Human Islet Oxygen Consumption Rate and DNA Measurements Predict Diabetes Reversal in Nude Mice

Abstract

There is a need for simple, quantitative and prospective assays for islet quality assessment that are predictive of islet transplantation outcome. The current state-of-the-art athymic nude mouse bioassay is costly, technically challenging and retrospective. In this study, we report on the ability of 2 parameters characterizing human islet quality: (1) oxygen consumption rate (OCR), a measure of viable volume; and (2) OCR/DNA, a measure of fractional viability, to predict diabetes reversal in nude mice. Results demonstrate that the probability for diabetes reversal increases as the graft's OCR/DNA and total OCR increase. For a given transplanted OCR dose, diabetes reversal is strongly dependent on OCR/DNA. The OCR and OCR/DNA (the 'OCR test') data exhibit 89% sensitivity and 77% specificity in predicting diabetes reversal in nude mice (n = 86). We conclude that the prospective OCR test can effectively replace the retrospective athymic nude mouse bioassay in assessing human islet quality prior to islet transplantation.

Sustained function of alginate-encapsulated human islet cell implants in the peritoneal cavity of mice leading to a pilot study in a type 1 diabetic patient

“…In a retrospective analysis of type 1 diabetic islet graft recipients, a weak correlation was seen between the number of duct cells injected and the acute insulin secretory response at post-transplant year 2, but this was not further examined against other variables [42]. Only a subgroup of free graft recipients (4/12) exhibited a metabolic correction, as in other animal studies with human islet cell grafts [43][44][45]. The effect was not achieved within the first week, probably reflecting the time needed to vascularise implants in an extravascular space [46], and probably not facilitated in compact subcapsular implants.…”

Transplantation of human islets without immunosuppression

“…It has been repeatedly shown that native pancreatic islets have a disproportionately high level of vascularization (13)(14)(15)(16)(17)(18). During the process of islet isolation their vasculature is disrupted, and after transplantation the islets depend on oxygen diffusion from tissue surrounding the transplantation site until revascularization has occurred.…”

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

“…This assay is especially well suited to encapsulated islets and was proven to be directly correlated to islet performance in vivo. According to several other groups, this assay is well established and verified as an excellent predictor of transplantation outcomes (58,59). …”