Implanting 1.1B4 human β-cell pseudoislets improves glycaemic control in diabetic severe combined immune deficient mice

AD Green, Srividya Vasu, Neville McClenaghan, Peter Flatt

Research output: Contribution to journalArticle

Abstract

AIMTo investigate the potential of implanting pseudoislets formed from human insulin-releasing β-cell lines as an alternative to islet transplantation. METHODSIn 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. RESULTSBoth 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. CONCLUSIONAlthough 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
LanguageEnglish
Pages523-533
JournalWorld Journal of Diabetes
Volume7
Issue number19
Early online date15 Nov 2016
DOIs
Publication statusE-pub ahead of print - 15 Nov 2016

Fingerprint

Insulin
Suspensions
Blood Glucose
Polydipsia
Cell Line
Islets of Langerhans Transplantation
Hyperphagia
Glucose Tolerance Test
Streptozocin
Glucagon
Islets of Langerhans
Hypoglycemic Agents
Hyperglycemia
Radioimmunoassay
Weight Loss
Eating
Fluorescence
Immunohistochemistry
Body Weight
Staining and Labeling

Keywords

  • Human β-cell line
  • 1.1B4
  • Cell therapy
  • Insulin
  • Pseudoislets

Cite this

Green, AD ; Vasu, Srividya ; McClenaghan, Neville ; Flatt, Peter. / Implanting 1.1B4 human β-cell pseudoislets improves glycaemic control in diabetic severe combined immune deficient mice. 2016 ; Vol. 7, No. 19. pp. 523-533.
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Implanting 1.1B4 human β-cell pseudoislets improves glycaemic control in diabetic severe combined immune deficient mice. / Green, AD; Vasu, Srividya; McClenaghan, Neville; Flatt, Peter.

Vol. 7, No. 19, 15.11.2016, p. 523-533.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Implanting 1.1B4 human β-cell pseudoislets improves glycaemic control in diabetic severe combined immune deficient mice

AU - Green, AD

AU - Vasu, Srividya

AU - McClenaghan, Neville

AU - Flatt, Peter

PY - 2016/11/15

Y1 - 2016/11/15

N2 - AIMTo investigate the potential of implanting pseudoislets formed from human insulin-releasing β-cell lines as an alternative to islet transplantation. METHODSIn 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. RESULTSBoth 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. CONCLUSIONAlthough 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

AB - AIMTo investigate the potential of implanting pseudoislets formed from human insulin-releasing β-cell lines as an alternative to islet transplantation. METHODSIn 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. RESULTSBoth 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. CONCLUSIONAlthough 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

KW - Human β-cell line

KW - 1.1B4

KW - Cell therapy

KW - Insulin

KW - Pseudoislets

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DO - 10.4239/wjd.v7.i19.523

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