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 Roach, Alan D. Cherrington

Research output: Contribution to journalArticle

25 Citations (Scopus)

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

Fingerprint

Glucagon
Hypoglycemia
Dogs
Insulin
Liver
Glycogen
Glucose
AMP-Activated Protein Kinases
Type 1 Diabetes Mellitus
Blood Glucose
Biopsy
Enzymes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Rivera, N., Ramnanan, C. J., An, Z., Farmer, T., Smith, M., Farmer, B., ... 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

Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs. / Rivera, Noelia; Ramnanan, Christopher J.; An, Zhibo; Farmer, Tiffany; Smith, Marta; Farmer, Ben; Irimia, Jose M.; Snead, Wanda; Lautz, Margaret; Roach, Peter; Cherrington, Alan D.

In: Journal of Clinical Investigation, Vol. 120, No. 12, 01.12.2010, p. 4425-4435.

Research output: Contribution to journalArticle

Rivera, N, Ramnanan, CJ, An, Z, Farmer, T, Smith, M, Farmer, B, Irimia, JM, Snead, W, Lautz, M, Roach, P & Cherrington, AD 2010, 'Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs', Journal of Clinical Investigation, vol. 120, no. 12, pp. 4425-4435. https://doi.org/10.1172/JCI40919
Rivera N, Ramnanan CJ, An Z, Farmer T, Smith M, Farmer B et al. Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs. Journal of Clinical Investigation. 2010 Dec 1;120(12):4425-4435. https://doi.org/10.1172/JCI40919
Rivera, Noelia ; Ramnanan, Christopher J. ; An, Zhibo ; Farmer, Tiffany ; Smith, Marta ; Farmer, Ben ; Irimia, Jose M. ; Snead, Wanda ; Lautz, Margaret ; Roach, Peter ; Cherrington, Alan D. / Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 12. pp. 4425-4435.
@article{df96f9b1af3146deb6dcfe134d188db8,
title = "Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs",
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.",
author = "Noelia Rivera and Ramnanan, {Christopher J.} and Zhibo An and Tiffany Farmer and Marta Smith and Ben Farmer and Irimia, {Jose M.} and Wanda Snead and Margaret Lautz and Peter Roach and Cherrington, {Alan D.}",
year = "2010",
month = "12",
day = "1",
doi = "10.1172/JCI40919",
language = "English",
volume = "120",
pages = "4425--4435",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "12",

}

TY - JOUR

T1 - Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs

AU - Rivera, Noelia

AU - Ramnanan, Christopher J.

AU - An, Zhibo

AU - Farmer, Tiffany

AU - Smith, Marta

AU - Farmer, Ben

AU - Irimia, Jose M.

AU - Snead, Wanda

AU - Lautz, Margaret

AU - Roach, Peter

AU - Cherrington, Alan D.

PY - 2010/12/1

Y1 - 2010/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=78649882282&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649882282&partnerID=8YFLogxK

U2 - 10.1172/JCI40919

DO - 10.1172/JCI40919

M3 - Article

C2 - 21084754

AN - SCOPUS:78649882282

VL - 120

SP - 4425

EP - 4435

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 12

ER -