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https://hdl.handle.net/2440/34058
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Type: | Journal article |
Title: | Glucose-regulated insulin expression in diabetic rats |
Author: | Barry, S. Ramesh, N. Lejnieks, D. Simonson, W. Kemper, L. Lernmark, A. Osborne, W. |
Citation: | Human Gene Therapy, 2001; 12(2):131-140 |
Publisher: | Mary Ann Liebert Inc |
Issue Date: | 2001 |
ISSN: | 1043-0342 1557-7422 |
Statement of Responsibility: | Simon C. Barry, N. Ramesh, D.V. Lejnieks, William T. Simonson, Lynne Kemper, Ake Lernmark, William R.A. Osborne |
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 alpha 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 microU (mean +/- SD) of insulin per 10(6) cells per day, respectively. After the onset of diabetes spontaneously diabetic congenic DR lyp/lyp BB rats received stomach implants containing 2 x 10(6) 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. |
Keywords: | Muscle, Smooth, Vascular Cells, Cultured Animals Rats, Inbred BB Humans Rats Diabetes Mellitus, Type 1 Weight Gain Insulin Furin Subtilisins Glucose Transforming Growth Factor alpha Erythropoietin RNA, Messenger Glucose Tolerance Test Transduction, Genetic Male Promoter Regions, Genetic |
DOI: | 10.1089/104303401750061195 |
Published version: | http://www.liebertonline.com/doi/abs/10.1089/104303401750061195 |
Appears in Collections: | Aurora harvest Paediatrics publications |
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