Tissue inflammation and nitric oxide-mediated alterations in cardiovascular function are major determinants of endotoxin-induced insulin resistance

House, Lawrence McLean; Morris, Robert T.; Barnes, Tammy M.; Lantier, Louise; Cyphert, Travis J.; McGuinness, Owen P.; Otero, Yolanda F.

doi:10.1186/s12933-015-0223-2

Cited by 29 publications

(26 citation statements)

References 62 publications

(77 reference statements)

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“…However, we found that NO had no effect on either TIE or accumulation of 2[ 14 C]DGP in the gastrocnemius. This finding is largely consistent with those of previous studies, which showed that SNP infusion either does not alter insulin-stimulated glucose disposal (50) or slightly reduces it (34). One limitation of our study is that, despite infusing a high dose of SNP, which was previously shown to have major cardiovascular and metabolic effects (34), BP was lowered by only ;10 mmHg, and the 40% increase in VASP activation (i.e., NO signaling) was not significant.…”

Section: Discussionsupporting

confidence: 93%

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Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial Insulin Efflux In Vivo

et al. 2018

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Before insulin can stimulate glucose uptake in muscle, it must be delivered to skeletal muscle (SkM) through the microvasculature. Insulin delivery is determined by SkM perfusion and the rate of movement of insulin across the capillary endothelium. The endothelium therefore plays a central role in regulating insulin access to SkM. Nitric oxide (NO) is a key regulator of endothelial function and stimulates arterial vasodilation, which increases SkM perfusion and the capillary surface area available for insulin exchange. The effects of NO on transendothelial insulin efflux (TIE), however, are unknown. We hypothesized that acute reduction of endothelial NO would reduce TIE. However, intravital imaging of TIE in mice revealed that reduction of NO by l--nitro-l-arginine methyl ester (l-NAME) enhanced the rate of TIE by ∼30% and increased total extravascular insulin delivery. This accelerated TIE was associated with more rapid insulin-stimulated glucose lowering. Sodium nitroprusside, an NO donor, had no effect on TIE in mice. The effects of l-NAME on TIE were not due to changes in blood pressure alone, as a direct-acting vasoconstrictor (phenylephrine) did not affect TIE. These results demonstrate that acute NO synthase inhibition increases the permeability of capillaries to insulin, leading to an increase in delivery of insulin to SkM.

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Section: Discussionsupporting

confidence: 93%

“…6A). This dose was chosen on the basis of a previous study that showed that a 37 mg/kg/min infusion lowered BP within 15 min (34). We increased this dose to ensure that SNP would be effective in anesthetized mice.…”

Section: Treatment Protocolsmentioning

confidence: 99%

Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial Insulin Efflux In Vivo

et al. 2018

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“…It did, however, attenuate the LPS-induced impairment in cardiac output and induced adaptations that sustained anaerobic glycolysis. Our previous findings suggested that alterations in muscle glucose delivery play a critical role in insulin resistance resulting from LPS (5, 19). These results suggest that the protective effect of GLUT4 overexpression is not due to maintenance of transport capacity but in part due to the maintenance of cardiac function in response to LPS.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Glucose Transport, but not Phosphorylation Capacity, Ameliorates Lipopolysaccharide-Induced Impairments in Insulin-Stimulated Muscle Glucose Uptake

