+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

A model for determining an effective in vivo dose of transplanted islets based on in vitro insulin secretion

A model for determining an effective in vivo dose of transplanted islets based on in vitro insulin secretion

Xenotransplantation 25(6): E12443

Label="BACKGROUND">Allogeneic islet transplantation for the treatment of type 1 diabetes often requires multiple implant procedures, from as many as several human pancreas donors, to achieve lasting clinical benefit. Given the limited availability of human pancreases for islet isolation, porcine islets have long been considered a potential option for clinical use. Agarose-encapsulated porcine islets (macrobeads) permit long-term culture and thus a thorough evaluation of microbiological safety and daily insulin secretory capacity, prior to implantation. The goal of this study was the development of a method for determining an effective dose of encapsulated islets based on their measured in vitro insulin secretion in a preclinical model of type 1 diabetes.Label="METHODS">Spontaneously diabetic BioBreeding diabetes-prone rats were implanted with osmotic insulin pumps in combination with continuous glucose monitoring to establish the daily insulin dose required to achieve continuous euglycaemia in individual animals. Rats were then implanted with a 1×, 2× or 3× dose (defined as the ratio of macrobead in vitro insulin secretion per 24 hours to the recipient animal's total daily insulin requirement) of porcine islet macrobeads, in the absence of immunosuppression. In vivo macrobead function was assessed by recipient non-fasted morning blood glucose values, continuous glucose monitoring and the presence of peritoneal porcine C-peptide. At the end of the study, the implanted macrobeads were removed and returned to in vitro culture for the evaluation of insulin secretion.Label="RESULTS">Diabetic rats receiving a 2× macrobead implant exhibited significantly improved blood glucose regulation compared to that of rats receiving a 1× dose during a 30-day pilot study. In a 3-month follow-up study, 2× and 3× macrobead doses initially controlled blood glucose levels equally well, although several animals receiving a 3× dose maintained euglycaemia throughout the study, compared to none of the 2× animals. The presence of porcine C-peptide in rat peritoneal fluid 3 months post-implant and the recurrence of hyperglycaemia following macrobead removal, along with the finding of persistent in vitro insulin secretion from retrieved macrobeads, confirmed long-term graft function.Label="CONCLUSIONS">Increasing dosages of islet macrobeads transplanted into diabetic rats, based on multiples of in vitro insulin secretion matched to the recipient's exogenous insulin requirements, correlated with improved blood glucose regulation and increased duration of graft function. These results demonstrate the usefulness of a standardized model for the evaluation of the functional effectiveness of islets intended for transplantation, in this case using intraperitoneally implanted agarose macrobeads, in diabetic rats. The results suggest that some features of this islet-dosing methodology may be applicable, and indeed necessary, to clinical allogeneic and xenogeneic islet transplantation.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 046427879

Download citation: RISBibTeXText

PMID: 30054944

DOI: 10.1111/xen.12443

Related references

Investigations on isolated islets of Langerhans in vitro. XIV. Insulin secretion and insulin stores of cultivated islets from sand rats (Psammomys obesus): investigations of glucose-dose response. Endokrinologie 68(1): 95, 1976

Investigations on isolated Islets of Langerhans in vitro. 14. Insulin secretion and insulin stores of cultivated islets from sand rats (Psammomys obesus): investigations of glucose-dose response. Endokrinologie 681: 95-103, 1976

Evaluation of the effect of insulin pump therapy on insulin secretion from transplanted human fetal islets in insulin-dependent diabetics. Transplantation Proceedings 26(2): 702-703, 1994

Multipotent mesenchymal stromal cells enhance insulin secretion from human islets via N-cadherin interaction and prolong function of transplanted encapsulated islets in mice. Stem Cell Research and Therapy 8(1): 199, 2017

A novel Gymnema sylvestre extract stimulates insulin secretion from human islets in vivo and in vitro. PhytoTherapy Research 24(9): 1370-1376, 2010

Effects of vitamin A deficiency and repletion on rat insulin secretion in vivo and in vitro from isolated islets. Journal of Clinical Investigation 79(1): 163-169, 1987

Myelin basic protein stimulates insulin and glucagon secretion from rat pancreatic islets in vitro and in vivo. Acta Physiologica Scandinavica 139(3): 493-501, 1990

Impaired insulin secretion in vivo but enhanced insulin secretion from isolated islets in pancreatic beta cell-specific vascular endothelial growth factor-A knock-out mice. Diabetologia 50(2): 380-389, 2007

A local glucose-and oxygen concentration-based insulin secretion model for pancreatic islets. Theoretical Biology & Medical Modelling 8(): 20-20, 2011

Insulin secretion in streptozotocin-diabetic rats transplanted with immunoisolated islets. Transplantation 51(3): 570-574, 1991

Coordinate pulsatile insulin secretion from chronic intrahepatic transplanted islets. Clinical Research 41(1): 92A, 1993

Investigations on islets of langerhans in vitro. VIII. Ultrastructure and insulin secretion of isolated rat islets after different digestion with collagenase. Acta Histochemica 51(1): 50-60, 1974

Cryopreservation increases insulin secretion of rat pancreatic islets transplanted into nude mice. Hormone & Metabolic Research 28(1): 46, 1996

Altered expression of somatostatin receptors in pancreatic islets from NOD mice cultured at different glucose concentrations in vitro and in islets transplanted to diabetic NOD mice in vivo. Experimental Diabetes Research 2011: 623472, 2011

Expression of the beacon gene in the rat pancreatic islets: opposite effects of beacon (47-73) protein (ubiquitin-like protein 5) on insulin secretion in vivo and insulin release by isolated islets. Pancreas 29(2): 99-103, 2004