Abstract
Type 1 diabetes mellitus is caused by a lack of insulin that results from the autoimmune destruction of the pancreatic beta-cells. Severe diabetes, if not controlled by periodic insulin injections, can lead to ketoacidosis and death. We have previously shown that sustained low level production of insulin in the liver of diabetic rats prevented their death from complications of diabetes. To test the hypothesis that there is a window of serum insulin concentrations that can prevent ketoacidosis without significant risk of hypoglycemia secondary to hyperinsulinemia, rats were infused with various doses of a recombinant retrovirus encoding an engineered rat preproinsulin-1 gene. The gene was engineered to allow processing into mature insulin by the protease furin. At the lower doses tested, fatal ketoacidosis was prevented, but the rats exhibited nonfasting hyperglycemia. At intermediate doses, which resulted in serum insulin concentrations of 1.6 mg/ml, the rats achieved near-normoglycemia and no serum ketones. These rats did not exhibit hypoglycemia even during a 24-h fast. At high virus doses, the animals achieved nonfasting normoglycemia but exhibited hypoglycemia during the fast. In conclusion, we have defined a therapeutic wi...Continue Reading
References
Jan 1, 1991·Biochimie·M RaymondjeanA Kahn
Oct 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·S C GriffenC S Nicoll
Dec 1, 1971·Diabetes·G F Cahill
Apr 11, 1995·Proceedings of the National Academy of Sciences of the United States of America·T M KolodkaS L Woo
May 29, 1995·FEBS Letters·R ChenA Kahn
Sep 1, 1993·Somatic Cell and Molecular Genetics·T M KolodkaS L Woo
Apr 1, 1994·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·A ValeraF Bosch
Sep 10, 1996·Human Gene Therapy·N E BowlesS L Woo
Citations
Sep 4, 2009·Gene Therapy·S B FotiT J McCown
Jul 1, 2005·Diabetologia·M ItoY Saito
Aug 30, 2008·Expert Opinion on Drug Delivery·Darin E Olson, Peter M Thulé
Feb 10, 2017·The Journal of Gene Medicine·Peter M ThuléAthanassios Sambanis
Nov 9, 2002·Gene Therapy·V SchmitzC Qian
Jul 19, 2002·The Journal of Gene Medicine·Xiang ChenOi Lian Kon
Nov 26, 1998·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·A W WolkoffB F Scharschmidt
May 6, 2003·The Journal of Gene Medicine·France Croze, Gérald J Prud'homme
Oct 2, 2004·Nature Reviews. Immunology·Yuti ChernajovskyOsvaldo L Podhajcer
Mar 1, 2000·Gene Therapy·P M ThuléL S Phillips
Nov 18, 2000·Gene Therapy·P M Thulé, J M Liu
Dec 8, 2000·Gene Therapy·R ChenS L Woo
May 1, 2004·Endocrinology·Yong Lian ZhuPriscilla S Dannies
Apr 9, 2015·Journal of Diabetes·Shen QuH Henry Dong
Feb 26, 2005·Endocrinology·Yu-Chun LuElena Zhukova
Feb 18, 2004·World Journal of Gastroenterology : WJG·Chen-Xia HeJing-Lun Xue
Nov 14, 1998·The American Journal of Physiology·D K ShortJ E Pessin
May 23, 2002·The Journal of Thoracic and Cardiovascular Surgery·Hitoshi SuharaHikaru Matsuda
Apr 26, 2001·Molecular Therapy : the Journal of the American Society of Gene Therapy·R ChenS L Woo
Oct 11, 2003·Biochemical and Biophysical Research Communications·Kakei YasutomiOsam Mazda
Aug 29, 2021·Pharmaceutics·Nolwenn TessierCatherine Martel