Clinacanthus nutans Leaves Extract Reverts Endothelial Dysfunction in Type 2 Diabetes Rats by Improving Protein Expression of eNOS

Diabetes mellitus is associated with endothelial dysfunction; it causes progressive vascular damage resulting from an impaired endothelium-dependent vasorelaxation. In the diabetes state, presence of hyperglycemia and insulin resistance predisposes to endothelial dysfunction. Clinacanthus nutans, widely used as a traditional medicine for diabetes is reported to have hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory properties. However, the possibility of C. nutans affecting the vascular endothelial function in diabetes remains unclear. This study was aimed at evaluating the effects of C. nutans methanolic leaves extract (CNME) on endothelial function in a type 2 diabetes (T2DM) rat model. Sixty male Sprague-Dawley rats were divided into five groups (n=12 per group): nondiabetic control, nondiabetic treated with four weeks of CNME (500 mg/kg/daily), untreated diabetic rats, diabetic treated with metformin (300 mg/kg/daily), and diabetic treated with CNME (500 mg/kg/daily). T2DM was induced by a single intraperitoneal injection of low-dose streptozotocin (STZ) to rats fed with high-fat diet (HFD). Endothelial-dependent and endothelial-independent relaxations and contractions of the thoracic aorta were determined using the organ bath. Aortic endothelial nitric oxide synthase (eNOS) expression was determined using Western blotting. Endothelial-dependent relaxation was reduced in diabetic rats. Both diabetic groups treated with CNME or metformin significantly improved the impairment in endothelium-dependent vasorelaxation; this was associated with increased expression of aortic eNOS protein. CNME- and metformin-treated groups also reduced aortic endothelium-dependent and aortic endothelium-independent contractions in diabetics. Both of these diabetic-treated groups also reduced blood glucose levels and increased body weight compared to the untreated diabetic group. In conclusion, C. nutans improves endothelial-dependent vasodilatation and reduces endothelial-dependent contraction, thus ameliorating endothelial dysfunction in diabetic rats. This may occur due to its effect on increasing eNOS protein expression.

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Type 2 diabetes progression differently affects endothelial function and vascular contractility in the aorta and the pulmonary artery

Scientific Reports ◽

10.1038/s41598-021-85606-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Bernardete F. Melo ◽

Jesus Prieto-Lloret ◽

Marlene D. Cabral ◽

Fatima O. Martins ◽

Inês B. Martins ◽

...

Keyword(s):

Type 2 Diabetes ◽

Endothelial Dysfunction ◽

Pulmonary Artery ◽

Endothelial Function ◽

Pulmonary Disease ◽

Systemic Circulation ◽

Diabetic Rats ◽

High Fat ◽

Vascular Contractility

AbstractType 2 diabetes (T2D) is associated with cardiovascular and pulmonary disease. How T2D affects pulmonary endothelial function is not well characterized. We investigated the effects of T2D progression on contractility machinery and endothelial function in the pulmonary and systemic circulation and the mechanisms promoting the dysfunction, using pulmonary artery (PA) and aorta. A high-fat (HF, 3 weeks 60% lipid-rich diet) and a high-fat/high-sucrose (HFHSu, combined 60% lipid-rich diet and 35% sucrose during 25 weeks) groups were used as prediabetes and T2D rat models. We found that T2D progression differently affects endothelial function and vascular contractility in the aorta and PA, with the contractile machinery being altered in the PA and aorta in prediabetes and T2D animals; and endothelial function being affected in both models in the aorta but only affected in the PA of T2D animals, meaning that PA is more resistant than aorta to endothelial dysfunction. Additionally, PA and systemic endothelial dysfunction in diabetic rats were associated with alterations in the nitrergic system and inflammatory pathways. PA dysfunction in T2D involves endothelial wall mineralization. The understanding of the mechanisms behind PA dysfunction in T2D can lead to significant advances in both preventative and therapeutic treatments of pulmonary disease-associated diabetes.

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An anxiolytic drug buspirone ameliorates hyperglycemia and endothelial dysfunction in type 2 diabetic rat model

Turkish Journal of Biochemistry ◽

10.1515/tjb-2019-0224 ◽

2020 ◽

Vol 45 (4) ◽

pp. 397-404

Author(s):

Tugba Gurpinar Çavuşoğlu ◽

Ertan Darıverenli ◽

Kamil Vural ◽

Nuran Ekerbicer ◽

Cevval Ulman ◽

...

