scholarly journals L-Citrulline Supplementation Increases Plasma Nitric Oxide Levels and Reduces Arginase Activity in Patients With Type 2 Diabetes

2020 ◽  
Vol 11 ◽  
Author(s):  
Alia Shatanawi ◽  
Munther S. Momani ◽  
Ruaa Al-Aqtash ◽  
Mohammad H Hamdan ◽  
Munir N. Gharaibeh
Keyword(s):  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Vascular Dysfunction ◽  
Arginase Activity ◽  
Diabetic Patients ◽  
No Production ◽  
Major Contributor ◽  
Therapeutic Benefits

Type 2 diabetes mellitus (T2DM) is becoming a major contributor to cardiovascular disease. One of the early signs of T2DM associated cardiovascular events is the development of vascular dysfunction. This dysfunction has been implicated in increasing the morbidity and mortality of T2DM patients. One of the important characteristics of vascular dysfunction is the impaired ability of endothelial cells to produce nitric oxide (NO). Additionally, decreases in the availability of NO is also a major contributor of this pathology. NO is produced by the activity of endothelial NO synthase (eNOS) on its substrate, L-arginine. Reduced availability of L-arginine to eNOS has been implicated in vascular dysfunction in diabetes. Arginase, which metabolizes L-arginine to urea and ornithine, competes directly with NOS for L-arginine. Hence, increases in arginase activity can decrease arginine levels, reducing its availability to eNOS and decreasing NO production. Diabetes has been linked to elevated arginase and associated vascular endothelial dysfunction. We aimed to determine levels of plasma NO and arginase activity in (T2DM) patients and the effects of L-citrulline supplementation, a natural arginase inhibitor, on inhibiting arginase activity in these patients. Levels of arginase correlated with HbA1c levels in diabetic patients. Twenty-five patients received L-citrulline supplements (2000 mg/day) for 1 month. Arginase activity decreased by 21% in T2DM patients after taking L-citrulline supplements. Additionally, plasma NO levels increased by 38%. There was a modest improvement on H1Ac levels in these patients, though not statistically significant. The effect of L-citrulline on arginase activity was also studied in bovine aortic endothelial cells (BAECs) grown in high glucose (HG) conditions. HG (25 mM, 72 h) caused a 2-fold increase in arginase activity in BAECs and decreased NO production by 30%. L-citrulline (2.5 mM) completely prevented the increase in arginase activity and restored NO production levels. These data indicate that L-citrulline can have therapeutic benefits in diabetic patients through increasing NO levels and thus maintaining vascular function possibly through an arginase inhibition related pathway.

Abstract 18673: JNK Inhibition Restores Endothelial Function in Type 2 Diabetes Mellitus

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Rosa Breton-Romero ◽  
Bihua Feng ◽  
Monika Holbrook ◽  
Melissa G Farb ◽  
Jessica L Fetterman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Diabetic Patients ◽  
Jnk Activation

Introduction: Diabetes mellitus type 2 is an increasingly public health problem and it is a major cause in the development of cardiovascular diseases. Endothelial dysfunction is a key mechanism that contributes to the pathogenesis of cardiovascular diseases and is a well-known feature of clinical diabetes. Prior studies have demonstrated an impaired nitric oxide bioavailability and a reduced endothelium-dependent vasodilation under diabetic conditions and in animal models, JNK activity has been widely described to be involved in systemic insulin resistance. Hypothesis: Our study aimed to evaluate the involvement of JNK in endothelial dysfunction, studying its potential role in altered eNOS activation and NO synthesis in diabetic patients. Methods: We measured endothelial function and JNK activity in freshly isolated endothelial cells from diabetic patients (n=38) and nondiabetic controls (n=40). Results: ECs from diabetic patients displayed impaired eNOS activation and reduced NO release after insulin and A23187 stimulation, consistent with the presence of endothelial dysfunction. JNK activation was higher in diabetic (**P=0.003), and was associated with lower flow-mediated dilation (r=-0.53, *P=0.02). In endothelial cells from diabetic patients, treatment with JNK chemical inhibitor (SP600125) restored eNOS activation and insulin response (***P<0.001). Nitric oxide bioactivity after A23187 stimuli with diabetes was also recovered in endothelial cells from patients with diabetes. Conclusions: In summary, our data suggest that JNK activation contributes to vascular insulin resistance and endothelial dysfunction in patients with type 2 diabetes and may represent a target in novel therapeutic opportunities.

