Published online Nov 15, 2016. doi: 10.4239/wjd.v7.i19.523
Peer-review started: April 12, 2016
First decision: May 19, 2016
Revised: August 20, 2016
Accepted: August 30, 2016
Article in press: August 31, 2016
Published online: November 15, 2016
To investigate the potential of implanting pseudoislets formed from human insulin-releasing β-cell lines as an alternative to islet transplantation.
In this study, the anti-diabetic potential of novel human insulin releasing 1.1B4 β-cells was evaluated by implanting the cells, either as free cell suspensions, or as three-dimensional pseudoislets, into the subscapular region of severe combined immune deficient mice rendered diabetic by single high-dose administration of streptozotocin. Metabolic parameters including food and fluid intake, bodyweight and blood glucose were monitored throughout the study. At the end of the study animals were given an intraperitoneal glucose tolerance test. Animals were then culled and blood and tissues were collected for analysis. Insulin and glucagon contents of plasma and tissues were measured by insulin radioimmunoassay and chemiluminescent enzyme-linked immunosorbance assay respectively. Histological analyses of pancreatic islets were carried out by quantitative fluorescence immunohistochemistry staining.
Both pseudoislet and cell suspension implants yielded well vascularised β-cell masses of similar insulin content. This was associated with progressive amelioration of hyperphagia (P < 0.05), polydipsia (P < 0.05), body weight loss (P < 0.05), hypoinsulinaemia (P < 0.05), hyperglycaemia (P < 0.05 - P < 0.001) and glucose tolerance (P < 0.01). Islet morphology was also significantly improved in both groups of transplanted mice, with increased β-cell (P < 0.05 - P < 0.001) and decreased alpha cell (P < 0.05 - P < 0.001) areas. Whereas mice receiving 1.1B4 cell suspensions eventually exhibited hypoglycaemic complications, pseudoislet recipients displayed a more gradual amelioration of diabetes, and achieved stable blood glucose control similar to non-diabetic mice at the end of the study.
Although further work is needed to address safety issues, these results provide proof of concept for possible therapeutic applicability of human β-cell line pseudoislets in diabetes.
Core tip: Human insulin-releasing 1.1B4 β-cell suspensions and psuedoislets were implanted in streptozotocin-diabetic severe combined immune deficient mice to assess their antidiabetic potential. Both cell configurations yielded vascularised, insulin positive β-cell masses. These were associated with beneficial effects on hyperphagia, polydipsia, body weight, hypoinsulinaemia, hyperglycaemia and glucose tolerance. Both treatments were also associated with significant improvements in islet morphology and increased β:α-cell ratio. Pseudoislet recipients displayed gradual glucose normalization, while cell suspension recipients ultimately presented with hypoglycaemic complications. These results provide proof of concept for possible clinical artificial human β-cell psuedoislets, although further work is needed to address the tumourigenicity of clonal cell-lines.