Y Hydroxychloroquine And Metabolic Outcomes In Patients Undergoing Total Pancreatectomy And Autologous Islet Transplantation

Rationale: Although autologous islet transplantation aims to prevent surgically-induced insulin-dependent diabetes in patients undergoing total pancreatectomy, only approximately one third of patients achieve insulin independence. To test the hypothesis that reducing nonspecific inflammation improves graft function post-AIT, we conducted a pilot clinical study using oral hydroxychloroquine (HCQ), an FDA-approved anti-malarial that inhibits thrombosis and a broad spectrum of inflammatory cytokines. Methods: We used a phase II, randomized, double-blinded, placebo-controlled trial to determine the effect of peri-transplant HCQ on individuals (n=8) undergoing total pancreatectomy with autologous islet transplantation (TPAIT). In vivo islet function was assessed via Mixed Meal Tolerance Test (MMTT) before and 6-12 months after surgery. We found that islet grafts were viable for at least 24 hours in culture and we optimized conditions for in vitro assessment of islet graft metabolic function via Seahorse Extracellular Flux. Results and Conclusions: Islet grafts from HCQ-treated patients showed a 4.7-fold greater mitochondrial spare respiratory capacity compared with placebo-treated patients (64.9 ± 20.7 vs. 13.7 ± 7.1% basal respiration, p = 0.058), suggesting that HCQ may improve metabolic function in the islet graft. We also found that the insulin incremental area under the curve after MMTT was 8.2-fold greater in HCQ-treated patients 6-12 months after surgery compared to that of placebo-treated patients (1154 ± 290 vs. 185 ± 180 mU/L, p = 0.026), suggesting that HCQ may also improve islet engraftment and/or function. Our results warrant further investigation into HCQ using a larger-scale clinical trial with the goal of reducing inflammatory islet destruction and enhancing mitochondrial function to improve metabolic outcomes in TPAIT. Disclosure R. McDowell: None. K.F. Ali: None. V.T. San Martin: None. R. Bottino: Research Support; Self; Imagine Pharma. J.P. Kirwan: None. B. Hatipoglu: Advisory Panel; Self; Novo Nordisk Inc. Speaker's Bureau; Self; Merck & Co., Inc. Funding Cleveland Clinic Foundation