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Glucose-regulated insulin expression in diabetic rats

Barry, S. C.; Ramesh, N.; Lejnieks, D. V.; Simonson, William T; Kemper, L.; Lernmark, Å LU and Osborne, W. R.A. (2001) In Human Gene Therapy 12(2). p.131-139
Abstract

Retroviral vectors encoding glucose-responsive promoters driving furin expression may provide an amplified, glucose-regulated secretion of insulin. We constructed LhI*TFSN virus to encode a glucose-regulatable transforming growth factor α promoter controlling furin expression with a viral LTR promoter driving constitutive expression of furin-cleavable human proinsulin. Autologous BB rat vascular smooth muscle cells transduced with LhI*TFSN virus and cultured in 1.7 and 16.7 mM glucose secreted 50.7 ± 3.2 and 136.0 ± 11.0 μU (mean ± SD) of insulin per 106 cells per day, respectively. After the onset of diabetes spontaneously diabetic congenic DR lyp/lyp BB rats received stomach implants containing 2 × 106... (More)

Retroviral vectors encoding glucose-responsive promoters driving furin expression may provide an amplified, glucose-regulated secretion of insulin. We constructed LhI*TFSN virus to encode a glucose-regulatable transforming growth factor α promoter controlling furin expression with a viral LTR promoter driving constitutive expression of furin-cleavable human proinsulin. Autologous BB rat vascular smooth muscle cells transduced with LhI*TFSN virus and cultured in 1.7 and 16.7 mM glucose secreted 50.7 ± 3.2 and 136.0 ± 11.0 μU (mean ± SD) of insulin per 106 cells per day, respectively. After the onset of diabetes spontaneously diabetic congenic DR lyp/lyp BB rats received stomach implants containing 2 × 106 LhI*TFSN-transduced primary rat vascular smooth muscle cells. In eight treated rats there was a major reduction in insulin requirement to as low as 25% of pretreatment level for up to 3 months and one rat became insulin free without hypoglycemia. Intraperitoneal glucose tolerance tests (IPGTTs) in diabetic rats receiving control implants did not show the characteristic decline in blood glucose of normal rats after glucose administration. In contrast, diabetic rats receiving LhI*TFSN-transduced cells showed significant clearances of blood glucose. These data suggest clinically significant levels of glucose-regulated insulin delivery from implanted vascular smooth muscle cells transduced with LhI*TFSN vector.

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author
publishing date
type
Contribution to journal
publication status
published
in
Human Gene Therapy
volume
12
issue
2
pages
9 pages
publisher
Mary Ann Liebert, Inc.
external identifiers
  • scopus:0035915762
ISSN
1043-0342
DOI
10.1089/104303401750061195
language
English
LU publication?
no
id
e392716e-0714-4b43-ac85-8255f88a04f3
date added to LUP
2017-09-07 09:35:04
date last changed
2018-05-29 11:32:10
@article{e392716e-0714-4b43-ac85-8255f88a04f3,
  abstract     = {<p>Retroviral vectors encoding glucose-responsive promoters driving furin expression may provide an amplified, glucose-regulated secretion of insulin. We constructed LhI*TFSN virus to encode a glucose-regulatable transforming growth factor α promoter controlling furin expression with a viral LTR promoter driving constitutive expression of furin-cleavable human proinsulin. Autologous BB rat vascular smooth muscle cells transduced with LhI*TFSN virus and cultured in 1.7 and 16.7 mM glucose secreted 50.7 ± 3.2 and 136.0 ± 11.0 μU (mean ± SD) of insulin per 10<sup>6</sup> cells per day, respectively. After the onset of diabetes spontaneously diabetic congenic DR lyp/lyp BB rats received stomach implants containing 2 × 10<sup>6</sup> LhI*TFSN-transduced primary rat vascular smooth muscle cells. In eight treated rats there was a major reduction in insulin requirement to as low as 25% of pretreatment level for up to 3 months and one rat became insulin free without hypoglycemia. Intraperitoneal glucose tolerance tests (IPGTTs) in diabetic rats receiving control implants did not show the characteristic decline in blood glucose of normal rats after glucose administration. In contrast, diabetic rats receiving LhI*TFSN-transduced cells showed significant clearances of blood glucose. These data suggest clinically significant levels of glucose-regulated insulin delivery from implanted vascular smooth muscle cells transduced with LhI*TFSN vector.</p>},
  author       = {Barry, S. C. and Ramesh, N. and Lejnieks, D. V. and Simonson, William T and Kemper, L. and Lernmark, Å and Osborne, W. R.A.},
  issn         = {1043-0342},
  language     = {eng},
  month        = {01},
  number       = {2},
  pages        = {131--139},
  publisher    = {Mary Ann Liebert, Inc.},
  series       = {Human Gene Therapy},
  title        = {Glucose-regulated insulin expression in diabetic rats},
  url          = {http://dx.doi.org/10.1089/104303401750061195},
  volume       = {12},
  year         = {2001},
}