Islet cell transplant (ICT) can functionally cure type 1 diabetes (T1D) by restoring insulin-producing ?-cells. However, human donor islets are scarce and many recipients convert back to T1D. While ICT is slowly improving, few consistent predictors of ICT outcomes, in particular recipient factors, have been identified. Consequently, there is a critical need to identify modifiable recipient predictors of ICT success. The long-term goal is to further improve ICT precision medicine. Therefore, the objective of this study is to identify modifiable recipient baseline factors that predict ICT clinical outcomes, to focus the development of feasible, effective pre- ICT interventions to enhance success. Our compelling preliminary data found that greater ?-cell function up to one year following first ICT was significantly related to recipient baseline levels of markers of better vascular health: higher HDL, lower blood pressure, narrower carotid intima-media thickness (all clinically available), and lower intercellular adhesion molecule-1. These data are the basis for our central hypothesis: favorable recipient baseline vascular health predicts better ICT outcomes, mediated by enhanced recipient insulin sensitivity and lower ?-cell death.
The first Aim will determine the utility of recipient baseline levels of clinically available vascular markers for predicting outcomes (?-cell function) of each ICT. Existing longitudinal data up to one- year post-ICT will be analyzed using multivariable techniques from both the University of Illinois at Chicago?s (UIC) clinical trials (Phase 1/2 and 3; n=30 with 56 total ICTs) as a ?discovery cohort?, and the multisite Clinical Islet Transplant (CIT) trials (-06 and -07; n=72 with 114 total ICTs) as a ?replication cohort?. Extensive data are available on multiple vascular markers and insulin sensitivity. Novel circulating microRNAs reflecting ?-cell death will be measured in archived serum from UIC.
The second Aim will determine the prospective association of recipient baseline endothelial function and arterial compliance with outcomes (?-cell function and glucose variability) of each ICT. Longitudinal data will be collected up to one-year post-ICT in 20 new UIC recipients, including direct vascular measures, e.g., flow-mediated dilation, microvascular reactivity, central pulse wave velocity, as well as insulin sensitivity via dual-tracer oral glucose tolerance test, and microRNA markers of ?-cell death. The study?s innovation reframes T1D?s negative effect on vascular health to identify T1D recipient vascular parameters that predict ICT?s ability to cure T1D. Our rationale is that identifying the specific recipient vascular factors that predict ICT success could translate into simple, evidence-based strategies such as diet, exercise, or medications targeting those vascular factors before ICT to enhance outcomes. The positive impact would be optimizing the capacity of scarce human islets to prevent re-transplant and so allow more T1D patients to benefit. Significantly, such strategies would remain highly relevant as cell- based therapies for T1D advance using limitless islet sources and encapsulation. The strategies may also be relevant to ICT for type 2 diabetes and autologous ICT for chronic pancreatitis.
The proposed research is relevant to public health focusing on the identification of islet cell transplant recipient factors that are associated with superior survival and function of transplanted islet cells, and better recipient glycemic control, with the long-term goal being to translate this knowledge into targeted strategies to continue to improve this cellular cure of type 1 diabetes. The associations discovered between islet cell transplant outcomes and specific recipient vascular factors prior to transplant are expected to focus pre-transplant interventions to improve vascular health, be it diet, exercise, or medications. Therefore, the proposed study is relevant to NIDDK?s mission in that it aims to optimize the functional and curative capacity of the limited human islet supply so that islet cell transplant can be extended to more in the growing population with type 1, and eventually type 2, diabetes.