Keyword(s):

Type 2 Diabetes ◽

Blood Glucose ◽

Endothelial Dysfunction ◽

Vascular Function ◽

Fasting Blood Glucose ◽

Diabetic Rats ◽

Diabetic Rat ◽

Insulin Levels ◽

Type 2 Diabetic

AbstractObjectivesType 2 diabetes is a common metabolic disease and anxiety disorders are very common among diabetics. Buspirone is used in the treatment of anxiety, also having blood glucose-lowering effects. The aim of the study was to investigate the effects of buspirone on the glucose and lipid metabolism as well as vascular function in type 2 diabetic rats.MethodsA type 2-diabetic model was induced through a high-fat diet for eight weeks followed by the administration of low-dose streptozotocin (35 mg/kg, intraperitoneal) in rats. Buspirone was given at two different doses (1.5 mg/kg/d and 5 mg/kg/d) and combined with metformin (300 mg/kg/d). The fasting glucose and insulin levels, lipid profile were analyzed, and vascular response measured from the thoracic aorta was also evaluated.ResultsBoth doses of buspirone caused a significant improvement in fasting blood glucose levels. In particular, the buspirone treatment, combined with metformin, improved endothelial dysfunction and was found to be correlated with decreased nitrate/nitrite levels.ConclusionsBuspirone may be effective in the treatment of type 2 diabetes, either alone or in combination with other treatments, particularly in terms of endothelial dysfunction, inflammation and impaired blood glucose, and insulin levels.

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Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

International Journal of Molecular Sciences ◽

10.3390/ijms20153775 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3775 ◽

Cited By ~ 23

Author(s):

Cesar A. Meza ◽

Justin D. La Favor ◽

Do-Houn Kim ◽

Robert C. Hickner

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Blood Flow ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Vascular Dysfunction ◽

Vascular Complications ◽

Enzymatic Production

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.

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Red Blood Cell Peroxynitrite Causes Endothelial Dysfunction in Type 2 Diabetes Mellitus via Arginase

Cells ◽

10.3390/cells9071712 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1712 ◽

Cited By ~ 4

Author(s):

Ali Mahdi ◽

John Tengbom ◽

Michael Alvarsson ◽

Bernhard Wernly ◽

Zhichao Zhou ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Arginase Activity ◽

Oxygen Species ◽

Wild Type ◽

Arginase I

We recently showed that red blood cells (RBCs) from patients with type 2 diabetes mellitus (T2DM-RBCs) induce endothelial dysfunction through a mechanism involving arginase I and reactive oxygen species. Peroxynitrite is known to activate arginase in endothelial cells. Whether peroxynitrite regulates arginase activity in RBCs, and whether it is involved in the cross-talk between RBCs and the vasculature in T2DM, is unclear and elusive. The present study was designed to test the hypothesis that endothelial dysfunction induced by T2DM-RBCs is driven by peroxynitrite and upregulation of arginase. RBCs were isolated from patients with T2DM and healthy age matched controls. RBCs were co-incubated with aortae isolated from wild type rats for 18 h in the absence and presence of peroxynitrite scavenger FeTTPS. Evaluation of endothelial function in organ chambers by cumulative addition of acetylcholine as well as measurement of RBC and vessel arginase activity was performed. In another set of experiments, RBCs isolated from healthy subjects (Healthy RBCs) were incubated with the peroxynitrite donor SIN-1 with subsequent evaluation of endothelial function and arginase activity. T2DM-RBCs, but not Healthy RBCs, induced impairment in endothelial function, which was fully reversed by scavenging of RBC but not vascular peroxynitrite with FeTPPS. Arginase activity was up-regulated by the peroxynitrite donor SIN-1 in Healthy RBCs, an effect that was inhibited by FeTTPS. Healthy RBCs co-incubated with aortae in the presence of SIN-1 caused impairment of endothelial function, which was inhibited by FeTTPS or the arginase inhibitor ABH. T2DM-RBCs induced up-regulation of vascular arginase, an effect that was fully inhibited by FeTTPS. Collectively, our data indicate that RBCs impair endothelial function in T2DM via an effect that is driven by a peroxynitrite-mediated increase in arginase activity. This mechanism may be targeted in patients with T2DM for improvement in endothelial function.