Platelet-Derived NO in Subjects Affected by Type 2 Diabetes with and without Complications: Is there any Relationship with their Offspring?

2017 ◽  
Vol 125 (05) ◽  
pp. 290-296 ◽  
Author(s):  
Jacopo Sabbatinelli ◽  
Arianna Vignini ◽  
Eleonora Salvolini ◽  
Laura Nanetti ◽  
Laura Mazzanti ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Microvascular Complications ◽  
Diabetic Patients ◽  
No Production ◽  
Type 2 Diabetic Patients ◽  
Adult Type ◽  
Male Adult ◽  
Type 2 Diabetic

Abstract Macro- and microvascular complications are currently the principal causes of morbidity and mortality in patients with diabetes mellitus. Aim of this study was to determine if type 2 diabetic patients with nephropathy and coronary artery disease showed altered platelet-derived nitric oxide (NO) production, compared with diabetic subjects without complications, and if this alteration is also present in their diabetic offspring. In this case-control observational study, platelet NO and peroxynitrite content was determined on plasma from 60 male adult type 2 diabetic patients and 60 male offspring type 2 diabetic patients. Plasmatic levels of homocysteine were also determined in the same individuals. Moreover, Western blot analysis of platelet lysates was performed with specific monoclonal antibody for endothelial (eNOS) and inducible (iNOS) nitric oxide synthase. Our study showed a lower piastrinic production of NO in the group of parents without complications (ADH), compared with the group of offspring without complications (YDH) and with the groups of parents with complications. Furthermore, we observed a lower synthesis of peroxynitrite in platelets from the ADH group than in the groups of patients with complications, and in the YDH group compared with all other groups. Subjects from YDH group also showed lower iNOS expression, compared with all other groups. Our data suggest that alterations in nitric oxide metabolism may represent potential risk factors in type 2 diabetes complications, such as nephropathy and cardiovascular diseases, leading to development of new therapeutic strategies in order to delay and prevent the onset of such complications.

scholarly journals Disturbance of Arginase Activity and Nitric Oxide Levels in Iraqi Type 2 Diabetes Mellitus

2018 ◽  
Vol 15 (2) ◽  
pp. 189-191
Author(s):  
Baghdad Science Journal
Keyword(s):  
Nitric Oxide ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Arginase Activity ◽  
Control Group ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Group I

This study is an attempt to find whether arginine metabolism dysregulation by arginase activity is related to hyperglycemia, followed by changes in nitric oxide (NO) generation in type 2 diabetic patients. This study includes 42 control subjects (Group I), and 92 Iraqi patients with type 2 diabetes mellitus (T2DM). The patient group was subdivided into two groups: Group II (54) with T2DM only and Group III (38) with T2DM and dyslipidemia (who were treating with atorvastatin along with diabetes treatment). The samples were obtained to measure arginase activity and NO levels. Serum arginase activity increased significantly in patients(groupII and groupIII) compared to control group. While serum NO level was significantly lower in diabetic patients as compared to control group, three significant correlations appeared in this study between glucose and arginase activity, glucose and NO levels, and between arginase activity and NO levels. The results also show that treatment with atorvastatin affects arginase activity and NO levels. Increasing in levels of arginase activity can be considered as an indicator of diabetic status. Endothelial dysfunctions accompanied with diabetes mellitus reverses correlation between arginase and NO in diabetic

scholarly journals Differential Telomere Shortening in Blood versus Arteries in an Animal Model of Type 2 Diabetes

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Samira Tajbakhsh ◽  
Kamelya Aliakbari ◽  
Damian J. Hussey ◽  
Karen M. Lower ◽  
Anthony J. Donato ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Sirtuin 1 ◽  
Telomere Shortening ◽  
Telomere Attrition ◽  
Clinical Complications

