Nitric oxide and diabetes management

This soreness is referred to as delayed-onset diabdtes soreness and usually feels oxixe strongest 24—72 hours after exercise Swedberg, K. Digital images were processed identically with Adobe Photoshop. BMC Pulm. About Contact Help Cookie Policy Privacy Policy. Chen, S.

Nitric oxide and diabetes management -
With the recent development of the next-generation HNO donors and their ongoing clinical evaluation, these concepts will need to be investigated.

To date, the therapeutic benefits of short-term HNO administration has been a key focus. Thus in addition to the vasodilatory, anti-aggregatory and inotropic actions of HNO donors, their ability to attenuate oxidative stress Lin et al.

Indeed, the long-term cardioprotective actions of HNO in the diabetic heart is supported by our finding that chronic in vivo administration of the HNO donor, 1-nitrosocyclohexyl acetate 1-NCA, daily i. injection for 4 weeks to streptozotocin-treated mice, attenuated left ventricular diastolic dysfunction and cardiomyocyte hypertrophy Cao et al.

With the recent development of HNO donors with more favorable pharmacokinetic properties del Rio et al. Given the short half-life, poor aqueous solubility and active by-products released by the abovementioned HNO donors, novel synthetic pure HNO donors have now been developed.

These include CXL, which non-enzymatically decomposes to HNO with a half-life of approximately 2. CXL has been shown to induce positive inotropic and lusitropic effects in murine cardiomyocytes from healthy or failing hearts, and these effects were also observed in vivo in failing canine hearts Sabbah et al.

In patients with acute decompensated heart failure, intravenous infusion 4—6 h of CXL enhanced cardiac function by reducing left and right ventricular pressures, decreasing systemic vascular resistance, and increasing cardiac output and stroke volume Sabbah et al.

These discoveries have led to the development of other HNO donors with greater tolerability and more suitable half-lives for therapeutic use in humans Hartman et al. Of these, the HNO donor BMS half-life; 40— min , has been shown to enhance cardiac contractile and relaxant responses, while promoting vasodilation and reducing myocardial oxygen consumption in canine models of heart failure Hartman et al.

Moreover, in a phase I clinical trial in healthy individuals, BMS or hour intravenous infusion was well tolerated, as the only drug-related adverse event reported was the development of headaches, which were alleviated following hydration, and are a common side effect of vasodilator therapy Cowart et al.

Further, the vasodilator capacity of BMS was evident with the HNO donor causing dose-dependent reductions in systolic and diastolic blood pressure, which were sustained during infusion, and returned to baseline following infusion cessation Cowart et al. Similar findings were also observed in patients with heart failure, where BMS reduced pulmonary arterial systolic and diastolic pressure, while decreasing total peripheral vascular resistance Tita et al.

Importantly, these hemodynamic changes were not associated with changes in heart rate or the presence of arrhythmias Tita et al. In the StandUP-AHF study Study Assessing Nitroxyl Donor Upon Presentation with Acute Heart Failure , patients hospitalized with heart failure with reduced ejection fraction HF-rEF will receive intravenous infusions of BMS at various doses or placebo for 48 h Felker et al.

The results of this multicenter, randomized, double-blind, placebo-controlled clinical trial will provide further information about the safety and tolerability of HNO donors with regard to hypotension Felker et al.

Whilst the poor aqueous solubility of BMS limits its clinical use to intravenous administration, orally bioavailable HNO donors are on the horizon Tita et al. CXL is an orally available HNO donor that also has a half-life 30 minutes suitable for in vivo use and has been shown to enhance cardiac contraction and relaxation, and reduce myocardial demand, without altering heart rate in a canine model of heart failure del Rio et al.

To date, much of the focus of HNO donors has been on their therapeutic potential in the treatment of acute decompensated heart failure. Although perhexiline, statins and some ACE inhibitors have shown promise in their ability to improve hemodynamic and vasodilator responses in diabetes, there are limitations associated with their use in emergency treatment of cardiovascular disorders.

AV and BK-H were responsible for the design and draft of the manuscript. CQ, OW, JH, and RR provided critical review and revision of the manuscript. All authors provide approval for publication of the content.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Almourani, R. Diabetes and cardiovascular disease: an update. doi: PubMed Abstract CrossRef Full Text Google Scholar.

Anderson, R. Platelet nitrate responsiveness in fasting and postprandial type 2 diabetes. Diabetes Vasc. CrossRef Full Text Google Scholar. Andrews, K. A role for nitroxyl HNO as an endothelium-derived relaxing and hyperpolarizing factor in resistance arteries.

Nitroxyl: a vasodilator of human vessels that is not susceptible to tolerance. Nitroxyl HNO reduces endothelial and monocyte activation and promotes M2 macrophage polarization.

Antonopoulos, A. Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: The regulatory role of perivascular adipose tissue. Diabetes 64, — Aon, M. Protective Mechanisms of Mitochondria and Heart Function in Diabetes.

Redox Signal. Ashrafian, H. Drug Rev. Barlovic, D. Targets 10, 7— Bermejo, E. Effect of nitroxyl on human platelets function. Böger, R. Borgognone, A. Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation.

Boustany-Kari, C. A soluble guanylate cyclase activator inhibits the progression of diabetic nephropathy in the ZSF1 rat. Breitenstein, S. Bauersachs, J. Cham: Springer International Publishing , — Brownlee, M.

The pathobiology of diabetic complications. Diabetes 54, Bullen, M. Nitroxyl HNO as a vasoprotective signaling molecule. Vasorelaxant and antiaggregatory actions of the nitroxyl donor isopropylamine NONOate are maintained in hypercholesterolemia.

Buys, E. Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential. Oxide - Biol. Cao, N. Chronic administration of the nitroxyl donor 1-nitrosocyclo hexyl acetate limits left ventricular diastolic dysfunction in a mouse model of diabetes mellitus in vivo.

Chandra, D. Nitric oxide prevents aldose reductase activation and sorbitol accumulation during diabetes. Diabetes 51, Chen, S. Negative regulation of NLRP3 inflammasome signaling. Protein Cell 4, — Chin, K.

The concomitant coronary vasodilator and positive inotropic actions of the nitroxyl donor Angeli's salt in the intact rat heart: Contribution of soluble guanylyl cyclase-dependent and -independent mechanisms. The HNO donor Angeli's salt offers potential haemodynamic advantages over NO or dobutamine in ischaemia-reperfusion injury in the rat heart ex vivo.

Chirkov, Y. Impaired tissue responsiveness to organic nitrates and nitric oxide: A new therapeutic frontier? Stable angina and acute coronary syndromes are associated with nitric oxide resistance in platelets.

Association of aortic stenosis with platelet hyperaggregability and impaired responsiveness to nitric oxide. Effect of perindopril on platelet nitric oxide resistance in patients with chronic heart failure secondary to ischemic left ventricular dysfunction. Chong, C. Reversal of hyperglycemia: effects on nitric oxide signaling.

Drugs that affect cardiac metabolism: focus on perhexiline. Drugs Ther. Coleman, J. Nitric oxide: A regulator of mast cell activation and mast cell-mediated inflammation.

Cooke, J. ADMA: Its role in vascular disease. Costell, M. Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress. Cowart, D. A phase 1 randomized study of single intravenous infusions of the novel nitroxyl donor BMS in healthy volunteers.

da Costa, R. Increased O-GlcNAcylation of endothelial nitric oxide synthase compromises the anti-contractile properties of perivascular adipose tissue in metabolic syndrome. Dautov, R. The nitric oxide redox sibling nitroxyl partially circumvents impairment of platelet nitric oxide responsiveness.

Hypoxic potentiation of nitrite effects in human vessels and platelets. Oxide Biol. De Caterina, R. Nitric oxide decreases cytokine-induced endothelial activation: Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.

Degrell, P. Evidence of O-linked N-acetylglucosamine in diabetic nephropathy. Life Sci. del Rio, C. Abstract nitroxyl HNO donated via slow-release oral pro-drug improves ventriculo-arterial coupling in conscious dogs with induced heart failure: enhanced load-independent mechano-energetics.

Circulation , A—A Dogra, G. Statin therapy improves brachial artery vasodilator function in patients with Type 1 diabetes and microalbuminuria. Drummond, G. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets.

Drug Discovery 10, — DuMond, J. The chemistry of nitroxyl-releasing compounds. Dupuis, J. Intensity of lipid lowering with statins and brachial artery vascular endothelium reactivity after acute coronary syndromes from the BRAVER trial. Elgert, C. A novel soluble guanylyl cyclase activator, BR , acts as a non-stabilising partial agonist of sGC.

Förstermann, U. Nitric oxide synthases: regulation and function. Heart J. Fülöp, N. Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart. Farah, C. Nitric oxide signalling in cardiovascular health and disease.

Fard, A. Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. Farhan, S. Advanced glycation end products AGEs and their soluble receptors sRAGE as early predictors of reno-vascular complications in patients with uncontrolled type 2 diabetes mellitus.

Diabetes Metab. Favaloro, J. The nitroxyl anion HNO is a potent dilator of rat coronary vasculature. Felker, G. Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure. Heart Fail. Fiorentino, T.

Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Follmann, M. The chemistry and biology of soluble guanylate cyclase stimulators and activators. Chemie - Int. Fox, K.

Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial the EUROPA study.

Lancet , — Fukuto, J. A recent history of nitroxyl chemistry, pharmacology and therapeutic potential. Gao, W. Nitroxyl-mediated disulfide bond formation between cardiac myofilament cysteines enhances contractile function.

Giacco, F. Oxidative stress and diabetic complications. Go, A. Statin therapy and risk of incident diabetes mellitus in adults with cardiovascular risk factors. Harrison, D. The nitrovasodilators: new ideas about old drugs.

Circulation 87, — Hartman, J. Intravenous infusion of the novel HNO donor BMS is associated With beneficial inotropic, lusitropic, and vasodilatory properties in 2 canine models of heart failure.

JACC Basic to Transl. Heitzer, T. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus.

Diabetologia 43, — Hernandez-Cuellar, E. Cutting edge: nitric oxide inhibits the NLRP3 inflammasome. Horowitz, J. Asymmetric and symmetric dimethylarginine predict outcomes in patients with atrial fibrillation: an ARISTOTLE substudy.

Htay, T. Mortality and cardiovascular disease in type 1 and type 2 diabetes. Ignarro, L. Nitric oxide is not just blowing in the wind. International Diabetes Federation Latest figures show million people now living with diabetes worldwide as numbers continue to rise.

Diabetes Res. Irvine, J. NO- activates soluble guanylate cyclase and Kv channels to vasodilate resistance arteries. Hypertension 41, — Nitroxyl anion donor, Angeli's salt, does not develop tolerance in rat isolated aortae. Hypertension 49, — Nitroxyl HNO : the Cinderella of the nitric oxide story.