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Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00237.2004 ◽

2004 ◽

Vol 287 (6) ◽

pp. E1209-E1215 ◽

Cited By ~ 432

Author(s):

Thomas Nyström ◽

Mark K. Gutniak ◽

Qimin Zhang ◽

Fan Zhang ◽

Jens Juul Holst ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Healthy Subjects ◽

Stable Coronary Artery Disease ◽

Artery Disease ◽

Type 2 Diabetic ◽

Diabetes Patients

GLP-1 stimulates insulin secretion, suppresses glucagon secretion, delays gastric emptying, and inhibits small bowel motility, all actions contributing to the anti-diabetogenic peptide effect. Endothelial dysfunction is strongly associated with insulin resistance and type 2 diabetes mellitus and may cause the angiopathy typifying this debilitating disease. Therefore, interventions affecting both endothelial dysfunction and insulin resistance may prove useful in improving survival in type 2 diabetes patients. We investigated GLP-1's effect on endothelial function and insulin sensitivity (SI) in two groups: 1) 12 type 2 diabetes patients with stable coronary artery disease and 2) 10 healthy subjects with normal endothelial function and SI. Subjects underwent infusion of recombinant GLP-1 or saline in a random crossover study. Endothelial function was measured by postischemic FMD of brachial artery, using ultrasonography. SI [in (10−4 dl·kg−1·min−1)/(μU/ml)] was measured by hyperinsulinemic isoglycemic clamp technique. In type 2 diabetic subjects, GLP-1 infusion significantly increased relative changes in brachial artery diameter from baseline FMD(%) (3.1 ± 0.6 vs. 6.6 ± 1.0%, P < 0.05), with no significant effects on SI (4.5 ± 0.8 vs. 5.2 ± 0.9, P = NS). In healthy subjects, GLP-1 infusion affected neither FMD(%) (11.9 ± 0.9 vs. 10.3 ± 1.0%, P = NS) nor SI (14.8 ± 1.8 vs. 11.6 ± 2.0, P = NS). We conclude that GLP-1 improves endothelial dysfunction but not insulin resistance in type 2 diabetic patients with coronary heart disease. This beneficial vascular effect of GLP-1 adds yet another salutary property of the peptide useful in diabetes treatment.

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Hyperglycemia and hyperlipidemia are associated with endothelial dysfunction during the development of type 2 diabetes

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y07-026 ◽

2007 ◽

Vol 85 (5) ◽

pp. 562-567 ◽

Cited By ~ 21

Author(s):

Elena B. Okon ◽

Ada W.Y. Chung ◽

Hongbin Zhang ◽

Ismail Laher ◽

Cornelis van Breemen

Keyword(s):

Type 2 Diabetes ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Plasma Levels ◽

Early Stage ◽

Cardiovascular Complications ◽

Older Age ◽

Metabolic Markers

Diabetes mellitus impairs endothelial function, which can be considered as the hallmark in the development of cardiovascular diseases. Hyperglycemia, hyperinsulinemia, and hyperlipidemia are believed to contribute to endothelial dysfunction. In the present study, we investigated the possible links among these plasma metabolic markers and endothelial function in a mouse model during the development of type 2 diabetes. C57BL/6J-Lepob/ob mice at 8, 12, and 16 weeks were used to study endothelial function during the establishment of type 2 diabetes. Endothelial function was accessed in vitro in the thoracic aorta by measuring acetylcholine (ACh)-stimulated vasodilatation. Blood plasma was obtained for the measurements of glucose, insulin, triglycerides, and cholesterol levels. Correlation and multiple regression analysis revealed strong negative associations between the ACh responsiveness and the plasma levels of glucose, insulin, and lipid profiles at the age of 8 weeks. Associations were observed at neither older age nor in C57BL/6J mice. In conclusion, the increase in plasma levels of glucose, insulin, and lipids is associated with the impairment of the endothelial function during the early stage of the development of type 2 diabetes. The loss of correlation at an older age suggests multifactorial regulation of endothelial function and cardiovascular complications at later stages of the disease.

