Beta-Cell Function and Human Islet Transplantation: Can We Improve?

248 3 Journal of J Chen and J E Gunton Islet transplantation 248:3 R99–R112 Endocrinology REVIEW Beta-cell function and human islet transplantation: can we improve? Jennifer Chen1 and Jenny E Gunton1,2,3,4 1The Westmead Institute for Medical Research, The University of Sydney Westmead Hospital, New South Wales, Australia 2Department of Endocrinology and Diabetes, Westmead Hospital, Sydney, New South Wales, Australia 3Garvan Institute of Medical Research, Sydney, New South Wales, Australia 4St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, Australia Correspondence should be addressed to J E Gunton: [email protected] Abstract Islet transplantation, a therapeutic option to treat type 1 diabetes, is not yet as Key Words successful as whole-pancreas transplantation as a treatment for diabetes. Mouse models f β-cells are commonly used for islet research. However, it is clear disparities exist between islet f islet transplantation transplantation outcomes in mice and humans. Given the shortage of transplant-grade f human islets, it is crucial that we further our understanding of factors that determine long-term f diabetes islet survival and function post-transplantation. In turn, this may lead to new therapeutic targets and strategies that will improve transplant outcomes. Here, we summarise the current landscape in clinical transplantation, highlight underlying similarities and differences between mouse and human islets, and review interventions that are being Journal of Endocrinology considered to create a new pool of β-cells for clinical application. (2021) 248, R99–R112 Introduction The pancreas lies posterior to the stomach, extending GLUT2 is the primary glucose transporter. Glucokinase from the spleen to the duodenum. It contains cells which phosphorylates glucose into glucose-6-phosphate, perform exocrine and endocrine functions. Endocrine preventing the diffusion of glucose back into circulation; cells are found in clusters called the islets of Langerhans it is the major β-cell glucose-sensor for both organisms or pancreatic islets. Although they consist of only 1–2% of (De Vos et al. 1995). Glucose-6-phosphate is catabolised the adult pancreas, islets are critical for regulating glucose through glycolysis and the Kreb’s cycle to produce homeostasis. The hormone insulin is secreted solely by ATP from adenosine diphosphate (ADP). Increased islet β-cells. When blood glucose levels rise, insulin is cytoplasmic ATP:ADP ratio is detected by ATP-sensing released. Diabetes occurs when β-cell dysfunction or loss potassium channels which then close, depolarising the leads to an inability to release enough insulin to control cell membrane. This opens voltage-gated Ca2+ channels, glucose. Other islet endocrine cell types include glucagon- triggering insulin granule exocytosis. secreting α-cells, δ-, pancreatic polypeptide (PP), and The key function of differentiated β-cells is glucose- ε-cells. stimulated insulin secretion (GSIS). GSIS normally Insulin reduces blood glucose by initiating peripheral occurs over two phases. First-phase GSIS occurs rapidly, glucose uptake particularly in muscle and adipose tissue, by definition, within 10 min of a glucose stimulus. and repressing glucagon activity. Glucose transporters This is thought to be mediated by the release of mature GLUT1, GLUT2 and GLUT3 (predominantly GLUT1) secretory insulin granules already close or docked to the facilitate glucose uptake in human β-cells. In mouse β-cells, β-cell plasma membrane. Then, there is a gradual second https://joe.bioscientifica.com © 2021 Society for Endocrinology https://doi.org/10.1530/JOE-20-0590 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 10:29:36AM via free access -20-0590 Journal of J Chen and J E Gunton Islet transplantation 248:3 R100 Endocrinology phase, beginning 10–20 min after glucose stimulus. In equivalents (IEQs) infused (CITR). Long-term graft humans, the activating threshold for GSIS is 3 mmol/L function is hindered by numerous factors including the glucose in the ‘lowest’ glucose-sensing cells, with a range toxicologic profile of immunosuppressives, limited graft of response thresholds recruiting more β-cells as glucose β-cell proliferation, and substantial islet necrosis and increases (Henquin et al. 2006). In rodents, the threshold apoptosis (Shapiro et al. 2017). is 5 mmol/L. Research efforts to study the human endocrine In type 1 (T1D) diabetes, β-cells are destroyed by the pancreas is limited by lack of access to tissue in living immune system (Atkinson & Eisenbarth 2001, Sherry et al. people, technical challenges in measuring β-cell function, 2005), and in type 2 (T2D) diabetes, they have impaired and inability to measure β-cell mass. Few studies have function (van Haeften 2002, Gunton et al. 2005). In the attempted to take pancreas tissue from a living person: early stages of T1D, there is preferential β-cell loss but later two Japanese studies described pancreatic punch biopsies there is often ‘by-stander’ damage and loss of the other as a safe procedure with minimal complications, but the islet cell types as a consequence of the immune attack. In Diabetes Virus Detection study (DiViD) was discontinued human T2D, there is differential β-cell loss, and insulin due to a high rate of complications (Imagawa et al. degranulation identified using electron microscopy. 