Dietary nitrite improves insulin signaling through GLUT4 translocation

Jiang, Hong; Torregrossa, Ashley C.; Potts, Amy; Pierini, Dan; Aranke, Mayank; Garg, Harsha K.; Bryan, Nathan S.

doi:10.1016/j.freeradbiomed.2013.10.809

Cited by 95 publications

(76 citation statements)

References 41 publications

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“…Here, we show that AMPK activation is severely impaired in obese ZSF1 rats, accompanied by decreased GLUT4 membrane translocation. Chronic oral nitrite supplementation, in turn, increases AMPK phosphorylation and restores GLUT4 localization to the membrane, which is consistent with previous studies 58, 59 . Thus, AMPK activation appears to be an important mechanism behind the observed effect of nitrite on improving glucose uptake.…”

Section: Discussionsupporting

confidence: 93%

SIRT3–AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction

et al. 2016

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Background Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is an increasingly recognized clinical complication of metabolic syndrome. No adequate animal model of PH-HFpEF is available and no effective therapies have been identified to date. A recent study suggested that dietary nitrate improves insulin resistance in eNOS null mice, and multiple studies have reported that both nitrate and its active metabolite, nitrite, have therapeutic activity in pre-clinical models of PH. Methods and Results In order to evaluate the efficacy and mechanism of nitrite in metabolic syndrome associated with PH-HFpEF, we developed a “two-hit” PH-HFpEF model in rats with multiple features of metabolic syndrome due to double leptin receptor defect (obese ZSF1) with the combined treatment of VEGF receptor blocker SU5416. Chronic oral nitrite treatment improved hyperglycemia in obese ZSF1 rats by a process that requires skeletal muscle SIRT3-AMPK-GLUT4 signaling. The glucose lowering effect of nitrite was abolished in SIRT3 deficient human skeletal muscle cells, as well as in SIRT3 knockout mice fed a high-fat diet. Skeletal muscle biopsies from humans with metabolic syndrome after 12 weeks of oral sodium nitrite and nitrate treatment (IND#115926) displayed increased activation of SIRT3 and AMPK. Finally, early treatments with nitrite and metformin at the time of SU5416 injection reduced pulmonary pressures and vascular remodeling in the PH-HFpEF model with robust activation of skeletal muscle SIRT3 and AMPK. Conclusions These studies validate a rodent model of metabolic syndrome and PH-HFpEF, suggesting a potential role of nitrite and metformin as a preventative treatment for this disease.

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Section: Discussionsupporting

confidence: 93%

SIRT3–AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction

et al. 2016

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“…15 Jiang et al. 33 have reported that dietary nitrite (50 mg/L for 4 weeks) in db/db diabetic mice improves insulin signaling through GLUT4 translocation to the membrane. 33 Ohtake et al have also shown that dietary nitrite (150 mg/L for 10 weeks) improves insulin resistance in type 2 diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

Effects of Nitrate Intake on Myocardial Ischemia-Reperfusion Injury in Diabetic Rats

Jeddi¹,

Khalifi²,

Ghanbari³

et al. 2016

Arquivos Brasileiros De Cardiologia

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BackgroundCoronary artery disease is 2-3 times more common in diabetic individuals. Dietary nitrate/nitrite has beneficial effects in both diabetes and cardiovascular disease. It also has protective effects against myocardial ischemia-reperfusion (IR) injury in healthy animals. However, the effects of nitrate on myocardial IR injury in diabetic rats have not yet been investigated.ObjectiveWe examined the effects of dietary nitrate on myocardial IR injury in streptozotocin-nicotinamide-induced diabetic rats.MethodRats were divided into four groups (n=7 in each group): control, control+nitrate, diabetes, and diabetes+nitrate. Type 2 diabetes was induced by injection of streptozotocin and nicotinamide. Nitrate (sodium nitrate) was added to drinking water (100 mg/L) for 2 months. The hearts were perfused in a Langendorff apparatus at 2 months and assessed before (baseline) and after myocardial IR for the following parameters: left ventricular developed pressure (LVDP), minimum and maximum rates of pressure change in the left ventricle (±dP/dt), endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) mRNA expression, and levels of malondialdehyde (MDA) and NO metabolites (NOx).ResultsRecovery of LVDP and ±dP/dt was lower in diabetic rats versus controls, but almost normalized after nitrate intake. Diabetic rats had lower eNOS and higher iNOS expression both at baseline and after IR, and dietary nitrate restored these parameters to normal values after IR. Compared with controls, heart NOx level was lower in diabetic rats at baseline but was higher after IR. Diabetic rats had higher MDA levels both at baseline and after IR, which along with heart NOx levels decreased following nitrate intake.ConclusionDietary nitrate in diabetic rats provides cardioprotection against IR injury by regulating eNOS and iNOS expression and inhibiting lipid peroxidation in the heart.

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“…As a major insulin-responsive glucose transporter, GLUT4 serves as the rate-controlling step in insulin-mediated glucose disposal which directly affects the insulin sensitivity (Herman & Kahn, 2006;Mueckler & Thorens, 2013). Extensive studies have been targeted exclusively on the expression of GLUT4 in glucose uptake in the control of T2DM (Jiang et al, 2014). Nonetheless, increasing evidence shows that the enhancement of glucose uptake can commence via GLUT1 (Choi et al, 2011).…”

Section: Effect Of Monoterpenes On Glucose Uptake In Mature 3t3-l1 Admentioning

confidence: 99%

Monoterpenes: Novel insights into their biological effects and roles on glucose uptake and lipid metabolism in 3T3-L1 adipocytes

et al. 2016

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Dietary nitrite improves insulin signaling through GLUT4 translocation

Cited by 95 publications

References 41 publications

SIRT3–AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction

SIRT3–AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction

Effects of Nitrate Intake on Myocardial Ischemia-Reperfusion Injury in Diabetic Rats

Monoterpenes: Novel insights into their biological effects and roles on glucose uptake and lipid metabolism in 3T3-L1 adipocytes

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