Total pancreatectomy and islet autotransplantation (IAT) is safe and effective in the management of intractable pain associated with chronic pancreatitis. A major problem associated with IAT is that the number of islets available for transplant is compromised by a severely diseased and fibrotic pancreas. Moreover, as many as 50-60% of islet cells undergo apoptosis at 2-3 days after intraportal transplantation when transplantation associated stressors (hypoxia, nutrient deprivation, reactive oxygen species, proinflammation cytokines) are induced during harvesting, isolation, and implantation of the islet cell mass. Although the quality-of-life parameters are significantly improved in our IAT patients, only 25% of patients become insulin independent (compared to 80% patients with normoglycemia before pancreatectomy). Strategies that produce more "robust" islets to resist stressors that induce ? cell apoptosis are an appealing and promising method to improve the efficiency of human IAT. Over the past 10 years we have focused on exploring strategies that can improve islet/? cell survival and function to treat patient with type-1 diabetes in the settingof allogeneic transplantation. Our novel findings indicate that exposing islets to low doses of carbon monoxide (CO, gaseous or dissolved in solutions) to the islet donor, or isolated islets, can protect those islets from stress-induced apoptosis and immune rejection after transplantation. Further study indicates that CO exposure to islet donor up-regulates expression of PPAR?, a transcriptional factor, in isolated islets. Donor treatment with PPAR? agonists leads to long-term (>100 days) survival of transplanted islets in a major mismatch islet transplantation model without any additional treatments. Islet autografts suffer from similar injuries as allograft and are spared the additional complexities of immune rejection response after transplantation. Thus, strategies such as PPAR? activation and CO exposure that can protect human islets from stress will bring immediate benefit to patients with chronic pancreatitis receiving an IAT and potentially serve as a platform on which to address the more complex allogeneic islet cell transplantation. In this study, we will test the hypothesis that stress-induced apoptosis of post IAT islets can be minimized leading to increased survival and function by harvesting islets in a CO-rich environment and/or PPAR? induction is isolated islets. Our state-of-the-art cGMP facility that undertakes IAT on a regular basis, our strong clinical and research team, clinical tral support, clinical trial nursing, clinical facilities, current patient pool and the biostatistics suport at MUSC offers powerful platform that can readily translate research finding from bench to bedside. Once the study is completed, it promises to advance the field of islet transplantation forward.
The major goal of this grant is to apply effective interventional protocols developed in animal models to minimize surgical diabetes in patients with chronic pancreatitis who undergo total pancreatectomy with islet auto-transplantation. If successful, our study will significantly advance the field of islet transplantation going forward.
|Dong, Huansheng; Huang, Hu; Yun, Xinxu et al. (2014) Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation. Endocrinology 155:818-28|