@article{d226973556a94123ba72b9b7afa179a7,
title = "Acyl-ghrelin is permissive for the normal counterregulatory response to insulin-induced hypoglycemia",
abstract = "Insulin-induced hypoglycemia leads to far-ranging negative consequences in patients with diabetes. Components of the counterregulatory response (CRR) system that help minimize and reverse hypoglycemia and coordination between those components are well studied but not yet fully characterized. Here, we tested the hypothesis that acyl-ghrelin, a hormone that defends against hypoglycemia in a preclinical starvation model, is permissive for the normal CRR to insulin-induced hypoglycemia. Ghrelin knockout (KO) mice and wild-type (WT) littermates underwent an insulin bolus-induced hypoglycemia test and a low-dose hyperinsulinemic-hypoglycemic clamp procedure. Clamps also were performed in ghrelin-KO mice and C57BL/6N mice administered the growth hormone secretagogue receptor agonist HM01 or vehicle. Results show that hypoglycemia, as induced by an insulin bolus, wasmore pronounced and prolonged in ghrelin-KO mice, supporting previous studies suggesting increased insulin sensitivity upon ghrelin deletion. Furthermore, during hyperinsulinemic-hypoglycemic clamps, ghrelin- KO mice required a 10-fold higher glucose infusion rate (GIR) and exhibited less robust corticosterone and growth hormone responses. Conversely, HM01 administration, which reduced the GIR required by ghrelin-KO mice during the clamps, increased plasma corticosterone and growth hormone. Thus, our data suggest that endogenously produced acyl-ghrelin not only influences insulin sensitivity but also is permissive for the normal CRR to insulin-induced hypoglycemia.",
author = "Kripa Shankar and Deepali Gupta and Mani, {Bharath K.} and Findley, {Brianna G.} and Lord, {Caleb C.} and Sherri Osborne-Lawrence and Metzger, {Nathan P.} and Claudio Pietra and Chen Liu and Berglund, {Eric D.} and Zigman, {Jeffrey M.}",
note = "Funding Information: Acknowledgments. The authors thank the Vanderbilt University Medical Center Hormone Assay and Analytical Services Core for performing the catecholamines assays. Funding. This work was supported through research grants from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-109408 to E.D.B., R01-DK-119341 to E.D.B. and J.M.Z., and R56-DK-071320 and R01-DK-103884 to J.M.Z.), a gift from the David & Teresa Disiere Foundation (to J.M.Z.), the Diana and Richard C. Strauss Professorship in Biomedical Research, the Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine, and the Kent and Jodi Foster Distinguished Chair in Endocrinology, in Honor of Daniel Foster, M.D. (to J.M.Z.). Duality of Interest. C.P. is employed by Helsinn Healthcare SA. No other potential conflicts of interest relevant to this article were reported. Author Contributions. K.S. conceptualized and performed the experiments, analyzed and interpreted the data, and helped write the manuscript. D.G. performed the experiments and helped analyze and interpret the data. B.K.M. and C.L. conceptualized and performed some experiments. B.G.F., C.C.L., S.O.-L., and N.P.M. performed the experiments. C.P. provided HM01. E.D.B. and J.M.Z. conceptualized the experiments, secured funding, interpreted the data, supervised the research activity, and helped write the manuscript. K.S., E.D.B., and J.M.Z. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2019 by the American Diabetes Association.",
year = "2020",
month = feb,
day = "1",
doi = "10.2337/db19-0438",
language = "English (US)",
volume = "69",
pages = "228--237",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "2",
}