Islet autotransplant (IAT) is performed at the time of total pancreatectomy (TP) in patients with chronic pancreatitis, to prevent or minimize postsurgical diabetes. Diabetes is completely prevented in only 40% of patients. The procedure of IAT is similar to allogenic islet transplantation performed in patients with type 1 diabetes, except that in the case of IAT, there is no rejection or autoimmunity, or toxicity from rejection drugs. The success of both forms of islet transplantation is limited by the loss of beta cell mass that occurs in the immediate posttransplant period, and suboptimal islet engraftment. However, we lack a uniform approach to measure engrafted islet mass early after transplant, and no techniques currently exist to directly measure islet loss. Furthermore, while we know that factors such as acute non-specific inflammation likely mediate much of this early islet loss, we lack any data to directly correlate these factors with engrafted islet mass.
The aims of the current application are: 1) To determine which metabolic tests may serve as the best marker of islet engraftment at 90 days post-transplant and as a surrogate for long-term outcomes;2) To validate the measurement of unmethylated insulin DNA-unique to the beta cell and released from dying beta cells into circulation-as a means to measure islet loss early after islet infusion; and 3) To measure and correlate measures of coagulation, complement deposition, and inflammation with islet loss and engraftment to identify which may be the best targets of future interventions. This study is a key first step towards clinical trials to identify new drug therapie that may improve islet engraftment. In order to efficiently conduct small pilot trials with new dru interventions, we must have reliable early measures of islet engraftment and islet loss as endpoints in these studies. Preliminary data is needed to identify which pathways may be most important to target therapeutically. To accomplish this, 20 non-diabetic patients age 10-65 years who are undergoing TP-IAT for management of severe chronic pancreatitis will be enrolled and studied prospectively, with a focus on early islet loss and early measures of islet engraftment. Patients will have multiple blood draws in the first week post-transplant aimed at measuring the innate inflammatory response and coagulation response upon infusion of the islets (proposed mediators of islet loss). A potential marker of beta cell death, the unmethylated insulin DNA level, will be measured at multiple time points over the first week and month after IAT, to validate this test as a novel measure of islet loss. Finally, patients will return for detailed metabolic testing at 90 days post-transplant, including mixed meal tolerance testing, intravenous glucose tolerance testing, and glucose potentiated arginine-induced insulin secretion studies. We will use this data to determine what test(s) may be most useful as a measure of islet engraftment, and which correlate best with 1 year insulin use outcomes. This will set the stage for metabolic protocols to be used in future clinical trials.
Islet transplantation (transplant of the insulin producing cells of the pancreas) is a promising therapy to treat type 1 diabetes mellitus and surgical diabetes mellitus in patients undergoing resection of the pancreas (pancreatectomy) for chronic pancreatitis. Although islet transplant is frequently successful in reducing the burden of diabetes, it often fails short of restoring long-term insulin independence. In this study, we will measure markers of islet loss and islet survival after transplant;these results will set the stage for future clinical trials aimed at improving insulin independence after islet transplant.
|Bellin, M D; Clark, P; Usmani-Brown, S et al. (2017) Unmethylated Insulin DNA Is Elevated After Total Pancreatectomy With Islet Autotransplantation: Assessment of a Novel Beta Cell Marker. Am J Transplant 17:1112-1118|
|Herold, Kevan C; Usmani-Brown, Sahar; Ghazi, Tara et al. (2015) ? cell death and dysfunction during type 1 diabetes development in at-risk individuals. J Clin Invest 125:1163-73|