Trends Pharmacol. Ito, H. Flow mediated dilatation is reduced with the progressive stages of glomerular filtration rate and albuminuria in type 2 diabetic patients without coronary heart disease. Jones, D. Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction.

Kövamees, O. Amino acid metabolism reflecting arginase activity is increased in patients with type 2 diabetes and associated with endothelial dysfunction. Kahlberg, N. Adverse vascular remodelling is more sensitive than endothelial dysfunction to hyperglycaemia in diabetic rat mesenteric arteries.

Kass, D. Phosphodiesterase regulation of nitric oxide signaling. Keceli, G. Nitroxyl HNO targets phospholamban cysteines 41 and 46 to enhance cardiac function. Kemp-Harper, B. Schmidt, H. Berlin, Heidelberg: Springer Berlin Heidelberg , — Therapeutic potential of nitroxyl HNO donors in the management of acute decompensated heart failure.

Drugs 76, — Nitroxyl HNO : A novel redox signaling molecule. Kennedy, J. Effect of the anti-anginal agent, perhexiline, on neutrophil, valvular and vascular superoxide formation. Kizub, I. Protein kinase C in enhanced vascular tone in diabetes mellitus.

Ko, M. Time- and dose-dependent association of statin use with risk of clinically relevant new-onset diabetes mellitus in primary prevention: a nationwide observational cohort study.

Kohr, M. Korkmaz, Y. Downregulation of the α1- and β1-subunit of sGC in arterial smooth muscle cells of OPSCC Is HPV-Independent. Kovanen, P. Mast cells in atherosclerotic cardiovascular disease - Activators and actions.

Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 92, — Laine, P.

Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation 99, — Lee, K. Cardioprotective effects of PKG activation by soluble GC activator, BAY , in ischemia-reperfusion-injured rat hearts. PloS One 12, 1— Lees, C.

Unexpected effect of a nitric oxide donor on uterine artery Doppler velocimetry in oligomenorrheic women with polycystic ovaries. Ultrasound Obstet. Leo, C. Endothelium-dependent nitroxyl-mediated relaxation is resistant to superoxide anion scavenging and preserved in diabetic rat aorta.

Lima, B. S-nitrosylation in cardiovascular signaling. Lin, E. Nitroxyl HNO stimulates soluble guanylyl cyclase to suppress cardiomyocyte hypertrophy and superoxide generation.

PloS One 7, 6— Lindholm, M. Diabetes mellitus and cardiogenic shock in acute myocardial infarction. Lob, H. Antioxidant and nitric oxide-sparing actions of dihydropyridines and ACE inhibitors differ in human endothelial cells.

Pharmacology 76, 8— Lorenzi, M. The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Lund, T.

Fibrin ogen may be an important target for methylglyoxal-derived AGE modification in elastic arteries of humans. Lundberg, J. Strategies to increase nitric oxide signalling in cardiovascular disease.

Drug Discovery 14, — Mátyás, C. The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus. Malmberg, K.

Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction DIGAMI study : Effects on mortality at 1 year. Mancardi, D. The Chemical Dynamics of NO and Reactive Nitrogen Oxides: A Practical Guide.

Mao, K. Nitric oxide suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock. Cell Res. Marsh, S. Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice.

Amino Acids 40, — Massion, P. Nitric oxide and cardiac function: Ten years after, and continuing. Matsushima, S. Increased myocardial NAD P H oxidase-derived superoxide causes the exacerbation of postinfarct heart failure in type 2 diabetes.

Mehta, S. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial. JAMA , — Mendes-Silverio, C. Activation of haem-oxidized soluble guanylyl cyclase with BAY in human platelets lead to overstimulation of the cyclic GMP signaling pathway.

PloS One 7, e Meurer, S. Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteasomal degradation.

Miller, T. The effects of nitroxyl HNO on soluble guanylate cyclase activity: interactions at ferrous heme and cysteine thiols. Miller, A. Nitroxyl HNO suppresses vascular Nox2 oxidase activity. Free Radic.

Miranda, K. Comparison of the reactivity of nitric oxide and nitroxyl with heme proteins: A chemical discussion of the differential biological effects of these redox related products of NOS. Murphey, L. Contribution of bradykinin to the cardioprotective effects of ACE inhibitors.

Napoli, C. Nitric oxide and atherosclerosis: An update. Neutel, J. Choosing among renin-angiotensin system blockers for the management of hypertension: From pharmacology to clinical efficacy.

Nightingale, A. Lack of association between aortic sclerosis and left ventricular hypertrophy in elderly subjects. Okon, E. Compromised arterial function in human type 2 diabetic patients.

Diabetes 54, — Ostadal, P. Statins as first-line therapy for acute coronary syndrome? PubMed Abstract Google Scholar. Pacher, P. Role of poly ADP-ribose polymerase-1 activation in the pathogenesis of diabetic complications: endothelial dysfunction, as a common underlying theme.

Paolocci, N. Oxygen radical-mediated reduction in basal and agonist-evoked no release in isolated rat heart. Nitroxyl anion exerts redox-sensitive positive cardiac inotropy in vivo by calcitonin gene-related peptide signaling.

John, M. Insulin-resistant states, such as diabetes and obesity, are characterized by impaired insulin-mediated vasodilation 13 , 16 , 18 , and the defect in insulin-stimulated vasodilation has been attributed to impaired NO generation by NOS 34 , This defect could explain the severe impairment in insulin-stimulated muscle NOS activity observed in the present study Fig.

In both human muscle 30 , 39 and rat arterial tissue 38 from type 2 diabetics, despite the severe defect in insulin-stimulated PI3-kinase activity, activation of the MAPK or mitogenic pathway by insulin is completely intact. Enhanced stimulation of the MAPK pathway results in vascular smooth muscle cell proliferation and migration and increased release of growth factors and inflammatory cytokines TNFα, IL-6, monocyte chemotactic protein , which are instrumental in the development of atherosclerosis Thus, intact MAPK pathway activity, in combination with reduced NO generation and endothelial dysfunction, may play a central role in the development of atherosclerosis in a variety of diverse phenotypes characterized by insulin resistance 1 , In healthy insulin-sensitive, nondiabetic subjects, there was a small, statistically insignificant rise in NOS activity at 30 min, and by min NOS activity was increased 2—2.

Given the relatively short time 4 h required for insulin to activate NOS, it is unlikely that augmented NOS transcription and translation can explain the increased NOS activity, and this is substantiated by the failure to observe any changes in NOS protein content during the 4-h study data not shown.

nNOS is the major isoform in muscle, but small amounts of eNOS and iNOS also are present Because the polyclonal antibody used to quantitate NOS protein cross-reacts with all three NOS isoforms, it is possible that changes in the level of a minor isoform could occur undetectably.

Although possible, we think it unlikely that a small increase in one specific NOS isoform could have occurred and accounted for the very large 2-fold insulin-stimulated increase in NOS activity. Future studies employing antibodies that are specific for each of the three NOS isoforms are needed to examine this possibility.

Although we cannot determine which NOS isoform is responsible for the defect in insulin-stimulated NOS activity in diabetic individuals, total NO generation would be expected to be deficient, and it is NO per se that is responsible for its metabolic and vasodilatory effects. The most likely mechanism responsible for the insulin-stimulated increase in NOS activity in the control group involves serine phosphorylation of nNOS, the major isoform in muscle Phosphorylation of human or bovine eNOS isoforms at serine or causes a 2- to 4-fold increase in the rate of NO synthesis 42 — The homologous serine residue to S in eNOS is S in nNOS, and mutation of nNOS S 46 , like that of eNOS S 47 , to aspartate mimics the negative charge imparted by phosphorylation and, in the case of eNOS, leads to an increase in the rate of NO production.

Insulin has been shown to increase serine phosphorylation of eNOS by a pathway involving Akt kinase In type 2 diabetics several potential mechanisms could explain the reduced ability of insulin to increase muscle NOS activity.

Reduced muscle concentration of l -arginine 43 or one of the essential cofactors, tetrahydrobiopterin 51 , also could contribute to the defective stimulation of NOS by insulin in diabetics. However, deficiencies in these cofactors cannot explain the differences in NO production between the diabetic and control subjects in the present study because all required cofactors and l -arginine are provided in the assay mixture.

Excessive accumulation of asymmetric dimethyl arginine in the muscle extract also is unlikely because this would have been diluted in the assay mixture. The relationship between insulin resistance Rd and other known risk factors for atherosclerotic cardiovascular disease also was examined.

Type 2 diabetic subjects were characterized by elevated levels of systolic and diastolic blood pressure, increased plasma triglyceride and FFA concentrations, and reduced plasma HDL cholesterol concentration. When the diabetic and control subjects were analyzed collectively, we observed an inverse correlation between Rd and systolic blood pressure, diastolic blood pressure, plasma triglyceride concentration, and plasma FFA concentration and a positive correlation between Rd and HDL concentration.

Similar correlations have been reported in previous publications 52 , We also observed a significant increase in plasma ICAM and VCAM concentrations, established cardiovascular risk markers 54 , 55 , in diabetic subjects Fig.

In our diabetic subjects, a strong correlation between VCAM and both HbA 1c and severity of insulin resistance was found. In summary, insulin resistance in T2DM is not only a metabolic disorder characterized by decreased insulin mediated Rd but also a vascular disorder associated with impaired NOS activity and elevated circulating risk factors for atherosclerotic cardiovascular disease.

Our results are consistent with the concept that reduced basal NOS activity and impaired insulin-stimulated NOS activity contribute to accelerated atherosclerosis, impaired endothelium-dependent vasodilatation, and hypertension in type 2 diabetic individuals.

We thank all volunteers and the invaluable efforts of the General Clinical Research Center nursing staff who were involved in their care. We are thankful for the skilled nursing assistance of James King, John Kincade, Norma Diaz, and Tricia Wolff, who helped to perform the metabolic studies.

Elva Gonzales and Lorrie Albarado provided expert secretarial support in preparing the manuscript. We also thank Richard Castillo, Cindy Munoz, Sheila Taylor, and Kathy Camp for their technical support in performing the many substrate, hormone, and isotopic assays.

This work was supported by National Institutes of Health Grant NRSA to S. DeFronzo RA , Ferrannini E Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and ASCVD.

Diabetes Care 14 : — Review. Google Scholar. Haffner SM , Stern MP , Hazuda HP , Mitchell BD , Patterson JK Cardiovascular risk factors in confirmed prediabetic individuals: does the clock for coronary heart disease start ticking before the onset of clinical diabetes?

