Islet Oxygen Consumption Rate Dose Predicts Insulin Independence for First Clinical Islet Allotransplants

Abstract

Human islet allotransplant (ITx) for the treatment of type 1 diabetes is in phase III clinical registration trials in the US and standard of care in several other countries. Current islet product release criteria include viability based on cell membrane integrity stains, glucose stimulated insulin release (GSIR), and islet equivalent (IE) dose based on counts. However, only a fraction of patients transplanted with islets that meet or exceed these release criteria become insulin independent following one transplant. Measurements of islet oxygen consumption rate (OCR) have been reported as highly predictive of transplant outcome in many models. In this paper we report on the assessment of clinical islet allograft preparations using islet oxygen consumption rate (OCR) dose (or viable IE dose) and current product release assays in a series of 13 first transplant recipients. The predictive capability of each assay was examined and successful graft function was defined as 100% insulin independence within 45 days post-transplant. Results showed that OCR dose was most predictive of CTO. IE dose was also highly predictive, while GSIR and membrane integrity stains were not. In conclusion, OCR dose can predict CTO with high specificity and sensitivity and is a useful tool for evaluating islet preparations prior to clinical ITx.

Continuous Quadrupole Magnetic Separation of Islets during Digestion Improves Purified Porcine Islet Viability

“…Combining this with the islet oxygen consumption rate to calculate the total OCR transplanted per kilogram body weight yields an even more reliable benchmark for predicting insulin independence in auto- and alloislet transplantation [45, 61–63], and this metric encompasses both the total amount of tissue transplanted and the viability of that tissue. By applying this approach to previously presented data [62, 63], the viability improvements observed with QMS would improve insulin independence rates from 29% to 69% in autograft patients and from 38% to 92% for allograft recipients.…”

Palmitate-induced impairment of glucose-stimulated insulin secretion precedes mitochondrial dysfunction in mouse pancreatic islets

“…In light of islet cell transplantation as promising treatment for Type 1 diabetes patients, the need for reliable assays ascertaining functional islet integrity prior to transplantation is increasing [16]. Assays that evaluate mitochondrial function show much promise in this respect [16] and the islet OCR, in particular, correlates positively with transplant outcomes in mice and pigs when normalised to islet size [41], and, without such normalisation, in humans too [42]. Bioenergetic parameters correlate generally much better with clinical transplant outcome than GSIS measures [16].…”

Human Islet Isolation and Distribution Efforts for Clinical and Basic Research

“…However, these membrane integrity stains do not provide a comprehensive picture of cell viability. Studies have recommended the use of additional assays such as measurement of adenosine triphosphate (ATP), mitochondrial function, and oxygen consumption rate (OCR), which can contribute to more effective predictions of islet status after transplantation [26][27][28].…”

“…This may partly be due to the presence of viable cells that do not respond to glucose in vitro, but recover and become functional after transplantation. Assays such as measurement of the OCR have been suggested to be better predictors of transplantation outcome [26]. Overall, a thorough assessment of the quality of isolated islets, which encompasses a suite of assays for determining islet mass, viability, and insulin secretory response, where practical, is likely required to select the preparations that may result in better clinical outcomes.…”