Hepatic portal venous delivery of a nitric oxide synthase inhibitor enhances net hepatic glucose uptake

Moore, Mary Courtney; DiCostanzo, Catherine A.; Smith, Marta S.; Farmer, Ben; Rodewald, Tiffany; Neal, Doss W.; Williams, Phillip E.; Cherrington, Alan D.

doi:10.1152/ajpendo.00184.2007

Cited by 6 publications

(7 citation statements)

References 44 publications

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“…In line with our current finding that intraportal infusion of the NO donor SIN-1 reduced NHGU in the presence of hyperinsulinemia and hyperglycemia, normal dogs that received an intraportal infusion of the NOS inhibitor L-NAME exhibited enhanced NHGU under hyperinsulinemic and hyperglycemic conditions (22).…”

Section: Discussionsupporting

confidence: 91%

Effects of the nitric oxide donor SIN-1 on net hepatic glucose uptake in the conscious dog

An¹,

DiCostanzo²,

Moore³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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An Z, DiCostanzo CA, Moore MC, Edgerton DS, Dardevet DP, Neal DW, Cherrington AD. Effects of the nitric oxide donor SIN-1 on net hepatic glucose uptake in the conscious dog. Am J Physiol Endocrinol Metab 294: E300-E306, 2008. First published November 20, 2007 doi:10.1152/ajpendo.00380.2007.-To determine the role of nitric oxide in regulating net hepatic glucose uptake (NHGU) in vivo, studies were performed on three groups of 42-h-fasted conscious dogs using a nitric oxide donor [3-morpholinosydnonimine (SIN-1)]. The experimental period was divided into period 1 (0 -90 min) and period 2 (P2; 90 -240 min). At 0 min, somatostatin was infused peripherally, and insulin (4-fold basal) and glucagon (basal) were given intraportally. Glucose was delivered intraportally (22.2 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and peripherally (as needed) to increase the hepatic glucose load twofold basal. At 90 min, an infusion of SIN-1 (4 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was started in a peripheral vein (PeSin-1, n ϭ 10) or the portal vein (PoSin-1, n ϭ 12) while the control group received saline (SAL, n ϭ 8). Both peripheral and portal infusion of SIN-1, unlike saline, significantly reduced systolic and diastolic blood pressure. Heart rate rose in PeSin-1 and PoSin-1 (96 Ϯ 5 to 120 Ϯ 10 and 88 Ϯ 6 to 107 Ϯ 5 beats/min, respectively, P Ͻ 0.05) but did not change in response to saline. NHGU during P2 was 31.0 Ϯ 2.4 and 29.9 Ϯ 2.0 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 in SAL and PeSin-1, respectively but was 23.7 Ϯ 1.7 in PoSin-1 (P Ͻ 0.05). Net hepatic carbon retention during P2 was significantly lower in PoSin-1 than SAL or PeSin-1 (21.4 Ϯ 1.2 vs. 27.1 Ϯ 1.5 and 26.1 Ϯ 1.0 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Nonhepatic glucose uptake did not change in response to saline or SIN-1 infusion. In conclusion, portal but not peripheral infusion of the nitric oxide donor SIN-1 inhibited NHGU.3-morpholinosydnominine; nitric oxide; net hepatic glucose uptake; hyperglycemia THE LIVER IS A PIVOTAL ORGAN in disposal of ingested glucose and, therefore, in limiting postprandial hyperglycemia. It has been shown that the response to infusion of glucose directly in the hepatic portal vein mimics the response to oral glucose delivery in the conscious dog (5). In comparing the effects of peripheral vs. portal venous glucose delivery on net hepatic glucose uptake (NHGU) during hyperglycemic clamps, we found that NHGU was considerably greater in the presence of intraportal glucose delivery, even when the hepatic glucose loads were well matched and insulin and glucagon levels were equivalent between groups (1, 2, 26, 28). This led us to suggest that a "portal glucose signal" is at least as important as insulin in determining NHGU after an oral glucose load. In addition, the portal glucose signal reduces glucose uptake by nonhepatic tissues, primarily muscle, at the same time as it increases NHGU, thereby ensuring appropriate distribution of glucose to muscle and liver (2). To date, it remains unclear how these coordinated responses of muscle and liver come about.Nitric oxide (NO) is a potent biological mediato...