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Type 2 diabetes: increased expression and contribution of IKCa channels to vasodilation in small mesenteric arteries of ZDF rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00240.2013 ◽

2014 ◽

Vol 307 (8) ◽

pp. H1093-H1102 ◽

Cited By ~ 20

Author(s):

Christian Schach ◽

Markus Resch ◽

Peter M. Schmid ◽

Guenter A. Riegger ◽

Dierk H. Endemann

Keyword(s):

Type 2 Diabetes ◽

Protein Expression ◽

Experimental Models ◽

Diabetic Rats ◽

Mesenteric Arteries ◽

Rt Pcr ◽

Mrna And Protein Expression ◽

Zdf Rats ◽

Endothelium Dependent Relaxation

Impaired endothelial function, which is dysregulated in diabetes, also precedes hypertension. We hypothesized that in Type 2 diabetes, the impaired endothelium-dependent relaxation is due to a loss of endothelium-derived hyperpolarization (EDH) that is regulated by impaired ion channel function. Zucker diabetic fatty (ZDF), Zucker heterozygote, and homozygote lean control rats were used as the experimental models in our study. Third-order mesenteric arteries were dissected and mounted on a pressure myograph; mRNA was quantified by RT-PCR and channel proteins by Western blotting. Under nitric oxide (NO) synthase and cyclooxygenase inhibition, endothelial stimulation with ACh fully relaxes control but not diabetic arteries. In contrast, when small-conductance calcium-activated potassium (KCa) channels and intermediate- and large-conductance KCa (I/BKCa) are inhibited with apamin and charybdotoxin, NO is able to compensate for ACh-induced relaxation in control but not in diabetic vessels. After replacement of charybdotoxin with 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34; IKCa inhibitor), ACh-induced relaxation in diabetic animals is attenuated. Specific inhibition with TRAM-34 or charybdotoxin attenuates ACh relaxation in diabetes. Stimulation with 1-ethyl-2-benzimidazolinone (IKCa activator) shows a reduced relaxation in diabetes. Activation of BKCa with 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one NS619 leads to similar relaxations of control and diabetic arteries. RT-PCR and Western blot analysis demonstrate elevated mRNA and protein expression levels of IKCa in diabetes. Our results suggest that the compensatory effect of NO and EDH-associated, endothelium-dependent relaxation is reduced in ZDF rats. Specific blockade of IKCa with TRAM-34 reduces NO and EDH-type relaxation in diabetic rats, indicating an elevated contribution of IKCa in diabetic small mesenteric artery relaxation. This finding correlates with increased IKCa mRNA and protein expression in this vessel.

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The Ratio of Oxidized Lipoprotein(a) to Native Lipoprotein(a) and the Endothelial Function in Patients with Type 2 Diabetes Mellitus

International Journal of Molecular Sciences ◽

10.3390/ijms20194909 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4909 ◽

Cited By ~ 1

Author(s):

Kazuhiko Kotani ◽

Shingo Yamada ◽

Hirokazu Takahashi ◽

Yoshitaka Iwazu ◽

Toshiyuki Yamada

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Enzyme Linked Immunosorbent Assay ◽

Lipoprotein A ◽

Oxidized Lipoprotein ◽

The Mean

The ratio of oxidized lipoprotein(a) to native lipoprotein(a) (oxLp(a)/Lp(a)) may be a reasonable index for assessing endothelial dysfunction in type 2 diabetes mellitus (T2DM). The present study investigated whether the oxLp(a)/Lp(a) level is correlated with the endothelial function using the Endo-PATTM, a newly developed device, in patients with T2DM. A total of 63 patients with T2DM (mean age: 59 years old) were enrolled in the study. The patients’ serum Lp(a) and oxLp(a) levels were measured using an enzyme-linked immunosorbent assay. The reactive hyperemia index (RHI) level was measured using an Endo-PATTM 2000. A correlation analysis between the measured variables was conducted. Among the patients, the mean hemoglobin A1c was 7.8%. The median level of oxLp(a)/Lp(a) was 0.28 (interquartile range: 0.07–0.54), and the mean RHI was 1.8 (standard deviation: 0.4). In a multiple linear regression analysis, the oxLp(a)/Lp(a) level was an independent, significant, and inverse variable for the RHI level (β = −0.26, p < 0.05), along with male gender. A high oxLp(a)/Lp(a) level may reflect endothelial dysfunction, as assessed by the Endo-PATTM, in patients with T2DM. Further studies are warranted to confirm the observed findings.