Otero

Mulligan

Barnes

et al. 2016

Shock

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Lipopolysaccharide (LPS) is known to impair insulin stimulated muscle glucose uptake. We determined if increased glucose transport (GLUT4) or phosphorylation capacity (hexokinase II; HKII) could overcome the impairment in muscle glucose uptake (MGU). We utilized mice that over-expressed GLUT4 (GLUT4Tg) or HKII (HKTg) in skeletal muscle. Studies were performed in conscious, chronically catheterized (carotid artery and jugular vein) mice. Mice received an intravenous bolus of either LPS (10μg/g body weight) or vehicle (VEH). After 5 h, a hyperinsulinemic-euglycemic clamp was performed. As MGU is also dependent on cardiovascular function that is negatively affected by LPS, cardiac function was assessed using echocardiography. LPS decreased whole body glucose disposal and MGU in WT and HKTg mice. In contrast, the decrease was attenuated in GLUT4Tg mice. While membrane-associated GLUT4 was increased in VEH-treated GLUT4Tg mice, LPS impaired membrane-associated GLUT4in GLUT4Tg mice to the same level as LPS-treated WT mice. This suggested that overexpression of GLUT4 had further benefits beyond preserving transport activity. In fact, GLUT4 overexpression attenuated the LPS-induced decrease in cardiac function. The maintenance of MGU in GLUT4Tg mice following LPS was accompanied by sustained anaerobic glycolytic flux as suggested by increased muscle Pdk4 expression, and elevated lactate availability. Thus, enhanced glucose transport, but not phosphorylation capacity, ameliorates LPS-induced impairments in MGU. This benefit is mediated by long-term adaptations to the overexpression of GLUT4 that sustain muscle anaerobic glycolytic flux and cardiac function in response to LPS.

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“…Animal experiments showed that ALP upregulation was demonstrated in the vascular wall of diabetic rat and mouse models of vascular calci cation [23]. (2) Higher serum ALP was associated with increased risk of endothelial dysfunction, a process related to insulin resistance, an initial process to diabetes [24]. This was explained that ALP could reduce nitric oxide (NO) bioavailability by inhibiting tyrosine kinase activity into endothelial cells [25], leading to the consequent impairment of endothelial NO synthase function [26].…”

Section: Discussionmentioning

confidence: 99%

Serum alkaline phosphatase levels and the risk of new-onset diabetes in hypertensive adults

Zhang

Zhou

et al. 2020

Preprint

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Background: The association between alkaline phosphatase (ALP) and incident diabetes remains uncertain. Our study aimed to investigate the prospective relation of serum ALP with the risk of new-onset diabetes, and explore possible effect modifiers, in hypertensive adults. Methods: A total 14,393 hypertensive patients with available ALP measurements and without diabetes and liver disease at baseline were included from the China Stroke Primary Prevention Trial (CSPPT). The primary outcome was new-onset diabetes, defined as physician-diagnosed diabetes or use of glucose-lowering drugs during follow-up, or fasting glucose ≥7.0mmol/L at the exit visit. The secondary study outcome was new-onset impaired fasting glucose (IFG), defined as FG <6.1mmol/L at baseline and ≥6.1 but <7.0mmol/L at the exit visit.Results: Over a median of 4.5 years follow-up, 1,549 (10.8%) participants developed diabetes. Overall, there was a positive relation of serum ALP and the risk of new-onset diabetes (per SD increment, adjusted OR, 1.07; 95%CI: 1.01, 1.14) and new-onset IFG (per SD increment, adjusted OR, 1.07; 95%CI: 1.02, 1.14). Moreover, a stronger positive association between baseline ALP (per SD increment) with new-onset diabetes was found in participants with total homocysteine (tHcy) <10μmol/L (adjusted OR, 1.24; 95%CI: 1.10, 1.40 vs. ≥10μmol/L: adjusted OR, 1.03; 95%CI: 0.96, 1.10; P-interaction=0.007) or FG ≥5.9mmol/L (adjusted OR, 1.16; 95%CI: 1.07, 1.27 vs. <5.9mmol/L: adjusted OR, 1.00; 95%CI: 0.93, 1.08; P-interaction =0.009)Conclusions: In this non-diabetic, hypertensive population, higher serum ALP was significantly associated with the increased risk of new-onset diabetes, especially in those with lower tHcy or higher FG levels.Clinical Trial Registration-URL: Trial registration: NCT00794885 (clinicaltrials.gov). Retrospectively registered November 20, 2008.

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Tissue inflammation and nitric oxide-mediated alterations in cardiovascular function are major determinants of endotoxin-induced insulin resistance

Cited by 29 publications

References 62 publications

Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial Insulin Efflux In Vivo

Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial Insulin Efflux In Vivo

Enhanced Glucose Transport, but not Phosphorylation Capacity, Ameliorates Lipopolysaccharide-Induced Impairments in Insulin-Stimulated Muscle Glucose Uptake

Serum alkaline phosphatase levels and the risk of new-onset diabetes in hypertensive adults

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