@article{d009f05129a84bf984ce4473ad0553d3,
title = "Thioredoxin-1 overexpression in the ventromedial nucleus of the hypothalamus preserves the counterregulatory response to hypoglycemia during type 1 diabetes in male rats",
abstract = "We previously showed that the glutathione precursor, Nacetylcysteine (NAC), prevented hypoglycemia-associated autonomic failure (HAAF) and impaired activation of ventromedial hypothalamus (VMH) glucose-inhibited (GI) neurons by low glucose after recurrent hypoglycemia (RH) in nondiabetic rats. However, NAC does not normalize glucose sensing by VMH GI neurons when RH occurs during diabetes. We hypothesized that recruiting the thioredoxin (Trx) antioxidant defense system would prevent HAAF and normalize glucose sensing after RH in diabetes. To test this hypothesis, we overexpressed Trx-1 (cytosolic form of Trx) in the VMH of rats with streptozotocin (STZ)-induced type 1 diabetes. The counterregulatory response (CRR) to hypoglycemia in vivo and the activation of VMH GI neurons in low glucose using membrane potential sensitive dye in vitro was measured before and after RH. VMH Trx-1 overexpression normalized both the CRR and glucose sensing by VMH GI neurons in STZ rats. VMH Trx-1 overexpression also lowered the insulin requirement to prevent severe hyperglycemia in STZ rats. However, like NAC, VMH Trx-1 overexpression did not prevent HAAF or normalize activation of VMH GI neurons by low glucose in STZ rats after RH. We conclude that preventing HAAF in type 1 diabetes may require the recruitment of both antioxidant systems.",
author = "Chunxue Zhou and Routh, {Vanessa H.}",
note = "Funding Information: Acknowledgments. The authors are deeply grateful to Dr. Owen Chan, University of Utah School of Medicine, Salt Lake City, UT, and Dr. Xavier Fioramonti, INRA, Universite de Bordeaux, Bordeaux, France, for advice in evaluating the CRR in diabetic rats and also thank Dr. Chan for advice in the care and prevention of severe hyperglycemia in diabetic rats. Dr. Zhenyu Sheng, Rutgers New Jersey Medical School, Newark, NJ, provided assistance with care of the diabetic rats. Funding. This work was partly supported by JDRF Award 2-SRA-2014-269-M-R and National Institutes of Health grant RO1-DK-081538-01A1. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. C.Z. collected the data. C.Z. and V.H.R. designed the study and wrote the manuscript. V.H.R. edited the manuscript. V.H.R. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9–13 June 2017, and at the American Society for Nutrition Scientific Sessions and Annual Meeting at Experimental Biology, Chicago, IL, 22–26 April 2017. Publisher Copyright: {\textcopyright} 2017 by the American Diabetes Association..",
year = "2018",
month = jan,
day = "1",
doi = "10.2337/db17-0930",
language = "English (US)",
volume = "67",
pages = "120--130",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "1",
}