Successful islet transplantation holds the potential to significantly enhance the quality of life for individuals with type 1 diabetes (1, 2). Nonetheless, the scarcity of suitable donor pancreata poses a significant hurdle to the widespread adoption of this therapeutic approach (3).

Donor characteristics and the effectiveness of the islet isolation process are highly related to the success of the procedure (4, 5).

The decision to accept or decline an organ for islet isolation remains challenging, as it relies on various factors predominantly grounded in donor characteristics, coupled with subsequent macroscopic evaluations of the organ (6–10). The capability to reliably reject poor-quality donor pancreata not only improves overall isolation success but also reduces the costs associated with failed isolations (11, 12).

Several donor variables, including donor age, body mass index (BMI), body surface area (BSA), and hemodynamic stability without the use of vasopressors during donor management, have been demonstrated to be associated with higher islet yields, leading to the development of several scoring systems for predicting the suitability of potential pancreatic donors before organ processing (11, 13). However, effective isolation, as assessed by islet yields, may not necessarily translate to good islet graft function after transplantation (14, 15).

Recent investigations have shed light on the significance of non-quantitative indicators in predicting the ultimate goal of any islet transplantation procedure: the normalization of blood sugar levels and relief from diabetic symptoms in transplant recipients (16, 17). Perifusion systems, employed for over 35 years (18–20), challenge islets with glucose and measure dynamic insulin release. They remain the gold standard procedure used by many research laboratories to test islet function in a more physiologically relevant way and attempt to predict islet transplantation outcomes.

However, relatively little attention has been given to donor and preparation characteristics that might influence the insulin-secreting properties of human islets in vitro (21, 22). This study aims to retrospectively evaluate, using organs discarded from clinical pancreas and islet transplantation, how features of the preparation and donor attributes impact islet secretory function.

From June 2020 to November 2022, a single team at our institution processed 58 consecutive islet isolation procedures from 29 human donor pancreata.

All the organs were divided into two segments, the head–neck portion and the body–tail portion, for use in paired isolation outcomes for other research purposes.

A total of six pancreata were excluded from our analysis for the following reasons: incomplete data (n = 2), technical failure in islet isolation (n = 1), contaminants (n = 1), and islet isolation from partial pancreata (n = 2). The remaining 46 islet isolations from 23 donors were analyzed.

Donor predictor variables used in the analysis were age, gender, body weight, height, BMI, BSA, cold ischemia time (CIT), warm ischemia time (WIT), length of cardiac arrest, cause of death, vasopressor requirement, medical history, and blood test values including peak levels of amylase, lipase, and hemoglobin at the time of procurement. Cause of death was categorized into cerebrovascular accident (CVA), trauma, and cardiac arrest.

Regarding medical history, the following information was collected: alcohol abuse, hypertension (high blood pressure (HBP)), drug abuse, malignancies, smoking, diabetes mellitus, infections, and cardiac arrest.

Islet isolation variables used in the analysis were the islet yield, islet purity, islet size, and pancreas weight.

The present study has identified donor- and isolation-related factors that are significantly positively or negatively associated with the islets’ secretory function after 1 day and 7 days of culture.

We first demonstrated that islet yield expressed as IEQ/g from islet isolation procedures is positively correlated to the islet secretory function expressed by the AUC of the insulin secretion.

Although this observation appears intuitive, it can have encouraging implications in the clinical setting.

Islet yield is the most common indicator in predicting both islet isolation and transplantation outcomes in diabetic patients (3–13).

Clinical studies have generated inconsistent findings concerning the correlation between transplanted IEQ and the likelihood of achieving insulin independence (14, 15). The inaccuracies associated with manual quantification of islet mass, characterized by subjectivity and the potential for error, likely contribute to these inconsistencies. Substantial efforts have been dedicated to overcoming the limitations of standard manual islet mass evaluation through the exploration of computer-assisted and digital-assisted approaches (27–30). Nevertheless, as of now, no precise method has been established.

In contrast, in vitro islet function tests are an objective method much less prone to subjective variability, possibly becoming a potentially more accurate indicator than islet quantification.

Nevertheless, since no specific pre-transplant test for evaluating islet quality has demonstrated predictive efficacy for the success of islet transplantation (31), our findings need validation in transplanted islets. This validation process may pave the way for the widespread acceptance of this predictive indicator.

