Insulin Therapy in Pancreas and Islet Transplantation

UoM administered thesis: Phd

Abstract

Pancreas and islet transplantation are highly-effective life-saving therapies in complex type 1 diabetes. Due to the well-documented shortage of organs for transplantation there is an urgent need to: a) optimise methods for assessment and selection of high quality pancreases; and b) identify the ideal conditions for a transplanted pancreas to achieve optimal long-term function. This thesis aims to determine whether data on insulin therapy can be used to improve clinical decision making in pancreas and islet transplantation. Donor insulin therapy predicts outcomes in pancreas and islet transplantation Hyperglycaemia, an abnormally high blood glucose level, occurs either because of reduced insulin secretion or reduced insulin sensitivity. Hyperglycaemia is a commonly seen parameter in surgery in people with diabetes mellitus, but can also occur in people without diabetes at times of extreme physiological stress. Organ donors experience severe physiological insults, which lead to either the declaration of brain death or circulatory death following the withdrawal of life sustaining treatment. Insulin is used to treat hyperglycaemia in ~50% of donors after brain death. Insulin use on intensive care could be a marker of beta cell death or reversible beta cell dysfunction. We hypothesized that insulin use in organ donors on the intensive care predicts graft failure after pancreas transplantation, and graft function after islet transplantation. We showed that donor insulin use is a predictor of better outcomes in pancreas transplantation but worse outcomes in islet transplantation. Donor insulin therapy as a marker of beta-cell death Hyperglycaemia leading to donor insulin use was previously believed to be caused by temporary reversible metabolic stress (insulin resistance). However, this theory could not account for our clinical findings in islet transplantation. We hypothesized that insulin use in organ donors was a marker of beta-cell death. Using circulating cell-free microRNA as a tissue specific marker of beta-cell death, we showed that levels of beta-cell death are higher in donors receiving insulin. The contrasting epidemiological findings between pancreas transplantation (98% exocrine cells) and islet transplantation (mostly endocrine cells) is further explained by published evidence that supports the notion that insulin is protective of pancreatic acinar cells. Optimising the donor pancreas allocation and selection processes We also hypothesized that a combination of traditional statistical and artificial intelligence methodologies, could improve the processes of donor pancreas allocation and selection by improving decision making. A series of decision-making algorithms was created for pancreas and islet transplantation and were drawn together in a decision making matrix based on our classification of pancreas donor phenotypes. Peri-transplant glycaemic control in pancreas and islet transplantation Patients who have undergone transplantation surgery are often at the limits of their physiological reserve and will often require multi-organ support. Stress hyperglycaemia is associated with increased morbidity and mortality and is frequently seen in patients suffering critical illness. We hypothesized that peri-transplant glucose levels predict outcomes after pancreas and islet transplantation independently of use of insulin therapy in recipients. In pancreas transplantation, we showed that higher glucose levels assessed over the first five days predict graft failure above, beyond and independently of a requirement for insulin during the hospital stay. However, it remains unclear whether peri-transplant hyperglycaemia is a cause or a consequence, or both, of graft dysfunction in the transplanted pancreas. Meanwhile, in islet transplant recipients with generally well-controlled glucose levels, peri-transplant glucose levels were not related to short-term measures of beta-cell function. Based on these data, there is no evidence to alter current glucose management strategies following islet cell transplantation. Peri-transplAnt InsuliN Therapy to improve outcomes after pancrEas tRansplantation (PAINTER): an open label randomised clinical trial Using the data from this thesis as a platform of evidence, we designed the PAINTER trial to determine whether it would be safe and feasible to perform a future mutli-centre trial of peri-transplant insulin therapy in patients undergoing pancreas transplantation.

Details

Original languageEnglish
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Supervisors/Advisors
Award date31 Dec 2019