Vascular dysfunction is an early feature of diabetic vascular disease, due to increased oxidative stress and reduced nitric oxide (NO) bioavailability. This can lead to endothelial cell senescence and clinical complications such as stroke. Cells can become senescent by shortened telomeres and oxidative stress is known to accelerate telomere attrition. Sirtuin 1 (SIRT1) has been linked to vascular health by upregulating endothelial nitric oxide synthase (eNOS), suppressing oxidative stress, and attenuating telomere shortening. Accelerated leukocyte telomere attrition appears to be a feature of clinical type 2 diabetes (T2D) and therefore the telomere system may be a potential therapeutic target in preventing vascular complications of T2D. However the effect of T2D on vascular telomere length is currently unknown. We hypothesized that T2D gives rise to shortened leukocyte and vascular telomeres alongside reduced vascular SIRT1 expression and increased oxidative stress. Accelerated telomere attrition was observed in circulating leukocytes, but not arteries, in T2D compared to control rats. T2D rats had blunted arterial SIRT1 and eNOS protein expression levels which were associated with reduced antioxidant defense capacity. Our findings suggest that hyperglycemia and a deficit in vascular SIRT1per seare not sufficient to prematurely shorten vascular telomeres.

Abstract 378: Red Blood Cells From Patients With Type 2 Diabetes Induce Endothelial Dysfunction Through Up-Regulation of Arginase I

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Zhichao Zhou ◽  
Ali Mahdi ◽  
Yahor Tratsiakovich ◽  
Oskar Kövamees ◽  
Jiangning Yang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Arginase Activity ◽  
Diabetic Patients ◽  
Functional Evaluation ◽  
Mammary Arteries ◽  
Arginase I

We previously showed that increased arginase activity is a key mechanism for endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM) thereby arginase inhibition improves endothelial function. Recently, we demonstrated a crucial role of red blood cells (RBCs) in control of cardiac function via an arginase-dependent regulation of nitric oxide export from RBCs, suggesting a direct interaction of RBCs with cardiovascular function. Considering an increase in arginase activity in T2DM, we hypothesized that RBCs induce endothelial dysfunction in T2DM via up-regulated arginase I. Healthy rat aortas were incubated with RBCs from patients with T2DM (T2DM-RBCs) and age-matched healthy subjects (H-RBCs) for 18 h in the absence and presence of the arginase inhibition or scavenging of reactive oxygen/nitrogen species (ROS/RNS). Following the incubation, endothelium-dependent and -independent relaxations (EDR and EIR) were determined using wire myograph. Human internal mammary arteries (IMAs) obtained from non-diabetic patients who underwent cardiac surgery were also incubated with RBCs for functional evaluation. Arginase activity and protein expression were determined in RBCs. EDR was impaired in vessels incubated with T2DM-RBCs (Emax: 43.2±3.0% in aortas, n=8; 32.3±2.7% in IMAs, n=3) but not H-RBCs (Emax: 74.3±3.4% in aortas; 71.5±5.1% in IMAs) in comparison with buffer (Emax: 74.4±2.3% in aortas; 73.1±5.0% in IMAs; P<0.01 vs. T2DM-RBCs). EIR was not affected by T2DM-RBCs. The impairment in EDR in rat aortas was fully reversed by inhibition of arginase, ROS and RNS in RBCs. Arginase activity was significantly elevated in T2DM-RBCs. The increased arginase activity was attributed to arginase I, as there was increased arginase I expression in RBCs, whereas no arginase II expression was detected. Moreover, high glucose and RNS stimulation increased arginase activity in H-RBCs, while ROS/RNS scavenging decreased arginase activity in T2DM-RBCs. This study demonstrates a novel mechanism behind endothelial dysfunction that T2DM-RBCs induce endothelial dysfunction via ROS/RNS-dependent up-regulation of arginase I. Targeting arginase I in RBCs may serve as a novel therapeutic tool for treatment of endothelial dysfunction in T2DM.

Abstract P632: Nlrp3/inflammasome Activation Contributes To Aldosterone-induced Vascular Dysfunction In Type 2 Diabetes.

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Nathanne S Ferreira ◽  
Thiago Bruder-Nascimento ◽  
Camila A Pereira ◽  
Camila Z Zanotto ◽  
Douglas S Prado ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Diabetic Patients ◽  
Inflammasome Activation ◽  
Caspase 1

