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Glucose-regulated insulin expression in diabetic rats

Author:
  • S. C. Barry
  • N. Ramesh
  • D. V. Lejnieks
  • William T Simonson
  • L. Kemper
  • Å Lernmark
  • W. R.A. Osborne
Publishing year: 2001-01-20
Language: English
Pages: 131-139
Publication/Series: Human Gene Therapy
Volume: 12
Issue: 2
Document type: Journal article
Publisher: Mary Ann Liebert, Inc.

Abstract english

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.

Other

Published
  • ISSN: 1043-0342
E-mail: ake [dot] lernmark [at] med [dot] lu [dot] se

Principal investigator

Diabetes and Celiac Unit

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+46 70 616 47 79

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Jan Waldenströms gata 35, Malmö

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Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00