The presence of GCG-secreting alpha cells and SST-secreting delta cells have been shown to affect insulin secretion, highlighting the critical role of intra-islet paracrine signaling by the endocrine cells, in addition to that of the nervous and vascular system
[48][49][50][51][52]. It is crucial to note that these secreted hormones are present at a higher concentration within the islet, thereby making the signaling cascades downstream of their receptors impactful in the islet endocrine cells. GCG and GCG-derived peptides have been shown to positively regulate the exocytosis of insulin-containing vesicles
[53][54]. In addition to the paracrine inhibitory effect of GCG and SST on insulin secretion, it has been found that alpha cells affect beta cell function through other secretagogues like acetylcholine
[51]. On the other hand, SST secreted from the delta cells of the islet inhibits insulin secretion
[55]. In addition, endocrine cells of the islet, such as alpha cells have been shown to have a high expression of insulin receptor (INSR). Furthermore, excessive insulin has been shown to have paracrine inhibitory effects on GCG secretion
[56]. Therefore, it is worthwhile to note that, due to the loss of insulin signaling from the compromised beta cells in diabetes mellitus, the development and functionality of the other endocrine cells could be affected
[57]. In this regard, it has been proposed that, in the T2D pancreas, there is an increase in the proportion of alpha to beta cells due to diminished beta cell numbers
[58]. Also, a recent study demonstrated that pancreatic alpha cells are more resistant to metabolic stress than beta cells in the T2D pancreas, because alpha cells express high levels of anti-apoptotic proteins
[59]. On the other hand, in T1D, alpha cell mass seems to be decreased
[60], indicating a complex inter-dependency between alpha and beta cells for development and functioning. Interestingly, the arrangement of endocrine cells within the human islet also hints at the developmental importance of paracrine signaling and coupling for the functional performance of these endocrine cells, as beta cells have multiple contacts with other endocrine cells within the islet
[48][52]. Therefore, it is worth studying if beta cell replacement options under diabetic conditions that considered co-employing alpha cells and delta cells along with beta cells could better correct hyperglycemia
[61]. To design a product that would include all major endocrine cells of the human islet, these cells could be purified individually using surface markers exclusive to each cell-type, followed by their aggregation in adequate percentages to represent a surrogate human islet, which can then be encapsulated and transplanted. However, if the cell-contact conferred functional properties of beta cells originate during fetal development of the pancreas, it may be more strategic to transplant progenitor cells that represent islet precursors and give rise to all desired endocrine populations assisting in glucose-responsiveness of beta cells in appropriate proportions, connected together as in the developing embryonic pancreas. However, the co-differentiation of ductal and acinar cell-types from transplanted pancreatic progenitors is an added disadvantage. Further studies on how to overcome this disadvantage are required. For example, the purification of multipotent pancreatic progenitors using markers, such as GP-2, prior to encapsulation is rather a convenient option to enhance the specification of beta cells
[22][34]. Nevertheless, manipulating physiological conditions may also favor endocrine differentiation, as in the case of macro-encapsulation devices that are designed to provide a high oxygen pressure to the transplanted cells to enhance cell viability. Importantly, oxygen is a crucial factor for specification of endocrine progenitors as a high oxygen pressure was shown inhibit Notch signaling
[62] which would in turn promote NGN3 expression at the expense of ductal specification
[63]. Beta-O2 devices that have been used for islet transplantation have a replenishable gas chamber that constantly stipulate the transplanted cells with oxygen (
https://beta-o2.com/efficient-oxygenation/). Improvements in the encapsulation system that would promote vascularization and engraftment to enhance oxygen supply are discussed later. In the case of no encapsulation, the selection of a transplantation site that has a higher oxygen pressure or is highly vascularized is rather preferable
[64]. Alternatively, beta cell differentiation protocols could be adapted to generate a pancreatic islet organoid in vitro, consisting of all endocrine cell-types proportionately, self-organized into an islet-like structure, that can be directly transplanted as a terminally differentiated surrogate islet. This may be achieved by the purification of endocrine progenitors specifically, or by using a modified cell line that cannot generate non-pancreatic endocrine cells.