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. 2010 Dec;59(12):2999-3007.
doi: 10.2337/db10-0138. Epub 2010 Sep 7.

A soluble guanylate cyclase-dependent mechanism is involved in the regulation of net hepatic glucose uptake by nitric oxide in vivo

Zhibo An  1 , Jason J Winnick, Ben Farmer, Doss Neal, Margaret Lautz, Jose M Irimia, Peter J Roach, Alan D Cherrington
Affiliations

A soluble guanylate cyclase-dependent mechanism is involved in the regulation of net hepatic glucose uptake by nitric oxide in vivo

Zhibo An et al. Diabetes. 2010 Dec.

Abstract

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.

Research design and 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.

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Figures

FIG. 1.
FIG. 1.
Schematic representation of the study (A) and hepatic cGMP levels (B). The protocol comprises the basal (−30 to 0 min) and experimental periods (period 1: 0–90 min; period 2: 90–270 min). Somatostatin was infused peripherally and insulin (fourfold basal) and glucagon (basal) were given intraportally, whereas glucose was delivered peripherally at a variable rate to increase the hepatic glucose load twofold basal during period 1 and period 2. Data are means ± SEM. *P < 0.05 compared with the SAL group. †P < 0.05 compared with the +NO group.
FIG. 2.
FIG. 2.
Arterial blood glucose (A), hepatic glucose loads (B), net hepatic glucose uptake (C), net hepatic fractional extraction of glucose (D), glucose infusion rate (E), and nonhepatic glucose uptake (F) in 42-h–fasted conscious dogs during the basal and experimental periods. See Fig. 1A for description of study conditions. Data are means ± SEM. Net hepatic fractional extraction of glucose data represent the averaged values for the last hour in each group. *P < 0.05 compared with the −sGC group. †P < 0.05 compared with the −sGC/+NO group.
FIG. 3.
FIG. 3.
Phosphorylation of AMPK at Thr172 and ACC at Ser79 in the liver biopsies at the end of the experiments. See Fig. 1A for a description of study conditions. Data are means ± SEM; *P < 0.05 compared with the SAL group. The blots shown are representative of 3 to 5 blots obtained from independent experiments.
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