Diabetic patients and animal models of type 2 diabetes (DM2) display increased plasma aldosterone (aldo) levels. Aldo induces vascular inflammation and endothelial dysfunction. NOD-like receptors, which are pattern recognition receptors involved in a variety of host innate immune responses, promote vascular inflammation. We hypothesized that aldo via mineralocorticoid receptors (MR) activates the inflammasome platform in the vasculature of DM2 mice. Control (db/+) and diabetic (db/db) mice were treated with vehicle or spironolactone (spiro - MR antagonist, 50 mg/Kg/day). Mesenteric resistance arteries (MA) from db/db mice exhibited reduced acetylcholine (ACh) dilation, which was reversed by spiro [Emax (% of relaxation): db/+: 78.5±4.1; db/db: 40.5±6.4; db/+spiro: 77.0±3.8; db/db+spiro: 62.8±5.9 n=3-6 p<0.05]. Spiro treatment reduced caspase-1 and mature IL-1β content in MA from db/db mice. Spiro also reduced caspase-1 activity in macrophages from peritoneal lavage of db/db mice [% of activity: db/+: 33.9±2.5; db/db: 51.8±7.4; db/+spiro: 31.1±1.9; db/db+spiro: 34.8±3.8 n=4-7, p<0.05]. In vitro, aldo increased mature IL-1β in vascular smooth muscle cells (VSMC) (cont: 0.9±0.01 ; LPS+Nigericine: 6.1±2.1 ; Aldo 4h: 9.7±2.6; LPS+Aldo 4h: 12.8±1.9 n=3-5, p<0.05). To determine whether aldo in vivo directly activates NLRP3/inflammasome in the vasculature and whether NLRP3 activation contributes to aldo-induced vascular injury, aldo was infused (600 ug/Kg/day for 14 days) in wild type (WT) and NLRP3 knockout mice ( NLRP3-/- ) after bone marrow transplantation from WT donor. The groups were constituted: WT->WT, WT->WT+aldo and WT-> NLRP3 -/-+aldo. NLRP3 -/- mice were protected against aldo-induced endothelial dysfunction [Emax: WT: 89.3±2.9; WT+aldo: 39.8±1.8; NLRP3-/- +aldo: 87.7±4.2, p<0.05]. Aldo treatment leaded to endothelial dysfunction in WT ->WT mice, but WT-> NLRP3 -/- mice were protected from aldo-induced endothelial dysfunction [Emax: WT->WT: 95.1±3.1; WT->WT+aldo: 57.1±4.7; WT->NLRP3-/-+aldo: 85.3±3.1 p<0.05]. These results suggest that NLRP3/inflammasome in the vasculature plays a crucial role on aldo/MR-induced vascular damage and on DM2-associated vascular dysfunction. Financial Support: FAPESP, CAPES, CNPq.

scholarly journals Augmented dilation to nitric oxide in uterine arteries from rats with type 2 diabetes: implications for vascular adaptations to pregnancy

2014 ◽  
Vol 306 (4) ◽  
pp. H610-H618 ◽  
Author(s):  
Styliani Goulopoulou ◽  
Johanna L. Hannan ◽  
Takayuki Matsumoto ◽  
Adviye Ergul ◽  
R. Clinton Webb
Keyword(s):  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Soluble Guanylate Cyclase ◽  
Vascular Dysfunction ◽  
Late Pregnancy ◽  
Gk Rats ◽  
Uterine Arteries

Pre-existing diabetes increases the risk of maternal and fetal complications during pregnancy, which may be due to underlying maternal vascular dysfunction and impaired blood supply to the uteroplacental unit. Endothelial dysfunction and reduced vascular smooth muscle responsiveness to nitric oxide (NO) are common vascular impairments in type 2 diabetes (T2D). We hypothesized that uterine arteries from diabetic rats would have reduced vascular smooth muscle sensitivity to NO compared with nondiabetic rats due to impairment in the NO/soluble guanylate cyclase (sGC)/cGMP signaling pathway. Uterine arteries from pregnant Goto-Kakizaki (GK; model of T2D) and Wistar (nondiabetic) rats were studied in a wire myograph. GK nonpregnant uterine arteries had reduced responses to ACh and sodium nitroprusside (SNP) but increased responses to propylamine propylamine NONOate and greater sensitivity to sildenafil compared with Wistar nonpregnant arteries. In late pregnancy, Wistar rats had reduced uterine vascular smooth muscle responsiveness to SNP, but GK rats failed to show this adaptation and had reduced expression of sGC compared with the nonpregnant state. GK rats had a smaller litter size (13.9 ± 0.48 vs. 9.8 ± 0.75; P < 0.05) and a greater number of resorptions compared with Wistar controls (0.8 ± 0.76% vs. 19.9 ± 6.06%; P < 0.05). These results suggest that uterine arteries from rats with T2D show reduced sensitivity of uterine vascular smooth muscle sGC to NO. During pregnancy, the GK uterine vascular smooth muscle fails to show relaxation responses similar to those of arteries from nondiabetic rats.