2001, Krogvold et al. 2014). Thus the safety of obtaining Insulin immunohistochemistry is the most commonly pancreatic biopsies is not clear, and if it is not safe, used technique for labelling β-cells. However, negative then it is arguably unethical. Furthermore, islets are not immunostaining may be due to severe degranulation homogenously distributed in the human pancreas, thus a rather than loss of β-cell mass (Butler et al. 2003, Marselli single biopsy may not be representative. et al. 2014, Cinti et al. 2016). However, some T2D patients In studying isolated islets, they are obtained only have comparable granule density in nonhormone- from organ donors. Availability is low, and there are expressing endocrine cells to nondiabetic controls which challenges in isolating good quality human islets (Ricordi questions the degranulation model. The presence of these et al. 2016). In addition, islets de-differentiate soon after nonhormone-expressing endocrine cells may be attributed isolation in culture, losing their specialised phenotype to β-cell dedifferentiation or formation of immature new (Negi et al. 2012, Spijker et al. 2013). Indeed, after 7 endocrine cells (Butler et al. 2016). Supporting reversion days, few islets retain GSIS. Consequently, many studies to a nonmature state is the elevated expression of gastrin, have looked at characterising islet physiology to further a foetal pancreas biomarker, found in diabetic mouse our understanding of mechanisms and pathways that β-cells and T2D human β- and δ-cells (Dahan et al. 2017). contribute to graft failure post-transplantation (Omori Islet transplantation is a promising treatment for adults et al. 2016, Cross et al. 2017, Gan et al. 2018). Others (>18 years) with T1D for a duration of 5 or more years and have focused on developing strategies to stimulate β-cell experiencing severe hypoglycemic unawareness events proliferation or providing an alternative source of β-cells (Transplantation Society of Australia and New Zealand). by inducing cell transdifferentiation. The procedure aims to restore insulin independence, A limitation of human β-cell lines is that very few defined by the Collaborative Islet Transplant Registry display GSIS (Halvorsen et al. 2000, Ravassard et al. (CITR) as the absence of the need for exogenous insulin 2011). In addition, in vitro models do not encapsulate administration for more than 14 consecutive days. the complex interactions between physiological systems However, clinical application is hampered by donor in whole organisms that can affect graft outcomes. Thus, availability, and in the early transplant patients, poor a commonly used model organism for studying β-cell rates of long-term graft function. Approximately half of function is the laboratory mouse, where advantages all transplant recipients remained insulin independent 12 include its relative genetic similarity of humans, shorter months after the last islet infusion; most experienced a lifespan and readily manipulable genome. gradual decline in function. While an overall reduction The drugs alloxan and streptozotocin are used to of exogenous insulin requirement and improved glucose induce diabetes in mice (Kodama et al. 2005). They are handling was observed, only 16% of recipients were taken up by the cells as glucose analogues and cause insulin independent across all follow-up times. However, free-radical induced DNA damage. However, these drugs importantly, severe hypoglycemia was eliminated in are one of the few examples where human islets are 90% of recipients over 5 years of follow-up. Variables more robust than the animal models; human β-cells affecting graft outcomes included recipient age, induction are resistant, possibly due to rapid export of the toxins and maintenance immunosuppression, and total islet (Yang & Wright 2002). This feature is useful when testing https://joe.bioscientifica.com © 2021 Society for Endocrinology https://doi.org/10.1530/JOE-20-0590 Published by Bioscientifica Ltd. 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