (2 0.8%) but significantly diminished GSIR (60 12%), while 40 9% b cells from diabetic CP patients were apoptotic and remaining 60 7.5% b cells had very minimal GSIR (2 1.5%). Similar results were seen on chronic exposure of normal islets to IFN-g. Preexposing b cells to EGCG (IFN-g inhibitor) reverted islet functions completely and reduced apoptosis significantly. Western blots of islet proteins revealed reduced phosphorylation of pdx1 (transcription factor) resulting in reduced insulin gene transcription and diminished GSIR. Conclusion: Our results suggest that arresting b cell dysfunction early in the course of CP can potentially prevent b cell apoptosis and diabetes.