Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs

Noelia Rivera, Christopher J. Ramnanan, Zhibo An, Tiffany Farmer, Marta Smith, Ben Farmer, Jose M. Irimia, Wanda Snead, Margaret Lautz, Peter J. Roach, Alan D. Cherrington

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25 Scopus citations

Abstract

In individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. Under conditions of insulin-induced hypoglycemia, glucagon is the most important stimulus for hepatic glucose production. In contrast, during euglycemia, insulin potently inhibits glucagon's effect on the liver. The first aim of the present study was to determine whether low blood sugar augments glucagon's ability to increase glucose production. Using a conscious catheterized dog model, we found that hypoglycemia increased glucagon's ability to overcome the inhibitory effect of insulin on hepatic glucose production by almost 3-fold, an effect exclusively attributable to marked enhancement of the effect of glucagon on net glycogen breakdown. To investigate the molecular mechanism by which this effect comes about, we analyzed hepatic biopsies from the same animals, and found that hypoglycemia resulted in a decrease in insulin signaling. Furthermore, hypoglycemia and glucagon had an additive effect on the activation of AMPK, which was associated with altered activity of the enzymes of glycogen metabolism.

Original languageEnglish (US)
Pages (from-to)4425-4435
Number of pages11
JournalJournal of Clinical Investigation
Volume120
Issue number12
DOIs
StatePublished - Dec 1 2010

ASJC Scopus subject areas

  • Medicine(all)

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    Rivera, N., Ramnanan, C. J., An, Z., Farmer, T., Smith, M., Farmer, B., Irimia, J. M., Snead, W., Lautz, M., Roach, P. J., & Cherrington, A. D. (2010). Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs. Journal of Clinical Investigation, 120(12), 4425-4435. https://doi.org/10.1172/JCI40919