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

An Z, Winnick JJ, Farmer B, Neal D, Lautz M, Irimia JM, Roach PJ, Cherrington AD - Diabetes (2010)

Bottom Line: Further elevating hepatic NO failed to reduce NHGU (4.5 ± 0.7 in -sGC/+NO).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee. USA. zhibo.an@uc.edu

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.

Show MeSH

Related in: MedlinePlus

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.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2992759&req=5

Figure 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.

Mentions: As described in Fig. 1A, each experiment consisted of a 90-min equilibration period (−120 to −30 min), a 30-min basal period (−30 to 0 min), and a 270-min experimental period (0 to 270 min), with the latter being divided into period one (P1), 0 to 90 min, and period two (P2), 90 to 270 min. In all experiments a constant infusion of indocyanine green dye (0.076 mg/min; Sigma Immunochemicals, St. Louis, MO) was initiated at −120 min via the left cephalic vein. At the start of P1 (0 min), a constant infusion of somatostatin (0.8 μg/kg/min; Bachem, Torrance, CA) was begun via the left saphenous vein to suppress endogenous insulin and glucagon secretion. At the same time, basal glucagon (0.57 ng/kg/min; Glucagen, Novo Nordisk, Bagsvaerd, Denmark) and fourfold basal insulin (1.2 mU/kg/min; Eli Lilly & Co., Indianapolis, IN) infusions were started through the splenic and jejunal catheters (i.e., intraportally) and maintained for the duration of the study. In addition, at 0 min, a primed continuous infusion of 50% dextrose was started via the right cephalic vein so that the blood glucose could be quickly clamped at the desired hyperglycemic level (∼160 mg/dl). In P2, saline was infused intraportally in the control group ([SAL], n = 10), whereas the sGC inhibitor 1H- (1,2,4) oxadiazolo[4,3-a] quinoxalin-1-one (ODQ; Cayman Chemical Company, Ann Arbor, MI) was infused intraportally at 0.8 μg/kg/min to inhibit the hepatic sGC pathway in the −sGC (n = 10) and −sGC/+NO (n = 6) groups. The NO donor SIN-1 (Cayman Chemical Company) was also infused intraportally (4 μg/kg/min) from 180 to 270 min in the −sGC/+NO group to elevate hepatic NO levels. In a separate group (+NO group; n = 3), SIN-1 was infused (4 μg/kg/min) from 90 to 270 min in the absence of ODQ. The peripheral glucose infusion rate was adjusted as needed in P2 to maintain a similar hepatic glucose load to that seen during P1.


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

An Z, Winnick JJ, Farmer B, Neal D, Lautz M, Irimia JM, Roach PJ, Cherrington AD - Diabetes (2010)

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.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992759&req=5

Figure 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.
Mentions: As described in Fig. 1A, each experiment consisted of a 90-min equilibration period (−120 to −30 min), a 30-min basal period (−30 to 0 min), and a 270-min experimental period (0 to 270 min), with the latter being divided into period one (P1), 0 to 90 min, and period two (P2), 90 to 270 min. In all experiments a constant infusion of indocyanine green dye (0.076 mg/min; Sigma Immunochemicals, St. Louis, MO) was initiated at −120 min via the left cephalic vein. At the start of P1 (0 min), a constant infusion of somatostatin (0.8 μg/kg/min; Bachem, Torrance, CA) was begun via the left saphenous vein to suppress endogenous insulin and glucagon secretion. At the same time, basal glucagon (0.57 ng/kg/min; Glucagen, Novo Nordisk, Bagsvaerd, Denmark) and fourfold basal insulin (1.2 mU/kg/min; Eli Lilly & Co., Indianapolis, IN) infusions were started through the splenic and jejunal catheters (i.e., intraportally) and maintained for the duration of the study. In addition, at 0 min, a primed continuous infusion of 50% dextrose was started via the right cephalic vein so that the blood glucose could be quickly clamped at the desired hyperglycemic level (∼160 mg/dl). In P2, saline was infused intraportally in the control group ([SAL], n = 10), whereas the sGC inhibitor 1H- (1,2,4) oxadiazolo[4,3-a] quinoxalin-1-one (ODQ; Cayman Chemical Company, Ann Arbor, MI) was infused intraportally at 0.8 μg/kg/min to inhibit the hepatic sGC pathway in the −sGC (n = 10) and −sGC/+NO (n = 6) groups. The NO donor SIN-1 (Cayman Chemical Company) was also infused intraportally (4 μg/kg/min) from 180 to 270 min in the −sGC/+NO group to elevate hepatic NO levels. In a separate group (+NO group; n = 3), SIN-1 was infused (4 μg/kg/min) from 90 to 270 min in the absence of ODQ. The peripheral glucose infusion rate was adjusted as needed in P2 to maintain a similar hepatic glucose load to that seen during P1.

Bottom Line: Further elevating hepatic NO failed to reduce NHGU (4.5 ± 0.7 in -sGC/+NO).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee. USA. zhibo.an@uc.edu

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.

Show MeSH
Related in: MedlinePlus