Islet Oxygen Consumption Rate (OCR) Dose Predicts Insulin Independence in Clinical Islet Autotransplantation

Abstract

BackgroundReliable in vitro islet quality assessment assays that can be performed routinely, prospectively, and are able to predict clinical transplant outcomes are needed. In this paper we present data on the utility of an assay based on cellular oxygen consumption rate (OCR) in predicting clinical islet autotransplant (IAT) insulin independence (II). IAT is an attractive model for evaluating characterization assays regarding their utility in predicting II due to an absence of confounding factors such as immune rejection and immunosuppressant toxicity.MethodsMembrane integrity staining (FDA/PI), OCR normalized to DNA (OCR/DNA), islet equivalent (IE) and OCR (viable IE) normalized to recipient body weight (IE dose and OCR dose), and OCR/DNA normalized to islet size index (ISI) were used to characterize autoislet preparations (n = 35). Correlation between pre-IAT islet product characteristics and II was determined using receiver operating characteristic analysis.ResultsPreparations that resulted in II had significantly higher OCR dose and IE dose (p<0.001). These islet characterization methods were highly correlated with II at 6–12 months post-IAT (area-under-the-curve (AUC) = 0.94 for IE dose and 0.96 for OCR dose). FDA/PI (AUC = 0.49) and OCR/DNA (AUC = 0.58) did not correlate with II. OCR/DNA/ISI may have some utility in predicting outcome (AUC = 0.72).ConclusionsCommonly used assays to determine whether a clinical islet preparation is of high quality prior to transplantation are greatly lacking in sensitivity and specificity. While IE dose is highly predictive, it does not take into account islet cell quality. OCR dose, which takes into consideration both islet cell quality and quantity, may enable a more accurate and prospective evaluation of clinical islet preparations.

Conformal Coating of Stem Cell-Derived Islets for β Cell Replacement in Type 1 Diabetes

“…Despite lower absolute insulin secretion in CC islets, comparable efficiency of reversing diabetes was observed after implantation in NOD-scid mice at comparable doses. The oxygen consumption rate has been shown to be predictive of the islet graft outcome (Papas et al, 2015), with poor oxygenation being a critical factor underlying islet encapsulation failure (Papas et al, 2016;Smith et al, 2017). We found that the in vitro oxygen consumption rate was similar between unencapsulated and encapsulated SC islets, suggesting that overall viability was not compromised by conformal coating.…”

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.…”

Mimicking the tumor microenvironment to regulate macrophage phenotype and assessing chemotherapeutic efficacy in embedded cancer cell/macrophage spheroid models

“…The growth profile is characterized by changes in percent oxygen saturation as this has been correlated to viability [36]. The 10C5M heterospheroid exhibits an early increase in oxygen consumption unlike any of the other cell systems, suggesting that the 10C5M heterospheroid uniquely demonstrates synergistic growth between the two cell types – cancer cell and macrophage, similar to that demonstrated in vivo .…”