JAMA : — Hsueh WA , Quinones MJ , Creager MA Endothelium in insulin resistance and diabetes. Diabetes Rev 5 : — Ross R The pathogenesis of atherosclerosis: a perspective for the s. Nature : — Cannon R Role of nitric oxide in cardiovascular disease: focus on the endothelium.

Clin Chem 44 : — Duplain H , Burcelin R , Sartori C , Cook S , Egli M , Lepori M , Vollenweider P , Pedrazzini T , Nicod P , Thoren B , Scherrer U Insulin resistance, hyperlipemia, and hypertension in mice lacking endothelial nitric oxide synthase.

Circulation : — Shankar R , Wu Y , Shen H , Zhu J , Baron A Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance.

Diabetes 49 : — Kapur S , Bedard S , Marcotte B , Cote CH , Marette A Expression of nitric oxide synthase in skeletal muscle. A novel role for nitric oxide as a modulator of insulin action. Diabetes 46 : — Perreault M , Marette A Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle.

Nature 7 : — Panza JA , Casino PR , Kilcoyne CM , Quyyumi AA Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. Gilligan DM , Guetta V , Panza JA , Garcia CE , Quyyumi AA , Cannon III RO Selective loss of microvascular endothelial function in human hypercholesterolemia.

Circulation 90 : 35 — Zeiher AM , Drexler H , Wollschlager H , Just H Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis.

Circulation 83 : — J Clin Invest 97 : — Aljada A , Saadeh R , Assian E , Ghanim H , Dandona P Insulin inhibits the expression of intercellular adhesion molecule-1 by human aortic endothelial cells through stimulation of nitric oxide.

J Clin Endocrinol Metab 85 : — Schnyder B , Pittet M , Durand J , Schnyder-Candrian S Rapid effects of glucose on the insulin signaling of endothelial NO generation and epithelial Na transport.

Am J Physiol Endocrinol Metab : E87 — E Laakso M , Edelman SV , Brechtel G , Baron AD Decreased effect of insulin to stimulate skeletal muscle flow in obese men. J Clin Invest 85 : — Anderson EA , Hoffman RP , Balon TW , Sinkey CA , Mark AL Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans.

J Clin Invest 87 : — Steinberg JO , Brechtel G , Johnson A , Fineberg N , Baron AD Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 94 : — DeFronzo RA Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes.

Diabetes Rev 4 : — Roy D , Perreault M , Marette A Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent. Am J Physiol Endocrinol Metab : E — E Biochem J : 73 — Young ME , Radda GK , Leighton B Nitric oxide stimulates glucose transport and metabolism in rat skeletal muscle in vitro.

Biochem J : — Higaki Y , Hirschman MF , Fuji N , Goodyear LJ Nitric oxide increases glucose uptake through a mechanism that is distinct from the insulin and contraction pathways in rat skeletal muscle.

Diabetes 50 : — Balon TW , Nadler JL Evidence that nitric oxide increases glucose transport in skeletal muscle. J Appl Physiol 82 : — Tanaka T , Nakatani K , Morioka K , Urakawa H , Maruyama N , Kitagawa N , Katsuki A , Araki-Sasaki R , Hori Y , Gabazza EC , Yano Y , Wada H , Nobori T , Sumida Y , Adachi Y Nitric oxide stimulates glucose transport through insulin-independent GLUT4 translocation in 3T3—L1 adipocytes.

Eur J Endocrinol 49 : 61 — Meneilly GS , Elliot T , Battistimi B , Floras JS N G -monomethyl- l -arginine alters insulin mediated calf blood flow but not glucose disposal in the elderly. Metabolism 50 : — Zavaroni I , Platti PM , Monti LD , Gasparini P , Barilli LA , Massironi P , Ardigo D , Valsecchi G , Delsignore R , Reaven GM Plasma nitric oxide concentrations are elevated in insulin-resistant healthy subjects.

Metabolism 49 : — DeFronzo RA Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med : — Cusi K , Maezono K , Osman A , Pendergrass M , Patti M , Pratipanawatr T , DeFronzo RA , Kahn CR , Mandarino LJ Insulin resistance differentially affects the PI3-kinase and MAP kinase-mediated signaling in human muscle.

J Clin Invest : — Towbin H , Staehelin J , Gordon J Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications.

Proc Natl Acad Sci USA 76 : — Shiuchi T , Cui TX , Wu L , Nakagami H , Takeda-Matsubara Y , Iwai M , Horiuchi M ACE inhibitor improves insulin-resistance in diabetic mice mouse via bradykinin and nitric oxide.

Hypertension 40 : — Stuhlinger MC , Abbasi F , Chu JW , Lamendola C , McLaughlin TL , Cooke JP , Reaven GM , Tsao PS Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor.

Williams IL , Wheatcroft SB , Shah AM , Kearney MT Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans. Int J Obes 26 : — Steinberg HO , Paradici G , Hook G , Crowder K , Cronin J , Baron AD Free fatty acids elevation impairs insulin-mediated vasodilation and nitric oxide production.

Zeng G , Quon MJ Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest 98 : — Diabetes 46 : 54 A. Hsueh WA , Law RF Insulin signaling in the arterial wall.

Am J Cardiol 84 : 21 J—24J. Pratipanawatr W , Pratipanawatr T , Cusi K , Berria R , Adams JM , Jenkinson CP , Maezono K , DeFronzo RA , Mandarino LJ Skeletal muscle insulin resistance in normoglycemic subjects with strong family history of type 2 diabetes is associated with decreased insulin stimulation of insulin receptor substrate-1 tyrosine phosphorylation.

Reaven GM Banting Lecture Role of insulin resistance in human disease. Diabetes 37 : — Groadanovic A NO message from muscle. Microsc Res Tech 55 : — Fulton D , Gratton J-P , McCabe TJ , Fontana J , Fujio Y , Walsh K , Franke TF , Papapetropoulos A , Sessa WC Regulation of endothelium-derived nitric oxide production by the protein kinase Akt.

Chen Z-P , Mitchelhill KI , Michell BJ , Stapleton D , Rodriquez-Crespo I , Witters LA , Power DA , Ortiz de Montellano PR , Kemp BE AMP-activated protein kinase phosphorylation of endothelial NO synthase.

FEBS Lett : — Butt E , Bernhardt M , Smolenski A , Kotsonis P , Frohlich BG , Sickmann A , Meyer HE , Lohmann SM , Schmidt HW Endothelial nitric-oxide synthase type III is activated and becomes calcium independent upon phosphorylation by cyclic nucleotide-dependent protein kinases.

J Biol Chem : — Dimmeler S , Fleming I , Fisslthaler B , Hermann C , Busse R , Zeihe AM Activation of endothelium-derived nitric oxide production by the protein kinase Akt. Roman LJ , Martasek P , Miller RT , Harris DE , de La Garza MA , Shea TM , Kim JJ , Masters BS The C termini of constitutive nitric-oxide synthases control electron flow through the flavin and heme domains and affect modulation by calmodulin.

Du XL , Edelstein D , Dimmeler S , Ju Q , Sui C , Brownlee N Hyperglycemia inhibits endothelial nitric oxide synthase activity by post translational modification at the Akt site. Federici M , Menghini R , Mauriello A , Hribal ML , Ferrelli F , Lauro D , Sbraccia P , Spagnoli LG , Sesti G , Lauro R Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells.

Cosentino F , Luscher TF Tetrahydrobiopterin and endothelial function. Eur Heart J 19 Suppl G : G3 — G8. Abbasi F , Brown BW , Lamendola C , McLaughlin T , Reaven GM Relationship between obesity, insulin sensitivity and coronary artery disease risk.

J Am Coll Cardiol 40 : 37 — Chen HS , Hwu CM , Kwok CF , Shih KC , Hsiao LC , Lee SH , Lin YT , Lin SH , Ho LT Insulin sensitivity in normotensive offspring of hypertensive parents.

Horm Metab Res 32 : — Nakai K , Itoh C , Kawazoe K , Miura Y , Sotoyanagi H , Hotta K , Itoh T , Kamata J , Hiramori K Concentration of soluble vascular cell adhesion molecule-1 VCAM-1 correlated with expression of VCAM-1 mRNA in the human atherosclerotic aorta. Coron Artery Dis 6 : — Haught WH , Mansour M , Rothlein R , Kishimoto TK , Mainolfi EA , Hendricks JB , Hendricks C , Mechta JL Alterations in circulating intercellular adhesion molecule-1 and l -selectin: further evidence for chronic inflammation in ischemic heart disease.

Kupatt C , Weber C , Wolf DA , Becker BF , Smith TW , Kelly RA Nitric oxide attenuates reoxygenation-induced ICAM-1 expression in coronary microvascular endothelium: role of NF-κB.

J Mol Cell Cardiol 29 : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

Sign In or Create an Account. Endocrine Society Journals. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Subjects and Methods. Journal Article. Insulin Resistance Is Associated with Impaired Nitric Oxide Synthase Activity in Skeletal Muscle of Type 2 Diabetic Subjects.

Kashyap , Sangeeta R. Oxford Academic. Linda J. Jennifer Lamont. Bettie Sue S. Mandeep Bajaj. Swangjit Suraamornkul.

Renata Belfort. Rachele Berria. Dean L. Kellogg, Jr. Yanjuan Liu. Ralph A. DeFronzo Ralph A. PDF Split View Views.

Cite Cite Sangeeta R. Select Format Select format. ris Mendeley, Papers, Zotero. enw EndNote. bibtex BibTex. txt Medlars, RefWorks Download citation. Permissions Icon Permissions. TABLE 1. Subject characteristics. Open in new tab.

Open in new tab Download slide. First Published Online November 23, and L. contributed equally to this work. intracellular adhesion molecule-1;. insulin-stimulated glucose disposal;. vascular cellular adhesion molecule. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and ASCVD.

Ocide Nitric oxide and diabetes management for visiting nature. You are using a browser Mindful eating for energy with limited support for CSS. To obtain the oxde experience, we recommend Niitric use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Hyperglycemia-induced overproduction of reactive oxygen species ROS and vascular insulin resistance are key players in this state.

Hans Erik BøtkerCircadian rhythm internal clock Møller; ON NO—The Continuing Story of Nitric Oxide, Diabetes, mabagement Cardiovascular Disease.

Diabetes 1 August ; 62 8 : — Nitric Nitroc NO Nltric a simple Bone health in adolescents compound—1 nitrogen and 1 Njtric atom coupled together—with complex biological ocide 12. A diaebtes prominent Immune function restoration of NO is Nitric oxide and diabetes management ability to cause managemenr, a quality that is used pharmacologically when treating ischemic heart disease with NO precursors such as nitroglycerin.

