{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T09:56:29Z","timestamp":1753869389643,"version":"3.41.2"},"reference-count":34,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,4,4]],"date-time":"2017-04-04T00:00:00Z","timestamp":1491264000000},"content-version":"vor","delay-in-days":34,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Hepatic insulin gene therapy (HIGT) employing a glucose and insulin sensitive promoter to direct insulin transcription can lower blood sugars within 2\u00a0h of an intraperitoneal glucose challenge. However, post\u2010challenge blood sugars frequently decline to below baseline. We hypothesize that this \u2018over\u2010shoot\u2019 hypoglycemia results from sustained translation of long\u2010lived transgene message, and that reducing pro\u2010insulin message half\u2010life will ameliorate post\u2010challenge hypoglycemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We compared pro\u2010insulin message content and insulin secretion from primary rat hepatocytes expressing insulin from either a standard construct (2xfur), or a construct producing a destabilized pro\u2010insulin message (InsTail), following exposure to stimulating or inhibitory conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hepatocytes transduced with a 2xfur construct accumulated pro\u2010insulin message, and exhibited increased insulin secretion, under conditions that both inhibit or stimulate transcription. By contrast, pro\u2010insulin message content remained stable in InsTail expressing cells, and insulin secretion increased less than 2xfur during prolonged stimulation. During transitions from stimulatory to inhibitory conditions, or vice versa, amounts of pro\u2010insulin message changed more rapidly in InsTail expressing cells than 2xfur expressing cells. Importantly, insulin secretion increased during the transition from stimulation to inhibition in 2xfur expressing cells, although it remained unchanged in InsTail expressing cells. Use of the InsTail destabilized insulin message tended to more rapidly reduce glucose induced glycemic excursions, and limit post\u2010load hypoglycemia in STZ\u2010diabetic mice <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The data obtained in the present study suggest that combining transcriptional and post\u2010transcriptional regulatory strategies may reduce undesirable glycemic excursion in models of HIGT.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.2946","type":"journal-article","created":{"date-parts":[[2017,2,9]],"date-time":"2017-02-09T01:32:40Z","timestamp":1486603960000},"source":"Crossref","is-referenced-by-count":0,"title":["mRNA destabilization improves glycemic responsiveness of transcriptionally regulated hepatic insulin gene therapy <i>in vitro<\/i> and <i>in vivo<\/i>"],"prefix":"10.1002","volume":"19","author":[{"given":"Peter M.","family":"Thul\u00e9","sequence":"first","affiliation":[{"name":"Atlanta VA Medical Center, Division of Endocrinology, Diabetes, &amp; Lipids Emory University School of Medicine  Decatur Georgia USA"},{"name":"Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulin","family":"Lin","sequence":"additional","affiliation":[{"name":"Atlanta VA Medical Center, Division of Endocrinology, Diabetes, &amp; Lipids Emory University School of Medicine  Decatur Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dingwu","family":"Jia","sequence":"additional","affiliation":[{"name":"Atlanta VA Medical Center, Division of Endocrinology, Diabetes, &amp; Lipids Emory University School of Medicine  Decatur Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darin E.","family":"Olson","sequence":"additional","affiliation":[{"name":"Atlanta VA Medical Center, Division of Endocrinology, Diabetes, &amp; Lipids Emory University School of Medicine  Decatur Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiue\u2010Cheng","family":"Tang","sequence":"additional","affiliation":[{"name":"Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"School of Chemical &amp; Biomolecular Engineering Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"Department of Medical Science National Tsing Hua University  Taiwan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Athanassios","family":"Sambanis","sequence":"additional","affiliation":[{"name":"Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"School of Chemical &amp; Biomolecular Engineering Georgia Institute of Technology  Atlanta Georgia USA"},{"name":"Department of Biomedical Engineering Georgia Institute of Technology  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,4,4]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.8.3293"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8227(01)00220-0"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/mend.11.6.0017"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1089\/104303403769211628"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301297"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.1341"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.97"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00019.2005"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301076"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(03)00121-2"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1980.tb29510.x"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1006\/abio.1999.4461"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.8.6.8168695"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1006\/mthe.2001.0299"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301746"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/35044106"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-200212270-00024"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2014.10.005"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.6.12.2219"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301076"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.135.5.1722"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1210\/mend.11.12.0021"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3130259"},{"key":"e_1_2_6_25_1","doi-asserted-by":"crossref","first-page":"13585","DOI":"10.1016\/S0021-9258(17)38764-1","article-title":"Control of insulin gene expression in pancreatic \u00e1\u2010cells and in an insulin\u2010producing cell line, RIN\u20105F cells. 1. 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