Modulation of basal hepatic glycogenolysis by nitric oxide

Borgs, Maria; Bollen, Mathieu; Keppens, Stefaan; Yap, Sing Hiem; Stalmans, Willy; Vanstapel, Florent

doi:10.1002/hep.510230637

Cited by 46 publications

(21 citation statements)

References 51 publications

(9 reference statements)

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“…They also found that glycogen synthesis is more sensitive to inhibition by NO than is gluconeogenesis (36). Borgs et al (6) observed that NO infusion (34 mol/l) increased the rate of glucose output in the perfused rat liver approximately threefold due to a stimulation of glycogenolysis that occurred as a result of activation of glycogen phosphorylase. Similarly, an in vivo study carried out by Ming et al (21) showed that portal SIN-1 infusion potentiates norepinephrine-induced glucose output from the liver in cats, and this potentiation is blocked by inhibition of guanylate cyclase, a key signaling molecule downstream of NO.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…In the liver, studies in animals have found that physiological endogenous NO production has a minor effect on hepatic glucose production by increasing both glycogenolysis [8] and glucose uptake [9]. In humans, the infusion of the arginine analogue L-NG-nitroarginine methyl ester (L-NAME) raised blood pressure but had no effect on fasting hepatic glucose production [10].…”

Section: Introductionmentioning

confidence: 99%

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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“…The subsequent decline with insulin administration may reflect mobilization of glycogen in the face of the insulin-stimulated increase in glucose oxidation. Nitric oxide also regulates glycogen metabolism in skeletal muscle and liver by inhibiting glycogen synthesis and stimulating glycogenolysis (59,60). Thus it is possible that this mechanism plays a role in decreasing the glycogen content in insulin-stimulated CIRKO hearts.…”

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confidence: 99%

Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression

Belke¹,

Bétuing²,

Tuttle³

et al. 2002

J. Clin. Invest.

222

183

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To investigate the role of insulin signaling on postnatal cardiac development, physiology, and cardiac metabolism, we generated mice with a cardiomyocyte-selective insulin receptor knockout (CIRKO) using cre/loxP recombination. Hearts of CIRKO mice were reduced in size by 20–30% due to reduced cardiomyocyte size and had persistent expression of the fetal β-myosin heavy chain isoform. In CIRKO hearts, glucose transporter 1 (GLUT1) expression was reduced by about 50%, but there was a twofold increase in GLUT4 expression as well as increased rates of cardiac glucose uptake in vivo and increased glycolysis in isolated working hearts. Fatty acid oxidation rates were diminished as a result of reduced expression of enzymes that catalyze mitochondrial β-oxidation. Although basal rates of glucose oxidation were reduced, insulin unexpectedly stimulated glucose oxidation and glycogenolysis in CIRKO hearts. Cardiac performance in vivo and in isolated hearts was mildly impaired. Thus, insulin signaling plays an important developmental role in regulating postnatal cardiac size, myosin isoform expression, and the switching of cardiac substrate utilization from glucose to fatty acids. Insulin may also modulate cardiac myocyte metabolism through paracrine mechanisms by activating insulin receptors in other cell types within the heart

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Modulation of basal hepatic glycogenolysis by nitric oxide

Cited by 46 publications

References 51 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

Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression

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