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Prolonged survival and improved glycemia in BioBreeding diabetic rats after early sustained exposure to glucagon-like peptide

Yanay, Ofer; Moralejo, Daniel H.; Kernan, Kelly; Brzezinski, Margaret; Fuller, Jessica M. LU ; Barton, Randall W.; Lernmark, Ake LU and Osborne, William R. (2010) In Journal of Gene Medicine 12(6). p.538-544
Abstract

Background: Type 1 diabetes (T1D) in both humans and BioBreeding (BB) rats is an autoimmune disease that results in complete destruction of islets and insulin dependency for life. Glucagon-like peptide 1 (GLP-1) promotes β cell proliferation and neogenesis and has a potent insulinotropic effect. We hypothesized that the expression of GLP-1 before disease onset would increase islet mass, delay diabetes and prolong survival of BB rats. Methods: Vascular smooth muscle cells retrovirally transduced to secrete GLP-1 were seeded into TheraCyte™ encapsulation devices, implanted subcutaneously, and rats were monitored for diabetes. Results: In untreated control rats, plasma GLP-1 levels were 34.5-39.5 pmol/l, whereas, in treated rats, plasma... (More)

Background: Type 1 diabetes (T1D) in both humans and BioBreeding (BB) rats is an autoimmune disease that results in complete destruction of islets and insulin dependency for life. Glucagon-like peptide 1 (GLP-1) promotes β cell proliferation and neogenesis and has a potent insulinotropic effect. We hypothesized that the expression of GLP-1 before disease onset would increase islet mass, delay diabetes and prolong survival of BB rats. Methods: Vascular smooth muscle cells retrovirally transduced to secrete GLP-1 were seeded into TheraCyte™ encapsulation devices, implanted subcutaneously, and rats were monitored for diabetes. Results: In untreated control rats, plasma GLP-1 levels were 34.5-39.5 pmol/l, whereas, in treated rats, plasma levels were elevated, in the range 90-250.4 pmol/l. Hypoglycemia was not detected and this was anticipated from the glucose-regulated action of GLP-1. Diabetes onset (mean ± SEM) in untreated rats occurred at 56.5 ± 0.6 days (n = 6) and, in GLP-1-treated rats, was delayed until 76.4 ± 3.3 days (n = 5) (p < 0.001). After disease onset, untreated control rats showed a rapid weight loss and elevated blood glucose (>650 mg/dl) and did not survive beyond 11 days. At 5 days after diabetes onset, insulin-secreting islets were absent in untreated rats. By contrast, treated rats maintained weight for up to 143 days of age and showed insulin-secreting β cells. Conclusions: Sustained GLP-1 expression delivered by encapsulated cells before diabetes onset in BB rats showed an improved clinical outcome, suggesting the potential for treating patients using long lasting GLP-1 analogs.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
BB rats, Bioisolator, Diabetes, GLP-1, β cells
in
Journal of Gene Medicine
volume
12
issue
6
pages
7 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:77954574031
ISSN
1099-498X
DOI
10.1002/jgm.1466
language
English
LU publication?
no
id
1cc0597c-de4c-4d8b-9aac-071fe5c87237
date added to LUP
2017-09-07 12:10:10
date last changed
2018-05-29 10:19:18
@article{1cc0597c-de4c-4d8b-9aac-071fe5c87237,
  abstract     = {<p>Background: Type 1 diabetes (T1D) in both humans and BioBreeding (BB) rats is an autoimmune disease that results in complete destruction of islets and insulin dependency for life. Glucagon-like peptide 1 (GLP-1) promotes β cell proliferation and neogenesis and has a potent insulinotropic effect. We hypothesized that the expression of GLP-1 before disease onset would increase islet mass, delay diabetes and prolong survival of BB rats. Methods: Vascular smooth muscle cells retrovirally transduced to secrete GLP-1 were seeded into TheraCyte™ encapsulation devices, implanted subcutaneously, and rats were monitored for diabetes. Results: In untreated control rats, plasma GLP-1 levels were 34.5-39.5 pmol/l, whereas, in treated rats, plasma levels were elevated, in the range 90-250.4 pmol/l. Hypoglycemia was not detected and this was anticipated from the glucose-regulated action of GLP-1. Diabetes onset (mean ± SEM) in untreated rats occurred at 56.5 ± 0.6 days (n = 6) and, in GLP-1-treated rats, was delayed until 76.4 ± 3.3 days (n = 5) (p &lt; 0.001). After disease onset, untreated control rats showed a rapid weight loss and elevated blood glucose (&gt;650 mg/dl) and did not survive beyond 11 days. At 5 days after diabetes onset, insulin-secreting islets were absent in untreated rats. By contrast, treated rats maintained weight for up to 143 days of age and showed insulin-secreting β cells. Conclusions: Sustained GLP-1 expression delivered by encapsulated cells before diabetes onset in BB rats showed an improved clinical outcome, suggesting the potential for treating patients using long lasting GLP-1 analogs.</p>},
  author       = {Yanay, Ofer and Moralejo, Daniel H. and Kernan, Kelly and Brzezinski, Margaret and Fuller, Jessica M. and Barton, Randall W. and Lernmark, Ake and Osborne, William R.},
  issn         = {1099-498X},
  keyword      = {BB rats,Bioisolator,Diabetes,GLP-1,β cells},
  language     = {eng},
  number       = {6},
  pages        = {538--544},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Gene Medicine},
  title        = {Prolonged survival and improved glycemia in BioBreeding diabetic rats after early sustained exposure to glucagon-like peptide},
  url          = {http://dx.doi.org/10.1002/jgm.1466},
  volume       = {12},
  year         = {2010},
}