InFurchgott manageement Zawadzki 3 showed that vascular Nitric oxide and diabetes management induced by acetylcholine was diabefes on the presence of endothelium and provided evidence for the release of a volatile humoral diagetes. This substance, later called endothelium-derived relaxing factor and now recognized as NO 4is a siabetes component of the insulin-signaling cascade Fig.

Vasodilation manageemnt the potential mmanagement decrease Gut health and nutrient absorption blood pressure and increase local tissue Nitric oxide and diabetes management flow in tissues Replenish clean beauty as muscle.

The Nitric oxide and diabetes management of decreased blood pressure and viabetes tissue Pycnogenol for allergies flow, together with specific beneficial endothelial effects, may serve to diabete hypertension, cardiovascular disease, and insulin mwnagement 56.

However, these effects remain exquisitely sensitive to impaired insulin signaling within the endogenous cardiovascular Managrment system and appear to be compromised in the managemsnt Nitric oxide and diabetes management insulin resistance 7.

So there is evidence managemnt impaired NO-dependent vasodilation causes hypertension disbetes insulin resistance and vice versa: that insulin oxidde, such manageent that observed in diabetes, the metabolic syndrome, and hypertension, impairs Oxiee vasodilation.

The existence of this vicious cycle is supported by epidemiological data from the Framingham Heart Nifric and other studies diaabetes that oxdie, diabetes, and cardiovascular disease cosegregate 89.

Turmeric hair masks picture of Herbal extract distributors insulin-signaling path Fat Burning Complex its involvement in endothelial dysfunction highlights the crucial role oxidd arginine and NO.

Niyric is important manabement underline Salvadoran coffee beans the diabetez of insulin are dual—insulin acts after Nitrif to its receptor and activates both phosphatidylinositol 3-kinase PIK and mitogen-activated protein kinase MAPK.

In the vasculature, NO is synthesized from the guanidine NNitric of the amino acid managemeent under critical control of the enzyme endothelial NO synthase eNOS. Given Nirric complex nature of the regulation of oxie tone oxidw endothelial function, it is of oxidde importance to define and describe the underlying mechanisms leading to vascular Oxkde and insulin resistance.

Nitric oxide and diabetes management a Rejuvenate point of view, there is a specific oxidf for experimental human Cramp relief products assessing NO synthesis and clearance rates and whether abnormalities of NO oxde relate to altered kinetics and impaired insulin stimulation.

In diavetes issue of DiabetesTessari et al. In these experiments, the investigators use a precursor product, isotope dilution technique. Because arginine is the precursor for NO Fig.

Compared with normal subjects, the new data showed that NO synthesis was lower in the elderly and in people with type 2 diabetes and generally increased after insulin stimulation.

Regression analysis using data for all subjects showed that NOx synthesis was inversely correlated with arginine metabolites ADMA, SDMA and age, but not with insulin sensitivity. The authors conclude that whole-body NOx production is decreased in aging and type 2 diabetes and that arginine metabolites, not insulin resistance, appear to be negative regulators of in vivo NOx production.

These are timely and pertinent data from a well-conducted human study, and the findings not only expand our understanding of the field but also suggest that insulin resistance and NO dysfunction may not be as intimately linked as hitherto believed.

A particular strength of the study is that it combines a complicated clinical setup in a relative large number of subjects with a state-of-the-art kinetic tracer technique. A recent study, using a saliva oral nitrate test and an intravenous glucose tolerance test, reported a correlation between insulin sensitivity and NO synthesis 15whereas the current study, using steady state isotope dilution and clamp techniques, fails to make this connection.

Insulin sensitivity is expressed by a glucose clamp—derived M or glucose infusion rate value, which predominantly reflects glucose uptake in muscle NO synthesis is measured systemically, leaving the contributing tissues unidentified. Hence, the new results do not necessarily reflect conditions in muscle.

Furthermore, the design of the study is quite complex, with many different subgroups and mixed pathologic features.

It is therefore possible that the heterogeneity of the study sample may have underpowered the study. The clinical implication of the current study relates to the effect of insulin resistance on endothelial dysfunction. Although Tessari et al. Several studies using multivariate analyses that adjust for other potential modulators of endothelial function have shown that insulin resistance may not be an independent predictor of endothelial function 17 — On the other hand, the UK Prospective Diabetes Study clearly showed that metformin intervention, aimed at improving insulin sensitivity and endothelium-dependent vasodilation, led to a significant reduction in cardiovascular events in patients with insulin resistance The extent to which other interventions that improve insulin sensitivity, such as caloric restriction, physical activity, and pharmacological agents, act via NO to improve cardiovascular outcomes are issues to be addressed by future studies.

See accompanying original article, p. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest.

filter your search All Content All Journals Diabetes. Advanced Search. User Tools Dropdown. Sign In. Skip Nav Destination Close navigation menu Article navigation. Volume 62, Issue 8. Previous Article Next Article. Article Navigation. Commentary July 17 ON NO—The Continuing Story of Nitric Oxide, Diabetes, and Cardiovascular Disease Hans Erik Bøtker ; Hans Erik Bøtker.

This Site. Google Scholar. Niels Møller Niels Møller. Corresponding author: Niels Møller, nielsem dadlnet.

Diabetes ;62 8 — Connected Content. A commentary has been published: Roles of Insulin, Age, and Asymmetric Dimethylarginine on Nitric Oxide Synthesis In Vivo. Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. View large Download slide.

No potential conflicts of interest relevant to this article were reported. Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities. Search ADS. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.

Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Cardiovascular outcomes in Framingham participants with diabetes: the importance of blood pressure.

The role of asymmetric dimethylarginine ADMA in endothelial dysfunction and cardiovascular disease. The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis.

Roles of insulin, age, and asymmetric dimethylarginine on nitric oxide synthesis in vivo. In vivo nitric oxide synthesis, insulin sensitivity, and asymmetric dimethylarginine in obese subjects without and with metabolic syndrome.

Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent type II diabetes mellitus. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes.

Relationship between brachial artery flow-mediated dilatation, hyperemic shear stress, and the metabolic syndrome. Endothelium-dependent vasodilation, insulin resistance and the metabolic syndrome in an elderly cohort: the Prospective Investigation of the Vasculature in Uppsala Seniors PIVUS study.

UK Prospective Diabetes Study UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

View Metrics. Email alerts Article Activity Alert. Online Ahead of Print Alert. Latest Issue Alert. See also Roles of Insulin, Age, and Asymmetric Dimethylarginine on Nitric Oxide Synthesis In Vivo.

Most Read Most Cited MRI Metrics of Cerebral Endothelial Cell—Derived Exosomes for the Treatment of Cognitive Dysfunction Induced in Aging Rats Subjected to Type 2 Diabetes.

Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel. Genetic Influences of Adiponectin on Insulin Resistance, Type 2 Diabetes, and Cardiovascular Disease.

Online ISSN X Print ISSN Books ShopDiabetes. org ADA Professional Books Clinical Compendia Clinical Compendia Home News Latest News DiabetesPro SmartBrief. Resources ADA Professional Membership ADA Member Directory Diabetes.

X Twitter Facebook LinkedIn. This Feature Is Available To Subscribers Only Sign In or Create an Account. Close Modal. This site uses cookies. By continuing to use our website, you are agreeing to our privacy policy.
: Nitric oxide and diabetes management