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Section: Discussionsupporting

confidence: 91%

Effects of the nitric oxide donor SIN-1 on net hepatic glucose uptake in the conscious dog

An¹,

DiCostanzo²,

Moore³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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“…We did not measure tissue blood flow; however, data from experimental studies do not support this possibility. In rats, intraportal L-NAME administration reduces liver perfusion [19], while systemic L-NAME has no effect on portal haemodynamics despite a 60% increase in arterial blood pressure [20]. In skeletal muscle, systemic L-NAME infusion either does not affect blood flow to muscle tissues or reduces it (as elegantly demonstrated by Majumdar et al [21]).…”

Section: Discussionmentioning

confidence: 94%

Systemic inhibition of nitric oxide synthesis in non-diabetic individuals produces a significant deterioration in glucose tolerance by increasing insulin clearance and inhibiting insulin secretion

et al. 2013

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Aims/hypothesis Endogenous NO inhibits insulin release in isolated beta cells and insulin-degrading enzyme activity in hepatocytes, while NO release from endothelial cells has been suggested to enhance insulin action. We assessed the overall effect of systemic inhibition of endogenous NO synthesis on glucose homeostasis in humans. Methods Twenty-four non-diabetic volunteers underwent two hyperglycaemic (+7 mmol/l) clamps with either saline or L-NGnitroarginine methyl ester (L-NAME, at rates of 2.5, 5, 10 and 20 μgmin −1 kg −1 ) infusion. Another five volunteers underwent an OGTT with either saline or L-NAME (20 μgmin −1 kg −1 ) infusion. Blood pressure and heart rate were measured to monitor NO blockade; during the OGTT, endothelial function was assessed by peripheral arterial tonometry and insulin secretion by C-peptide deconvolution and insulin secretion modelling. Results Compared with saline, L-NAME at the highest dose raised mean blood pressure (+20±2 mmHg), depressed heart rate (−12±2 bpm) and increased insulin clearance (+50%).First-phase insulin secretion was impaired, but insulin sensitivity (M/I index) was unchanged. During the OGTT, L-NAME raised 2 h plasma glucose by 1.8 mmol/l (p<0.01), doubled insulin clearance and impaired beta cell glucose sensitivity while depressing endothelial function. Conclusions/interpretation In humans, systemic NO blockade titrated to increase blood pressure and induce endothelial dysfunction does not affect insulin action but significantly impairs glucose tolerance by increasing plasma insulin clearance and depressing insulin secretion, namely first-phase and beta cell glucose sensitivity.

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“…As mentioned previously, intraportal infusion of SIN-1 and L-NAME had suppressive and stimulatory effects, respectively, on NHGU (52,53). Thus, we were interested in determining the mechanisms(s) by which changes in NO levels affected liver glucose uptake.…”

Section: Portal Glucose Signalmentioning

confidence: 98%

“…Surgical ablation of the hepatic sympathetic nerves resulted in an increase in NHGU during glucose infusion into a peripheral vein (51). Likewise, increasing hepatic nitric oxide (NO) using the NO donor 3-morpholinosydnominine HCl (SIN-1) or lowering it using the NO synthase (NOS) inhibitor N v -nitro-L-arginine methyl ester (L-NAME) brought about reduced and enhanced NHGU, respectively (52,53). Taken together, these data suggest that both adrenergic and nitrergic input to the liver exerts a basal restraining effect on NHGU that is removed in response to feeding or portal glucose delivery.…”

Section: Portal Glucose Signalmentioning

confidence: 99%

Regulation of Hepatic Glucose Uptake and Storage In Vivo

Moore

Coate

Winnick

et al. 2012

Advances in Nutrition

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In the postprandial state, the liver takes up and stores glucose to minimize the fluctuation of glycemia. Elevated insulin concentrations, an increase in the load of glucose reaching the liver, and the oral/enteral/portal vein route of glucose delivery (compared with the peripheral intravenous route) are factors that increase the rate of net hepatic glucose uptake (NHGU). The entry of glucose into the portal vein stimulates a portal glucose signal that not only enhances NHGU but concomitantly reduces muscle glucose uptake to ensure appropriate partitioning of a glucose load. This coordinated regulation of glucose uptake is likely neurally mediated, at least in part, because it is not observed after total hepatic denervation. Moreover, there is evidence that both the sympathetic and the nitrergic innervation of the liver exert a tonic repression of NHGU that is relieved under feeding conditions. Further, the energy sensor 5'AMP-activated protein kinase appears to be involved in regulation of NHGU and glycogen storage. Consumption of a high-fat and high-fructose diet impairs NHGU and glycogen storage in association with a reduction in glucokinase protein and activity. An understanding of the impact of nutrients themselves and the route of nutrient delivery on liver carbohydrate metabolism is fundamental to the development of therapies for impaired postprandial glucoregulation.

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Hepatic portal venous delivery of a nitric oxide synthase inhibitor enhances net hepatic glucose uptake

Cited by 6 publications

References 44 publications

Effects of the nitric oxide donor SIN-1 on net hepatic glucose uptake in the conscious dog

Effects of the nitric oxide donor SIN-1 on net hepatic glucose uptake in the conscious dog

Systemic inhibition of nitric oxide synthesis in non-diabetic individuals produces a significant deterioration in glucose tolerance by increasing insulin clearance and inhibiting insulin secretion

Regulation of Hepatic Glucose Uptake and Storage In Vivo

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