Long-Term Islet Function and Impact after Total Pancreatectomy with Islet Autotransplant (LIFT)

Abstract Total pancreatectomy with islet autotransplant (TPIAT) is performed to treat the severe, intractable pain of chronic pancreatitis for patients who have failed medical or endoscopic therapies. The TP relieves the source of pain, while the IAT reduces risk or severity of post-operative diabetes; after 1 year, up to 40% of patients are off insulin and nearly 90% have islet function (C-peptide positive). However, little is known about the long-term function of the islet graft. Rigorous studies are needed to determine what proportion of patients maintain islet function long term and whether islet function improves glycemic control and reduces diabetes complications in this population. This carries high potential for impact in clinical care: currently some patients are denied coverage for IAT due to lack of rigorous studies establishing the benefit of IAT. Furthermore, we know little about how changes in gut anatomy and associated hormones (GLP-1) and alpha cell dysregulation (glucagon) of intraportally transplanted islets impact long-term glycemic regulation. Hypoglycemia has been increasingly reported after TPIAT, with exaggerated incretin response and/or defective glucagon counterregulation suggested as possible mechanisms. We propose to study islet function, glycemic control, diabetes complications, and mechanisms impacting glycemic control (incretin hormone axis, counterregulatory hormones) in patients who are 5-20 years out from TPIAT. The study’s overall aim is to determine the long-term benefit of IAT. To assess islet graft function, we will use C-peptide levels from mixed meal tolerance testing (MMTT) as the marker of endogenous islet function. We will enroll at least 200 participants in this cross-sectional study, who are 5-20 years after TPIAT for chronic or recurrent acute pancreatitis. The study's first aim is to determine the proportion of patients who maintain islet graft function 5-20 years after TPIAT and to determine whether C-peptide levels from a MMTT are associated with concurrent glycemic control measures. The second aim is to determine whether islet graft function is inversely associated with diabetes-specific complications (severe hypoglycemia, diabetic ketoacidosis, and micro- or macrovascular disease). The third aim is to determine other mechanisms that impact long-term glycemic control in TPIAT, including incretin function, alpha cell function, and markers of beta cell stress. As an exploratory aim we will recruit a subgroup of patients who are 5-20 years out from TP alone to undergo the same testing protocol for comparison with TPIAT recipients without and with graft function. This study's significance lies in its potential to directly impact clinical care and access to IAT when TP is needed. We hypothesize that islet graft function improves glycemic control and reduces diabetes complications even in recipients who are not insulin-independent, but that dysfunctional incretin and counter-regulatory responses will impact hypoglycemia risk.