5 Ways Nitric Oxide Supplements Boost Your Health and Performance	Effect of the anti-anginal agent, perhexiline, on neutrophil, valvular and vascular superoxide formation. Time- and dose-dependent association of statin use with risk of clinically relevant new-onset diabetes mellitus in primary prevention: a nationwide observational cohort study. See also The Vascular Endothelium, a Benign Restrictive Barrier? PloS One 7, e toolbar search Search Dropdown Menu. Article PubMed Google Scholar Yu Q, Gao F, Ma XL: Insulin says NO to cardiovascular disease.
The Role of Nitric Oxide in Type 2 Diabetes	Chirkov YY, Horowitz JD. Impaired tissue responsiveness to organic nitrates and nitric oxide: a new therapeutic frontier? Pharmacol Therapeutics. Article CAS Google Scholar. Velagic A, Qin C, Woodman OL, Horowitz JD, Ritchie RH, Kemp-Harper BK. Nitroxyl: a novel strategy to circumvent diabetes associated impairments in nitric oxide signaling. Front Pharmacol. Anderson R, Ellis G, Chirkov Y, Holmes A, Payne N, Blackman D, et al. Determinants of platelet responsiveness to nitric oxide in patients with chronic heart failure. Eur J Heart Fail. Young ME, Leighton B. Biochemical J. Russo I, Del Mese P, Doronzo G, Mattiello L, Viretto M, Bosia A, et al. Tawa M, Kinoshita T, Asai T, Suzuki T, Imamura T, Okamura T. Impact of type 2 diabetes on vascular reactivity to cGMP generators in human internal thoracic arteries. Vasc Pharmacol. Bock JM, Hughes WE, Ueda K, Feider AJ, Hanada S, Casey DP. Glycemic management is inversely related to skeletal muscle microvascular endothelial function in patients with type 2 diabetes. Physiological Rep. Vavuranakis M, Stefanadis C, Triandaphyllidi E, Toutouzas K, Toutouzas P. Coronary artery distensibility in diabetic patients with simultaneous measurements of luminal area and intracoronary pressure: evidence of impaired reactivity to nitroglycerin. Morris SJ, Shore AC, Tooke JE. Responses of the skin microcirculation to acetylcholine and sodium nitroprusside in patients with NIDDM. Caballero AE, Arora S, Saouaf R, Lim SC, Smakowski P, Park JY, et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Sokolnicki LA, Roberts SK, Wilkins BW, Basu A, Charkoudian N. Contribution of nitric oxide to cutaneous microvascular dilation in individuals with type 2 diabetes mellitus. Am J Physiol Endocrinol Metab. Beer S, Feihl F, Ruiz J, Juhan-Vague I, Aillaud MF, Wetzel SG, et al. Comparison of skin microvascular reactivity with hemostatic markers of endothelial dysfunction and damage in type 2 diabetes. Schächinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, et al. Prognostic value of coronary vascular endothelial dysfunction. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Implications for the syndrome of insulin resistance. Steinberg HO, Paradisi G, Cronin J, Crowde K, Hempfling A, Hook G, et al. Type II diabetes abrogates sex differences in endothelial function in premenopausal women. Sivitz WI, Wayson SM, Bayless ML, Sinkey CA, Haynes WG. Obesity impairs vascular relaxation in human subjects: hyperglycemia exaggerates adrenergic vasoconstriction arterial dysfunction in obesity and diabetes. J Diabetes Complications. McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR, et al. Impaired endothelium-dependent and independent vasodilation in patients with type 2 non-insulin-dependent diabetes mellitus. Watts GF, O'Brien SF, Silvester W, Millar JA. Impaired endothelium-dependent and independent dilatation of forearm resistance arteries in men with diet-treated non-insulin-dependent diabetes: role of dyslipidaemia. Clin Sci. Hogikyan RV, Galecki AT, Pitt B, Halter JB, Greene DA, Supiano MA. Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity. J Clin Endocrinol Metab. CAS PubMed Google Scholar. Enderle MD, Benda N, Schmuelling RM, Haering HU, Pfohl M. Preserved endothelial function in IDDM patients, but not in NIDDM patients, compared with healthy subjects. Diabetes Care. Mäkimattila S, Liu M-L, Vakkilainen J, Schlenzka A, Lahdenperä S, Syvänne M, et al. Impaired endothelium-dependent vasodilation in type 2 diabetes. Relation to LDL size, oxidized LDL, and antioxidants. Gazis A, White DJ, Page SR, Cockcroft JR. Effect of oral vitamin E alpha-tocopherol supplementation on vascular endothelial function in Type 2 diabetes mellitus. Diabet Med: J Br Diabet Assoc. Preik M, Kelm M, Rösen P, Tschöpe D, Strauer BE. Additive effect of coexistent type 2 diabetes and arterial hypertension on endothelial dysfunction in resistance arteries of human forearm vasculature. Heitzer T, Krohn K, Albers S, Meinertz T. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus. Kimura Y, Matsumoto M, Miyauchi E, Deng YB, Iwai K, Hattori H. Noninvasive detection of endothelial dysfunction in elderly with NIDDM by ultrasonography. van Etten RW, de Koning EJ, Verhaar MC, Gaillard CA, Rabelink TJ. Impaired NO-dependent vasodilation in patients with Type II non-insulin-dependent diabetes mellitus is restored by acute administration of folate. Vehkavaara S, Yki-Järvinen H. Arterioscler Thromb Vasc Biol. Ifrim S, Vasilescu R. Early detection of atherosclerosis in type 2 diabetic patients by endothelial dysfunction and intima-media thickness. Google Scholar. Natali A, Toschi E, Baldeweg S, Casolaro A, Baldi S, Sironi AM, et al. Haematocrit, type 2 diabetes, and endothelium-dependent vasodilatation of resistance vessels. Woodman RJ, Playford DA, Watts GF. Basal production of nitric oxide NO and non-NO vasodilators in the forearm microcirculation in Type 2 diabetes: associations with blood pressure and HDL cholesterol. Natali A, Toschi E, Baldeweg S, Ciociaro D, Favilla S, Saccà L, et al. Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes. Karasu C, Soncul H, Altan VM. Effects of non-insulin dependent diabetes mellitus on the reactivity of human internal mammary artery and human saphenous vein. Life Sci. Brooks BA, Franjic B, Ban CR, Swaraj K, Yue DK, Celermajer DS, et al. Diastolic dysfunction and abnormalities of the microcirculation in type 2 diabetes. Diabetes, Obes Metab. Sokolnicki LA, Strom NA, Roberts SK, Kingsley-Berg SA, Basu A, Charkoudian N. Skin blood flow and nitric oxide during body heating in type 2 diabetes mellitus. J Appl Physiol. Green DJ, Dawson EA, Groenewoud HM, Jones H, Thijssen DH. Is flow-mediated dilation nitric oxide mediated? Goodfellow J, Ramsey MW, Luddington LA, Jones CJ, Coates PA, Dunstan F, et al. Endothelium and inelastic arteries: an early marker of vascular dysfunction in non-insulin dependent diabetes. BMJ Clin Res Ed. Avogaro A, Piarulli F, Valerio A, Miola M, Calveri M, Pavan P, et al. Forearm nitric oxide balance, vascular relaxation, and glucose metabolism in NIDDM patients. Pitei DL, Watkins PJ, Edmonds ME. NO-dependent smooth muscle vasodilatation is reduced in NIDDM patients with peripheral sensory neuropathy. Goulopoulou S, Hannan JL, Matsumoto T, Ogbi S, Ergul A, Webb RC. Reduced vascular responses to soluble guanylyl cyclase but increased sensitivity to sildenafil in female rats with type 2 diabetes. Am J Physiol Heart Circ Physiol. Goulopoulou S, Hannan JL, Matsumoto T, Ergul A, Webb RC. Augmented dilation to nitric oxide in uterine arteries from rats with type 2 diabetes: implications for vascular adaptations to pregnancy. Oniki H, Goto K, Fujii K, Kansui Y, Murakami N, Ohtsubo T, et al. Effects of the superoxide dismutase mimetic tempol on impaired endothelium-dependent and endothelium-independent relaxations in type II diabetic rats. Clin Exp Hypertension. Mishra RC, Kyle BD, Kendrick DJ, Svystonyuk D, Kieser TM, Fedak PWM, et al. Metab: Clin Exp. Oniki H, Fujii K, Kansui Y, Goto K, Iida M. Effects of angiotensin II receptor antagonist on impaired endothelium-dependent and endothelium-independent relaxations in type II diabetic rats. J Hypertension. Pannirselvam M, Verma S, Anderson TJ, Triggle CR. Br J Pharmacol. Melo BF, Prieto-Lloret J, Cabral MD, Martins FO, Martins IB, Sacramento JF, et al. Type 2 diabetes progression differently affects endothelial function and vascular contractility in the aorta and the pulmonary artery. Sci Rep. Leo CH, Hart JL, Woodman OL. Eur J Pharmacol. Belin de Chantemèle EJ, Vessières E, Guihot AL, Toutain B, Maquignau M, Loufrani L, et al. Type 2 diabetes severely impairs structural and functional adaptation of rat resistance arteries to chronic changes in blood flow. Cardiovasc Res. Wang H, Zhou Y, Guo Z, Dong Y, Xu J, Huang H, et al. Sitagliptin attenuates endothelial dysfunction of zucker diabetic fatty rats: implication of the antiperoxynitrite and autophagy. J Cardiovasc Pharm Ther. Lu X, Guo X, Karathanasis SK, Zimmerman KM, Onyia JE, Peterson RG, et al. Rosiglitazone reverses endothelial dysfunction but not remodeling of femoral artery in Zucker diabetic fatty rats. Cardiovasc Diabetol. Oltman CL, Richou LL, Davidson EP, Coppey LJ, Lund DD, Yorek MA. Progression of coronary and mesenteric vascular dysfunction in Zucker obese and Zucker diabetic fatty rats. Mourmoura E, Vial G, Laillet B, Rigaudière JP, Hininger-Favier I, Dubouchaud H, et al. Preserved endothelium-dependent dilatation of the coronary microvasculature at the early phase of diabetes mellitus despite the increased oxidative stress and depressed cardiac mechanical function ex vivo. Belin de Chantemèle EJ, Vessières E, Guihot AL, Toutain B, Loufrani L, Henrion D. Cyclooxygenase-2 preserves flow-mediated remodelling in old obese Zucker rat mesenteric arteries. Vessières E, Belin De Chantemèle EJ, Toutain B, Guihot A-L, Jardel A, Loufrani L, et al. Cyclooxygenase-2 inhibition restored endothelium-mediated relaxation in old obese zucker rat mesenteric arteries. Front Physiol. Qiu S, Mintz JD, Salet CD, Han W, Giannis A, Chen F, et al. J Am Heart Assoc. Chen K, Pittman RN, Popel AS. Nitric oxide in the vasculature: where does it come from and where does it go? A quantitative perspective. Antioxid Redox Signal. Wood KC, Cortese-Krott MM, Kovacic JC, Noguchi A, Liu VB, Wang X, et al. Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis. Kashiwagi S, Kajimura M, Yoshimura Y, Suematsu M. Nonendothelial source of nitric oxide in arterioles but not in venules. Circulation Res. Buchwalow IB, Podzuweit T, Bocker W, Samoilova VE, Thomas S, Wellner M, et al. Vascular smooth muscle and nitric oxide synthase. FASEB J. Grange RW, Isotani E, Lau KS, Kamm KE, Huang PL, Stull JT. Nitric oxide contributes to vascular smooth muscle relaxation in contracting fast-twitch muscles. Physiol Genomics. Al-Shabrawey M, El-Remessy A, Gu X, Brooks SS, Hamed MS, Huang P, et al. Normal vascular development in mice deficient in endothelial NO synthase: possible role of neuronal NO synthase. Mol Vis. Boulanger CM, Heymes C, Benessiano J, Geske RS, Lévy BI, Vanhoutte PM. Neuronal nitric oxide synthase is expressed in rat vascular smooth muscle cells: activation by angiotensin II in hypertension. Wilcox JN, Subramanian RR, Sundell CL, Tracey WR, Pollock JS, Harrison DG, et al. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Leo F, Suvorava T, Heuser SK, Li J, LoBue A, Barbarino F, et al. Red blood cell and endothelial eNOS independently regulate circulating nitric oxide metabolites and blood pressure. Ghasemi A. Quantitative aspects of nitric oxide production from nitrate and nitrite. EXCLI J. PubMed PubMed Central Google Scholar. Ghasemi A, Jeddi S. Quantitative aspects of nitric oxide production in the heart. Mol Biol Rep. Malinski T, Taha Z, Grunfeld S, Patton S, Kapturczak M, Tomboulian P. Diffusion of nitric oxide in the aorta wall monitored in situ by porphyrinic microsensors. Biochem Biophys Res Commun. Cheah LS, Gwee M, Das R, Ballard H, Yang YF, Daniel EE, et al. Evidence for the existence of a constitutive nitric oxide synthase in vascular smooth muscle. Clin Exp Pharmacol Physiol. Melikian N, Seddon MD, Casadei B, Chowienczyk PJ, Shah AM. Neuronal nitric oxide synthase and human vascular regulation. Trends Cardiovasc Med. Xia N, Horke S, Habermeier A, Closs EI, Reifenberg G, Gericke A, et al. Uncoupling of endothelial nitric oxide synthase in perivascular adipose tissue of diet-induced obese mice. Arteriosclerosis Thrombosis Vasc Biol. Withers SB, Simpson L, Fattah S, Werner ME, Heagerty AM. cGMP-dependent protein kinase PKG mediates the anticontractile capacity of perivascular adipose tissue. Nakladal D, Sijbesma JWA, Visser LM, Tietge UJF, Slart R, Deelman LE, et al. Perivascular adipose tissue-derived nitric oxide compensates endothelial dysfunction in aged pre-atherosclerotic apolipoprotein E-deficient rats. Nava E, Llorens S. The local regulation of vascular function: from an inside-outside to an outside-inside model. Kleschyov AL, Muller B, Schott C, Stoclet JC. Role of adventitial nitric oxide in vascular hyporeactivity induced by lipopolysaccharide in rat aorta. Rassaf T, Bryan NS, Kelm M, Feelisch M. Concomitant presence of N-nitroso and S-nitroso proteins in human plasma. Free Radic Biol Med. Rassaf T, Preik M, Kleinbongard P, Lauer T, Heiß C, Strauer BE, et al. Evidence for in vivo transport of bioactive nitric oxide in human plasma. Robinson JM, Lancaster JR Jr. Hemoglobin-mediated, hypoxia-induced vasodilation via nitric oxide: mechanism s and physiologic versus pathophysiologic relevance. Am J Respiratory Cell Mol Biol. Ford E, Hughes MN, Wardman P. The reaction of superoxide radicals with S-nitrosoglutathione and the products of its reductive heterolysis. J Biol Chem. Singh RJ, Hogg N, Joseph J, Kalyanaraman B. Mechanism of nitric oxide release from S-nitrosothiols. Bohlen HG, Zhou X, Unthank JL, Miller SJ, Bills R. Transfer of nitric oxide by blood from upstream to downstream resistance vessels causes microvascular dilation. Stamler JS, Jaraki O, Osborne J, Simon DI, Keaney J, Vita J, et al. Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin. Proc Natl Acad Sci. Rassaf T, Feelisch M, Kelm M. Circulating NO pool: assessment of nitrite and nitroso species in blood and tissues. Chen K, Piknova B, Pittman RN, Schechter AN, Popel AS. Nitric oxide from nitrite reduction by hemoglobin in the plasma and erythrocytes. Nitric Oxide. Vascular smooth muscle NO exposure from intraerythrocytic SNOHb: a mathematical model. Adela R, Nethi SK, Bagul PK, Barui AK, Mattapally S, Kuncha M, et al. Hyperglycaemia enhances nitric oxide production in diabetes: a study from South Indian patients. PLoS ONE. Tessari P, Cecchet D, Cosma A, Vettore M, Coracina A, Millioni R, et al. Nitric oxide synthesis is reduced in subjects with type 2 diabetes and nephropathy. Avogaro A, Toffolo G, Kiwanuka E, de Kreutzenberg SV, Tessari P, Cobelli C. L-arginine-nitric oxide kinetics in normal and type 2 diabetic subjects: a stable-labelled 15N arginine approach. Salvatore T, Galiero R, Caturano A, Vetrano E, Loffredo G, Rinaldi L, et al. Coronary microvascular dysfunction in diabetes mellitus: pathogenetic mechanisms and potential therapeutic options. Pieper GM. Review of alterations in endothelial nitric oxide production in diabetes: protective role of arginine on endothelial dysfunction. Bonini MG, Dull RO, Minshall RD. Caveolin-1 regulation of endothelial nitric oxide synthase eNOS function and oxidative stress in the endothelium. In: Laher I, editor. Systems biology of free radicals and antioxidants. Berlin, Heidelberg: Springer; Haddad D, Al Madhoun A, Nizam R, Al-Mulla F. Role of Caveolin-1 in diabetes and its complications. Oxid Med Cell Longev. Butler M, McKay RA, Popoff IJ, Gaarde WA, Witchell D, Murray SF, et al. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes ;— Caldwell RB, Zhang W, Rojas M, Bartoli M, El-Remessy AB, Tsai N-T, et al. Decreased nitric oxide bioavailability in diabetic retinopathy: involvement of arginase activity. Investigative Ophthalmol Vis Sci. Kövamees O, Shemyakin A, Checa A, Wheelock CE, Lundberg JO, Östenson C-G, et al. Arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes mellitus. Faria AM, Papadimitriou A, Silva KC, Lopes de Faria JM, Lopes de Faria JB. Uncoupling endothelial nitric oxide synthase is ameliorated by green tea in experimental diabetes by re-establishing tetrahydrobiopterin levels. Kobayashi T, Matsumoto T, Ooishi K, Kamata K. Differential expression of alpha2D-adrenoceptor and eNOS in aortas from early and later stages of diabetes in Goto-Kakizaki rats. Halvorson BD, Whitehead SN, McGuire JJ, Wiseman RW, Frisbee JC. Endothelium-dependent impairments to cerebral vascular reactivity with type 2 diabetes mellitus in the Goto-Kakizaki rat. Am J Physiol Regulatory Integr Comp Physiol. Stadler K, Jenei V, von Bölcsházy G, Somogyi A, Jakus J. Increased nitric oxide levels as an early sign of premature aging in diabetes. Gil-Ortega M, Stucchi P, Guzmán-Ruiz RO, Cano V, Arribas S, González MC, et al. Adaptative nitric oxide overproduction in perivascular adipose tissue during early diet-induced obesity. Jaap AJ, Tooke JE. Pathophysiology of microvascular disease in non-insulin-dependent diabetes. Mouse models without the SCAN enzyme appeared to be shielded from diabetes, suggesting that too much nitric oxide on proteins may be a cause of such diseases. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation at the Case Western Reserve School of Medicine and president of Harrington Discovery Institute at University Hospitals. With this discovery, Stamler said, enzymes that attach the nitric oxide become a focus. With diabetes, the body often stops responding normally to insulin. The resulting increased blood sugar stays in the bloodstream and, over time, can cause serious health problems. AV and BK-H were responsible for the design and draft of the manuscript. CQ, OW, JH, and RR provided critical review and revision of the manuscript. All authors provide approval for publication of the content. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Almourani, R. Diabetes and cardiovascular disease: an update. doi: PubMed Abstract CrossRef Full Text Google Scholar. Anderson, R. Platelet nitrate responsiveness in fasting and postprandial type 2 diabetes. Diabetes Vasc. CrossRef Full Text Google Scholar. Andrews, K. A role for nitroxyl HNO as an endothelium-derived relaxing and hyperpolarizing factor in resistance arteries. Nitroxyl: a vasodilator of human vessels that is not susceptible to tolerance. Nitroxyl HNO reduces endothelial and monocyte activation and promotes M2 macrophage polarization. Antonopoulos, A. Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: The regulatory role of perivascular adipose tissue. Diabetes 64, — Aon, M. Protective Mechanisms of Mitochondria and Heart Function in Diabetes. Redox Signal. Ashrafian, H. Drug Rev. Barlovic, D. Targets 10, 7— Bermejo, E. Effect of nitroxyl on human platelets function. Böger, R. Borgognone, A. Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation. Boustany-Kari, C. A soluble guanylate cyclase activator inhibits the progression of diabetic nephropathy in the ZSF1 rat. Breitenstein, S. Bauersachs, J. Cham: Springer International Publishing , — Brownlee, M. The pathobiology of diabetic complications. Diabetes 54, Bullen, M. Nitroxyl HNO as a vasoprotective signaling molecule. Vasorelaxant and antiaggregatory actions of the nitroxyl donor isopropylamine NONOate are maintained in hypercholesterolemia. Buys, E. Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential. Oxide - Biol. Cao, N. Chronic administration of the nitroxyl donor 1-nitrosocyclo hexyl acetate limits left ventricular diastolic dysfunction in a mouse model of diabetes mellitus in vivo. Chandra, D. Nitric oxide prevents aldose reductase activation and sorbitol accumulation during diabetes. Diabetes 51, Chen, S. Negative regulation of NLRP3 inflammasome signaling. Protein Cell 4, — Chin, K. The concomitant coronary vasodilator and positive inotropic actions of the nitroxyl donor Angeli's salt in the intact rat heart: Contribution of soluble guanylyl cyclase-dependent and -independent mechanisms. The HNO donor Angeli's salt offers potential haemodynamic advantages over NO or dobutamine in ischaemia-reperfusion injury in the rat heart ex vivo. Chirkov, Y. Impaired tissue responsiveness to organic nitrates and nitric oxide: A new therapeutic frontier? Stable angina and acute coronary syndromes are associated with nitric oxide resistance in platelets. Association of aortic stenosis with platelet hyperaggregability and impaired responsiveness to nitric oxide. Effect of perindopril on platelet nitric oxide resistance in patients with chronic heart failure secondary to ischemic left ventricular dysfunction. Chong, C. Reversal of hyperglycemia: effects on nitric oxide signaling. Drugs that affect cardiac metabolism: focus on perhexiline. Drugs Ther. Coleman, J. Nitric oxide: A regulator of mast cell activation and mast cell-mediated inflammation. Cooke, J. ADMA: Its role in vascular disease. Costell, M. Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress. Cowart, D. A phase 1 randomized study of single intravenous infusions of the novel nitroxyl donor BMS in healthy volunteers. da Costa, R. Increased O-GlcNAcylation of endothelial nitric oxide synthase compromises the anti-contractile properties of perivascular adipose tissue in metabolic syndrome. Dautov, R. The nitric oxide redox sibling nitroxyl partially circumvents impairment of platelet nitric oxide responsiveness. Hypoxic potentiation of nitrite effects in human vessels and platelets. Oxide Biol. De Caterina, R. Nitric oxide decreases cytokine-induced endothelial activation: Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. Degrell, P. Evidence of O-linked N-acetylglucosamine in diabetic nephropathy. Life Sci. del Rio, C. Abstract nitroxyl HNO donated via slow-release oral pro-drug improves ventriculo-arterial coupling in conscious dogs with induced heart failure: enhanced load-independent mechano-energetics. Circulation , A—A Dogra, G. Statin therapy improves brachial artery vasodilator function in patients with Type 1 diabetes and microalbuminuria. Drummond, G. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Drug Discovery 10, — DuMond, J. The chemistry of nitroxyl-releasing compounds. Dupuis, J. Intensity of lipid lowering with statins and brachial artery vascular endothelium reactivity after acute coronary syndromes from the BRAVER trial. Elgert, C. A novel soluble guanylyl cyclase activator, BR , acts as a non-stabilising partial agonist of sGC. Förstermann, U. Nitric oxide synthases: regulation and function. Heart J. Fülöp, N. Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart. Farah, C. Nitric oxide signalling in cardiovascular health and disease. Fard, A. Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. Farhan, S. Advanced glycation end products AGEs and their soluble receptors sRAGE as early predictors of reno-vascular complications in patients with uncontrolled type 2 diabetes mellitus. Diabetes Metab. Favaloro, J. The nitroxyl anion HNO is a potent dilator of rat coronary vasculature. Felker, G. Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure. Heart Fail. Fiorentino, T. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Follmann, M. The chemistry and biology of soluble guanylate cyclase stimulators and activators. Chemie - Int. Fox, K. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial the EUROPA study. Lancet , — Fukuto, J. A recent history of nitroxyl chemistry, pharmacology and therapeutic potential. Gao, W. Nitroxyl-mediated disulfide bond formation between cardiac myofilament cysteines enhances contractile function. Giacco, F. Oxidative stress and diabetic complications. Go, A. Statin therapy and risk of incident diabetes mellitus in adults with cardiovascular risk factors. Harrison, D. The nitrovasodilators: new ideas about old drugs. Circulation 87, — Hartman, J. Intravenous infusion of the novel HNO donor BMS is associated With beneficial inotropic, lusitropic, and vasodilatory properties in 2 canine models of heart failure. JACC Basic to Transl. Heitzer, T. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus. Diabetologia 43, — Hernandez-Cuellar, E. Cutting edge: nitric oxide inhibits the NLRP3 inflammasome. Horowitz, J. Asymmetric and symmetric dimethylarginine predict outcomes in patients with atrial fibrillation: an ARISTOTLE substudy. Htay, T. Mortality and cardiovascular disease in type 1 and type 2 diabetes. Ignarro, L. Nitric oxide is not just blowing in the wind. International Diabetes Federation Latest figures show million people now living with diabetes worldwide as numbers continue to rise. Diabetes Res. Irvine, J. NO- activates soluble guanylate cyclase and Kv channels to vasodilate resistance arteries. Hypertension 41, — Nitroxyl anion donor, Angeli's salt, does not develop tolerance in rat isolated aortae. Hypertension 49, — Nitroxyl HNO : the Cinderella of the nitric oxide story. Trends Pharmacol. Ito, H. Flow mediated dilatation is reduced with the progressive stages of glomerular filtration rate and albuminuria in type 2 diabetic patients without coronary heart disease. Jones, D. Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction. Kövamees, O. Amino acid metabolism reflecting arginase activity is increased in patients with type 2 diabetes and associated with endothelial dysfunction. Kahlberg, N. Adverse vascular remodelling is more sensitive than endothelial dysfunction to hyperglycaemia in diabetic rat mesenteric arteries. Kass, D. Phosphodiesterase regulation of nitric oxide signaling. Keceli, G. Nitroxyl HNO targets phospholamban cysteines 41 and 46 to enhance cardiac function. Kemp-Harper, B. Schmidt, H. Berlin, Heidelberg: Springer Berlin Heidelberg , — Therapeutic potential of nitroxyl HNO donors in the management of acute decompensated heart failure. Drugs 76, — Nitroxyl HNO : A novel redox signaling molecule. Kennedy, J. Effect of the anti-anginal agent, perhexiline, on neutrophil, valvular and vascular superoxide formation. Kizub, I. Protein kinase C in enhanced vascular tone in diabetes mellitus. Ko, M. Time- and dose-dependent association of statin use with risk of clinically relevant new-onset diabetes mellitus in primary prevention: a nationwide observational cohort study. Kohr, M. Korkmaz, Y. Downregulation of the α1- and β1-subunit of sGC in arterial smooth muscle cells of OPSCC Is HPV-Independent. Kovanen, P. Mast cells in atherosclerotic cardiovascular disease - Activators and actions. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 92, — Laine, P. Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation 99, — Lee, K.
Top bar navigation	The resulting increased blood sugar stays in the bloodstream and, over time, can cause serious health problems. Individuals with diabetes, the Centers for Disease Control reports, are more likely to suffer such conditions as heart disease, vision loss and kidney disease. Too much enzyme activity causes diabetes. But a case is made for many enzymes putting nitric oxide on many proteins, and, thus, new treatments for many diseases. For more information, contact Bill Lubinger at william. lubinger case. Current medications approved for use in the management of T2D include biguanides, thiazolidinediones, sulfonylureas, meglitinides, dipeptidyl peptidase-4 DPP-4 inhibitors, glucagon-like peptide-1 GLP- 1 receptor agonists, alpha-glucosidase inhibitors, and sodium-glucose co-transporter 2 SGLT2 inhibitors. These drugs mitigate the many adverse effects associated with T2D. This chapter discusses these classes of drugs, examines their mechanism of action, and presents evidence that these drugs directly or indirectly modulate NO levels. Brain insulin resistance appears to contribute significantly to the pathology and cognitive deficits among several pathological mechanisms. Brain insulin resistance has been demonstrated in animal models of AD and postmortem human brain tissue from patients with AD dementia. Studies conducted in AD models and humans suggest attenuating brain insulin resistance by agents such as glucagon-like peptide1 GLP-1 analogs and small molecule drug candidate PTI reduces many AD pathologic features and symptoms. Insulin affects NO levels by activating endothelial and neuronal nitric oxide synthase eNOS, nNOS , and systemic insulin resistance has been linked to reduced nitric oxide NO bioavailability. Increasing NO availability reduces systemic insulin resistance, and the insulin signaling pathway is associated with the activation of eNOS, implying a causal relationship. This chapter explores this relationship and the role of impaired NO availability in brain insulin resistance in AD dementia. L Arginine Arg , a semi-essential essential amino acid, has received significant research interest over the last two decades as nitric oxide NO precursor. Arg is widely used as a complementary treatment in various NO-disrupted conditions, e. Here, we provide an overview of the potential efficacy of Arg as a NO precursor and its effects on glucose and insulin homeostasis and diabetes-induced cardiovascular complications. L-citrulline Cit , a neutral, non-essential, and non-protein amino acid, is a precursor of L-arginine Arg and is involved in nitric oxide NO synthesis. Since oral ingestion of Cit can effectively elevate total Arg flux in the entire body and promote NO production, its supplementation has recently received much attention in the realm of cardio-metabolic diseases where NO metabolism is disrupted. Although preliminary data obtained from in vitro and in vivo animal experiments indicates that Cit improves glucose and insulin homeostasis and can effectively prevent hyperglycemia-induced complications such as inflammation, oxidative stress, renal dysfunction, and endothelial dysfunction, these findings are yet to be realized in well-designed longterm clinical studies in patients with type 2 diabetes T2D. If Cit is shown to be an effective anti-diabetic agent with a good safety profile, its supplementation will be superior to that of Arg because it effectively increases systemic Arg availability more than Arg itself, and hence NO production. Recent research punctuates that the nitrate NO3 -nitrite NO2 -nitric oxide NO pathway may be a potential therapeutic target in type 2 diabetes T2D , a NOdisrupted metabolic disorder. Nutritional aspects of the NO3-NO2-NO pathway has been highlighted by focusing on the protective effects of some traditional high-NO3 diet, such as Mediterranean and DASH Dietary Approaches to Stop Hypertension diets and their NO3-rich components, i. Both acute and long-term administration of inorganic NO3 and NO2 in animal experiments display anti-diabetic properties; inorganic NO3 decreases fasting blood glucose, glycosylated hemoglobin, and proinsulin to insulin ratio and improves glucose tolerance. This lost-i- -translation remains an open question, and long-term clinical trials are needed to confirm the salutary effects of inorganic NO3 and NO2 as the natural NO boosters in patients with T2D. Nitric oxide NO donors are chemical agents that produce NO-related activity in biological systems, mimic endogenous NO-related responses, or compensate for NO deficiency. NO donors have been increasingly studied as promising therapeutic agents for insulin resistance and type 2 diabetes T2D. Here, we provide evidence, which investigated the effects of the most frequently studied and implemented NOreleasing compounds, including sodium nitroprusside SNP , S-nitrosothiols [RSNOs, i. Available evidence could not draw a clear conclusion regarding therapeutic applications of NO donors in T2D due to different methodological approaches i. in vivo and different doses and formulations used to assess the potential effects of NO donors on carbohydrate metabolism. Considering key properties and different kinetic behaviors between various classes of NO donors, targeted compound selection, defining optimum doses, and appropriate use of NO-releasing platforms topical vs. systemic delivery mode seem to be critical issues that can accelerate the bench-to-beside translation of NO donors in T2D. Page: 16 Author: DOI: Type 2 diabetes T2D is a complex metabolic disorder characterized by impaired glucose metabolism and pancreatic β-cell dysfunction. No effective treatments are available for T2D, although there have been many developments in the therapeutic arena. Nitric oxide NO is an endocrine agent with multiple and important biological roles in most mammalian tissues. NO has emerged as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in T2D. Several of the pharmaceuticals used in T2D affect the NO system and perhaps even more so by the drugs we use to treat diabetic cardiovascular complications. Experimental works in animal models of T2D show promising results with interventions aimed to increase NO signaling. However, translation into human studies has so far been less successful, but more large-scale prolonged studies are clearly needed to understand its role. This book is a collection of reviews that deal with the role of nitric oxide in type 2 diabetes, providing a unique overview of NO signaling, and pointing out key areas for more detailed research. Low Wang CC, Hess CN, Hiatt WR and Goldfin AB: Clinical update: Cardiovascular disease in diabetes mellitus: Atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus mechanisms, management, and clinical considerations. Wang W, Shang C, Zhang W, Jin Z, Yao F, He Y, Wang B, Li Y, Zhang J and Lin R: Hydroxityrosol regulates oxidative stress and NO production through SIRT1 in diabetic mice and vascular endothelial cells. Assman TS, Brondani LA, Bouças AP, Rheinheimer J, de Souzza BM, Canani LH, Bauer AC and Crispim D: Nitric oxide levels in patients with diabetes mellitus: A systematic review and meta-analysis. Millerbon FJ, Gutterman DD, Rios CD, Heistad DD and Davidson BI: Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis. Circ Res. Tabit CE, Chung WB, Hamburg NM and Vita JA: Endothelial dysfunction in diabetes mellitus: Molecular mechanisms and clinical implications. Rev Endocr Metab Disord. Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, et al: Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. Totzeck M, Hengen-Cotta UB, Luedike P, Berenbrink M, Klare JP, Steinhoff HJ, Semmler D, Shiva S, Williams D, Kipar A, et al: Nitrite regulates hypoxic vasodilatation via myoglobin-dependent nitric oxide generation. Wu G, Fang YZ, Yang S, Lupton JR and Turner ND: Glutathione metabolism and its implications for health. J Nutr. Sundaram RK, Bhaskar A, Vijayalingam S, Viswanathan M, Mohan R and Shanmugasundaram KR: Antioxidant status and lipid peroxidation in type II diabetes mellitus with and without complications. Clin Sci Lond. Nguyen D, Hsu JW, Jahoor F and Sekhar RV: Effect of increasing glutathione with cysteine and glycine supplementation on mitochondrial fuel oxidation, insulin sensitivity, and body composition in older HIVinfected patients. J Clin Endocrinol Metab. Sekhar RV, McKay SV, Patel SG, Guthikonda AP, Reddy VT, Balasubramanyam A and Jahoor F: Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes Care. Lagman M, Ly J, Saing T, Kaur Singh M, Vera Tudela E, Morris D, Chi P-T, Ochoa C, Sathananthan A and Venketaran V: Investigating the causes for decreased levels of glutathione in individuals with type II diabetes. PLoS One. Lutchmansingh FK, Hsu JW, Bennett FI, Badaloo AV, McFarlane-Anderson N, Gordon-Strachan GM, Wright-Pascoe RA, Jahoor F, Michael S and Boyne MS: Glutathione metabolism in type 2 diabetes and its relationship with microvascular complications and glycaemia. Parsanathan R and Jain SK: Glutathione deficiency alters the vitamin D-metabolizing enzymes CYP27B1 and CYP24A1 in human renal proximal tubule epithelial cells and kidney of HFD-fed mic. Free Radic Biol Med. Ilyer AKV, Rojanasakul Y and Azad N: Nitrosothiols signaling and protein nitrosation in cell death. Ganzarolli de Oliveira M: S-nitrosothiols as platforms for topical nitric oxide delivery. Basic Clin Pharmacol Toxicol. Payabvash S, Ghahremani MH, Goliaei A, Mandegary A, Shafaroodi H, Amanlou M and Dehpour AR: Nitric oxide modulates glutathione synthesis during endotoxemia. Free Rad Biol Med. Surh F, Gehlert S, Grau M and Bloch W: Skeletal muscle function during exercisefine-tuning of diverse subsystems by nitric oxide. Int J Mol Sci. Yaribeygi HY, Butler AE and Sahebkar A: Aerobic exercise can modulate the underlying mechanisms involved in the development of diabetic complications. J Cell Physiol. Kahraman S, Düz B, Kayali H, Korkmaz A, Öter S, Aydin A and Sayal A: Effects of methylprednisolone and hyperbaric oxygen on oxidative status after experimental spinal cord injury: Comparative study in rats. Neurochem Res. Cheng O, Ostrowski RP, Wu B, Liu W, Chen C and Zhang JH: Cyclooxygenase2 mediated hyperbaric oxygen preconditioning in the rat model of transient global cerebral ischemia. Fuller AM, Giardina C, Hightower LE, Perdrizet GA and Tierney CA: Hyperbaric oxygen preconditioning protects skin from UV-A damage. Cell Stress Chaperones. Feng Y, Zhang Z, Li Q, Li W, Xu J and Cao H: Hyperbaric oxygen preconditioning protects lung against hyperoxic acute lung injury via heme oxygenase-1 induction. Biochem Biophys Res Comm. Guevara-Balcazar G, Lara-Padilla E, Kormanovski A, Ramirez-Sanchez I, Castillo-Henkel EF and Castillo-Hernandez MC: Changes in oxidative stress and vascular reactivity of thoracic and abdominal rat aorta with different periods of exposure to hyperbaric oxygenation. Int J Pharmac. Thom SR: Oxidative stress is fundamental to hyperbaric oxygen therapy. J Appl Physiol Castillo-Hernandez MC, Lara-Padilla E, Kormanovski A, Perez-Tuñon JG, Lopez-Calderon EM and Guevara-Balcazar G: Normalization of QRS segment, blood pressure and heartbeat in an experimental model of amintriptyline intoxication in rats following hyperbaric oxygenation therapy. Buras JA, Sthal GL, Svoboda KK and Reenstra WR: Hyperbaric oxygen down-regulates ICAM-1 expression induced by hypoxia and hypoglycemia: The role of NOS. Am J Physiol Cell Physiol. Cabigas BP, Su J, Hutchins W, Shi Y, Schaefer RB, Recinos RF, Nilakantan V, Kindwall E, Niezgoda JA and Baker JE: Hyperoxic and hyperbaric-induced cardioprotection: Role of nitric oxide synthase 3. Cardiovasc Res. Buerk DG: Nitric oxide regulation of microvascular oxygen. Antiox Red Signal. Thibault L: Animal models of dietary-induced obesity. In animal models for the study of human disease. Sah SP, Singh B, Choudhary S and Kumar A: Animal models of insulin resistance: A review. Pharmacol Rep. Ravi Kiran T, Subramanyam MV and Asha Devi S: Swim exercise training and adaptations in the antioxidant defense system of myocardium of old rats: Relation to swim intensity and duration. Comp Biochem Physiol B Biochem Mol Biol. Nacao C, Ookawara S, Kizaki T, Oh-Ishi S, Miyazaki H, Haga S, Sato Y, Ji LL and Ohno H: Effects of swimming training on three superoxide dismutase isoenzymes in mouse tissue. Jung UJ and Choi MS: Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Rogers P and Webb GP: Estimation of body fat in normal and obese mice. Brit J Nutr. Weyer C, Bogardus C, Mott DM and Pratley RE: The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. Defronzo RA, Eldor R and Abdul-Ghani M: Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diab Care Suppl 2 :S—S Mol Cell Biochem. Vickers SP, Jackson HC and Cheetham SC: The utility of animal models to evaluate novel anti-obesity agents. Br J Pharmacol. Makarov M and Makarov V: Diet-induced models of metabolic disturbances. Report 2: Experimental obesity. Lab Animals Sci. Rosini TC, da Silva ASR and de Moraes C: Diet-induced obesity: Rodent model for the study of obesity related disorders. Rev Assoc Med Bras Schmidt HH and Walter U: NO at work. Napoli C and Ignarro LJ: Nitric oxide and pathogenic mechanisms involved in the development of vascular diseases. Arch Pharmacol Res. Davies MJ, Fu S, Wang H and Dean RT: Stable markers of oxidant damage to proteins and their application in the study of human disease. Minamiyama Y, Takemura S, Koyama K, Yu H, Miyamoto M and Inone M: Dynamic aspects of glutathione and nitric oxide metabolism in endotoxemic rats. Sun Q, Liu Y, Sun X and Tao H: Anti-apoptotic effect of hyperbaric oxygen preconditioning on a rat model of myocardial infarction. J Surg Res. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, Bracale R, Valerio A, Francolini M, Moncada S and Carruba MO: Mitochondrial biogenesis in mammal: The role of endogenous nitric oxide. Miller MW, Knaub LA, Olivera-Fragoso LF, Keller AC, Balasubramaniam V, Watson PA and Reusch JEB: Nitric oxide regulates vascular adaptive mitochondrial dynamics. Am J Physiol Heart Circ Physiol. Whal MP, Scalzo RL, Regensteiner JG and Reusch JEB: Mechanisms of aerobic exercise impairment in diabetes: A narrative review. Front Endocrinol Lausanne. Kormanovski A, Castillo-Hernández MC, Guevara-Balcazar G, Pérez T and Lara-Padilla E: Gender difference in nitric oxide and antioxidant response to physical stress in tissues of trained mice after hyperbaric oxygen preconditioning: Part 2. Physiol Pharmac. May Volume 12 Issue 5. Sign up for eToc alerts. You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy. I agree. Home Submit Manuscript My Account. Advanced Search. Register Login. Oncology Letters International Journal of Oncology Molecular and Clinical Oncology Experimental and Therapeutic Medicine International Journal of Molecular Medicine Biomedical Reports Oncology Reports Molecular Medicine Reports World Academy of Sciences Journal International Journal of Functional Nutrition International Journal of Epigenetics Medicine International. Biomedical Reports. Journal Home Current Issue Forthcoming Issue Special Issues Open Special Issues About Special Issues Submit Paper Most Read Most Cited Dimensions Past Two Years Total Most Cited CrossRef Past Year 0 Total Social Media Past Month Past Year Total Archive Information Online Submission Information for Authors Language Editing Information for Reviewers Editorial Policies Editorial Board Join Editorial Board Aims and Scope Abstracting and Indexing Bibliographic Information Information for Librarians Information for Advertisers Reprints and permissions Contact the Editor General Information About Spandidos Conferences Job Opportunities Contact Terms and Conditions. Metrics: Total Views: 0 Spandidos Publications: PMC Statistics: Metrics: Total PDF Downloads: 0 Spandidos Publications: PMC Statistics:. Cited By CrossRef : 0 citations Loading Articles This article is mentioned in:. Introduction Nitric oxide NO acts as an intracellular messenger in physiological and pathological conditions 1. Materials and methods Animals and study design A total of 70 3-month-old female CD1 mice average weight, Table I Time frame of the protocol used and the different groups used. Figure 1 Weight and body composition of the animals in the control and experimental groups. Figure 2 Glucose tolerance curves of mice in the C and D groups at the end of phase 1. Table II Initial, final and post-treatments levels of NO, 3NT and GSH in all tissues. Table III Direction of significant changes of measured parameters in all tissues based on Table II. A, Animal model Initial levels, Control vs. diabetic group Control, final vs. initial levels Diabetic group, final vs. Related Articles.
Vascular nitric oxide resistance in type 2 diabetes \| Cell Death & Disease	Diabbetes results clearly Diabetic foot specialists that NO Nitirc were increased in T2DM patients with coronary artery disease but not with hypertension. Karasu C, Soncul H, Altan VM. Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Percent transport of total added I-insulin at 60 min was calculated. Article CAS Google Scholar Kubaszewski E, Peters A, McClain S, Bohr D, Malinski T.
Indexed In	Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation. Haridoss M, Viswanathan M, Mohan D, Subash B Vivekanandhan A Increased Th1 and suppressed Th2 serum cytokine levels in subjects with diabetic coronary artery disease. Jonathan Stamler. Du XL , Edelstein D , Dimmeler S , Ju Q , Sui C , Brownlee N Hyperglycemia inhibits endothelial nitric oxide synthase activity by post translational modification at the Akt site. Anderson EA , Hoffman RP , Balon TW , Sinkey CA , Mark AL Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. The presence of these consensus sites is consistent with evidence showing that levels of eNOS transcripts are elevated by sheer stress, exercise and hypoxia [ 12 ]. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans.

Sangeeta R. Managenent, Linda J. Roman, Jennifer Lamont, Bettie Sue S. Masters, Mandeep Bajaj, Swangjit Suraamornkul, Renata Belfort, Rachele Berria, Dean L. Kellogg, Yanjuan Liu, Ralph A.

3 thoughts on “Nitric oxide and diabetes management”

Mosar:

19.12.2023 в 10:52

Ich entschuldige mich, aber meiner Meinung nach sind Sie nicht recht. Ich kann die Position verteidigen. Schreiben Sie mir in PM, wir werden umgehen.

Answer
Megar:

19.12.2023 в 11:53

Ich empfehle Ihnen, die Webseite zu besuchen, auf der viele Artikel zum Sie interessierenden Thema gibt.

Answer
Kigale:

20.12.2023 в 10:21

Diese Mitteilung, ist))) unvergleichlich

Answer

Category: Family

Nitric oxide and diabetes management

3 thoughts on “Nitric oxide and diabetes management”

Leave a comment Cancel