Our study also allowed us to determine several donor characteristics affecting in vitro islet secretory function, including the donor BMI, gender, HBP cause of death, and pancreas weight.

Numerous studies have highlighted a positive correlation between donor BMI and successful islet yield outcomes (13, 32, 33). Conversely, donors with a low BMI (<21 kg/m²) often yield less satisfactory results in terms of islet production (34). However, as previously discussed, the critical focus lies in evaluating the functionality of islets obtained from obese donors. In a specific study, islets isolated from donors with a BMI exceeding 30 kg/m² displayed nearly identical viability (33). This was determined through in vitro assessments, including insulin response to glucose in static incubation assays, as well as in vivo evaluations, such as the time required to reverse chemical diabetes in a nude mouse bioassay.

Remarkably, our research indicates that although there is no statistically significant correlation between BMI and the AUC of insulin secretion, SI increases with the gradual reduction of BMI. These findings, prompting further exploration, may be influenced by confounding factors. On the one hand, the origin of donor organs—rejected for clinical use—often entails higher overall risk factors than commonly utilized organs. On the other hand, longer ischemia times, exceeding those typically accepted by the scientific community, could also contribute to these outcomes.

Furthermore, our study provides valuable insights by establishing a positive correlation between organ weight and the functional activity of isolated islets. Numerous studies have consistently shown a positive association between pancreas weight and both pre-purification and post-purification islet yields (13, 35). However, it is crucial to note that this parameter remains indeterminable prior to organ procurement, prompting a focus on identifying metrics reliably correlated with pancreas weight. As a result, common practice has adopted body weight and body surface area as crucial metrics for organ selection and predicting outcomes in islet isolation (35). The crucial impact of organ weight on islet function underscores the importance of accurately predicting this parameter.

Recent evidence indicates that recipients of islets from at least one female donor experienced prolonged graft survival in comparison to recipients exclusively receiving male donor islets (36). This observation is believed to be associated with the cell-intrinsic properties of female islets (37). A study reported that the higher β-cell content in transplanted islets from female donors led to significant improvements in recipient outcomes compared to islets transplanted from male donors (38).

Our data also show that male donor is negatively related to the in vitro islet secretory function.

Our study additionally reveals that donor hypertension (HBP) is linked to decreased in vitro functional performance of isolated islets in terms of AUC. Drawing insights from kidney transplant research, the authors posit that the adverse impact of HBP on islet function might stem from vascular damage, resulting in a compromised organ blood supply (39). Furthermore, a recent study reported that donors with a history of HBP exhibited increased pancreatic lipid content and islet lipid content, irrespective of gender. This association was correlated with poorer islet performance after isolation (40).

Finally, our findings substantiate a noteworthy negative correlation between cardiac arrest as a cause of death and islet function when contrasted with alternative causes like trauma or cerebrovascular accidents.

This observed correlation could be closely tied to the varying durations of low or absent blood flow during the phases of donor resuscitation. The prolonged periods of diminished perfusion or complete cessation of blood flow during these critical stages exert a detrimental influence on pancreas perfusion, thereby contributing to the development of ischemia–reperfusion injuries (41, 42).

This study has certain limitations, primarily stemming from the relatively low number of cases and the presence of numerous potential confounding variables, mainly associated with the nature of the pancreas discarded for clinical purposes and the extended ischemia times. Additionally, in vivo function tests were not conducted in this study.

In conclusion, this study identified donor- and isolation-related factors that influence in vitro islet secretory function. Further studies are essential to evaluate the reliability of these results in clinical practice.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Cliniques Universitaires Saint Luc. The studies were conducted in accordance with the local legislation and institutional requirements. The human samples used in this study were acquired from primarily isolated as part of your previous study for which ethical approval was obtained. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

AB: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. NM: Investigation, Methodology, Validation, Visualization, Writing – review & editing. JA: Data curation, Methodology, Validation, Writing – review & editing. DH: Methodology, Writing – review & editing. AD: Validation, Visualization, Writing – review & editing. TD: Visualization, Writing – review & editing. NK: Visualization, Writing – review & editing. PG: Visualization, Writing – review & editing. MM: Validation, Writing – review & editing.