scholarly journals THE RELATIONSHIP BETWEEN NITRIC OXIDE AND GLYCEMIC CONTROL IN CONTROLLED AND UNCONTROLLED TYPE 2 DIABETES MELLITUS PATIENTS IN THE ADAM MALIK HOSPITAL MEDAN

2018 ◽  
Vol 25 (1) ◽  
pp. 91
Author(s):  
Yessy Suziarty ◽  
Ratna Akbari Ganie ◽  
Santi Syafril
Keyword(s):  
Nitric Oxide ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Significant Relationship ◽  
Enzyme Linked Immunosorbent Assay ◽  
No Production ◽  
Chronic Hyperglycemia ◽  
Diabetes Patients

Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia. Hyperglycemia and other metabolic changes can cause Nitric Oxide (NO) production disturbance. This study investigated the difference in the levels of NO and its’relationship with HbA1c in controlled and uncontrolled diabetes mellitus type 2 patients in the Adam Malik Hospital. This study was a cross-sectional study, conducted in Outpatient Clinic and Inpatient Ward of Internal Medicine Section of Endocrinology in the Adam Malik Hospital on June through October 2016, involving 70 patients type 2 Diabetes Mellitus (DM) consisting of 35 controlled type 2 diabetes patients and 35 uncontrolled type 2 diabetes patients that fulfill this study’s criteria. Nitric Oxide examination conducted by using Chemwell analyzer with the principle of double-antibody sandwich using Enzyme-Linked Immunosorbent Assay (ELISA). There was no significant relationship between HbA1c and Nitric Oxide in patients with controlled (r = 0.264) (p = 0.125) and uncontrolled (r = 0.194) (p = 0.265) type 2 diabetes mellitus. But there was a significant relationship between HbA1c and NO in patients with type 2 DM (r = 0,636) (p = 0.0001). In this study, there was no significant association between HbA1c and Nitric Oxide levels in patients with controlled and uncontrolled type 2 diabetes mellitus. There is a statistically significant relationship between HbA1C and NO in patients with type 2 diabetes.

scholarly journals Nitric oxide modulation of renal and cardiac hemodynamics in type 2 diabetes

2002 ◽  
pp. 687-694 ◽  
Author(s):  
M Dalla Vestra ◽  
D Sacerdoti ◽  
G Bombonato ◽  
P Fioretto ◽  
G Finucci ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Cardiac Output ◽  
Diabetic Nephropathy ◽  
Renal Plasma Flow ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Control Subjects ◽  
Type 2 Diabetic

OBJECTIVE: To evaluate endothelial function in type 2 diabetic patients with and without diabetic nephropathy. METHODS: We studied the effects of systemic infusion of the nitric oxide (NO) synthase inhibitor NG-monomethyl-l-arginine (L-NMMA) on cardiovascular and renal hemodynamics in six type 2 diabetic patients with microalbuminuria (D2-MA), six type 2 diabetic patients with normoalbuminuria (D2-NA) and five control subjects. Both type 2 diabetic patients and control subjects had mild arterial hypertension. RESULTS: L-NMMA infusion decreased the cardiac index in all groups. A reduction in glomerular filtration rate (GFR) and an increase in filtration fraction were observed only in controls. Renal plasma flow decreased in controls and D2-NA patients and renal vascular resistance increased in all groups. CONCLUSIONS: The effect of L-NMMA on cardiac output was similar in controls and type 2 diabetic patients with and without diabetic nephropathy. In contrast, the effect on GFR was impaired in both diabetic groups, suggesting that glomerular NO homeostasis is altered in type 2 diabetes. Moreover the discrepancy, in diabetic patients, between cardiac and renal effects during L-NMMA infusion suggests that the modulation of glomerular hemodynamics is independent from NO-regulated cardiac output.

scholarly journals Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner

2016 ◽  
Vol 310 (11) ◽  
pp. E947-E957 ◽  
Author(s):  
Rui Wei ◽  
Shifeng Ma ◽  
Chen Wang ◽  
Jing Ke ◽  
Jin Yang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Endothelial Function ◽  
No Production ◽  
Dependent Manner ◽  
Protective Effects ◽  
Newly Diagnosed ◽  
Coronary Endothelial Function ◽  
Enos Phosphorylation

Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9–39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9–39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.

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