A soluble guanylate cyclase-dependent mechanism is involved in the regulation of net hepatic glucose uptake by nitric oxide in vivo.
OBJECTIVE
We previously showed that elevating hepatic nitric oxide (NO) levels reduced net hepatic glucose uptake (NHGU) in the presence of portal glucose delivery, hyperglycemia, and hyperinsulinemia. The aim of the present study was to determine the role of a downstream signal, soluble guanylate cyclase (sGC), in the regulation of NHGU by NO.


METHODS
Studies were performed on 42-h-fasted conscious dogs fitted with vascular catheters. At 0 min, somatostatin was given peripherally along with 4× basal insulin and basal glucagon intraportally. Glucose was delivered at a variable rate via a leg vein to double the blood glucose level and hepatic glucose load throughout the study. From 90 to 270 min, an intraportal infusion of the sGC inhibitor 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) was given in -sGC (n = 10) and -sGC/+NO (n = 6), whereas saline was given in saline infusion (SAL) (n = 10). The -sGC/+NO group also received intraportal SIN-1 (NO donor) to elevate hepatic NO from 180 to 270 min.


RESULTS
In the presence of 4× basal insulin, basal glucagon, and hyperglycemia (2× basal ), inhibition of sGC in the liver enhanced NHGU (mg/kg/min; 210-270 min) by ∼55% (2.9 ± 0.2 in SAL vs. 4.6 ± 0.5 in -sGC). Further elevating hepatic NO failed to reduce NHGU (4.5 ± 0.7 in -sGC/+NO). Net hepatic carbon retention (i.e., glycogen synthesis; mg glucose equivalents/kg/min) increased to 3.8 ± 0.2 in -sGC and 3.8 ± 0.4 in -sGC/+NO vs. 2.4 ± 0.2 in SAL (P < 0.05).


CONCLUSIONS
NO regulates liver glucose uptake through a sGC-dependent pathway. The latter could be a target for pharmacologic intervention to increase meal-associated hepatic glucose uptake in individuals with type 2 diabetes.
An
Zhibo
Z
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee. USA. zhibo.an@uc.edu
Winnick
Jason J
JJ
Farmer
Ben
B
Neal
Doss
D
Lautz
Margaret
M
Irimia
Jose M
JM
Roach
Peter J
PJ
Cherrington
Alan D
AD
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004285:Dogs; D005260:Female; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006400:Hematocrit; D006503:Hepatic Veins / Q000502:physiology; D006706:Homeostasis; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D013004:Somatostatin / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; D009569:Nitric Oxide; D013004:Somatostatin; D005934:Glucagon; D006162:Guanylate Cyclase; D005947:Glucose
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