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Endothelial dysfunction and diabetes

Medicinski pregled ◽

10.2298/mpns0510459s ◽

2005 ◽

Vol 58 (9-10) ◽

pp. 459-464 ◽

Cited By ~ 2

Author(s):

Edita Stokic ◽

Mirjana Djeric ◽

Djordje Radak

Keyword(s):

Nitric Oxide ◽

Type 2 Diabetes ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Enzyme Inhibitors ◽

Angiotensin Converting Enzyme Inhibitors ◽

Lipid Lowering ◽

Converting Enzyme Inhibitors ◽

Lipid Lowering Agents

Endothelial function and dysfunction During the past two decades, there has been an increasing recognition of the importance of normal endothelial function in the maintenance of vascular homeostasis and vascular health. Abnormalities in the function of endothelium have been recognized in a number of conditions. One of the most important abnormalities of endothelial dysfunction appears to be changes in the bioavailability of nitric oxide. It now appears clear that abnormalities in endothelial dysfunction are associated with abnormalities in the production of nitric oxide and/or abnormalities in the rate of its degradation. Either way, loss of the functional availability of nitric oxide appears to be an important characteristic of endothelial dysfunction. Endothetial dysfunction and diabetes lmpaired endothcliul-dependent vasodilatation has been described in patients with type 1 and type 2 diabetes, and the degree of impairment may correlate with glycemic control Hyperglycemia itself appears to affect multiple mechanisms that increase atherosclerosis. Hyperglycemia enhances oxidation, thrombosis, inflammation, matrix production, and the formation of advanced glycation end-products and other metabolites that can potentially damage the vasculature. Treatment of endothelial dysfunction A number of trials have demonstrated that therapy with lipid lowering agents (statins) as well as angiotensin converting enzyme inhibitors is associated with improvements in endothelial function in diabetes. These agents have also been shown to improve prognosis in patients with a number of underlying cardiac diseases and risk factors for cardiac disease. Therefore, it seems that interventions that lead to improvement in endothelial function can be associated with improvements in cardiovascular outcome. The role of antioxidant therapy is controversial. No data have been published regarding the effects of hormonal replacement therapy on endothelial dysfunction in postmenopausal women with type 2 diabetes.

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An Inconvenient Relationship of Hemoglobin A1c Level with Endothelial Function in Type 2 Diabetes

10.21203/rs.3.rs-23581/v1 ◽

2020 ◽

Author(s):

Takayuki Yamaji ◽

Takahiro Harada ◽

Yu Hashimoto ◽

Yuji Takaeko ◽

Masato Kajikawa ◽

...

Keyword(s):

Type 2 Diabetes ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Hba1c Level ◽

Hemoglobin A1c ◽

Antidiabetic Drugs ◽

Flow Mediated Vasodilation ◽

Relationship Of ◽

The Relationship

Abstract Background Diabetes is associated with endothelial dysfunction. However, there is little information on the relationship between hemoglobin A1c (HbA1c) level and endothelial function. This study evaluated the relationship between HbA1c level and flow-mediated vasodilation (FMD).Methods We measured FMD in 1215 patients with type 2 diabetes including 349 patients not taking antidiabetic drugs and 866 patients taking antidiabetic drugs. The patients were divided into four groups based on HbA1c levels: <48 mmol/mol, 48–52 mmol/mol, 53–63 mmol/mol, and ≥ 64 mmol/mol. (< 6.5%, 6.5–6.9%, 7.0-7.9%, ≥ 8.0%)Results An inverted U-shaped pattern of association between HbA1c level and FMD was observed at the peak of HbA1c of about 53 mmol/mol (7%). FMD was significantly smaller in the HbA1c < 48 mmol/mol (6.5%) group than in the HbA1c 48–52 mmol/mol (6.5–6.9%) group and HbA1c 53–63 mmol/mol (7.0-7.9%) group (p < 0.001 and p < 0.001), and FMD values were similar in the HbA1c < 48 mmol/mol (6.5%) group and HbA1c ≥ 64 mmol/mol (8.0%) group. There were no significant differences in nitroglycerine-induced vasodilation (NID) values among the four groups. After adjustments for confounding factors, FMD was significantly smaller in the HbA1c < 48 mmol/mol (6.5%) group than in the HbA1c 48–52 mmol/mol (6.5–6.9%) and HbA1c 53–63 mmol/mol (7.0-7.9%) group (p = 0.002 and p = 0.04). In patients not taking antidiabetic drugs, FMD was also significantly smaller in the HbA1c < 48 mmol/mol (6.5%) group than in the HbA1c 48–52 mmol/mol (6.5–6.9%) group and HbA1c 53–63 mmol/mol (7.0-7.9%) group (p < 0.001 and p = 0.02), and there were no significant differences in NID values among the four groups.Conclusions These findings suggest that a low HbA1c level of < 48 mmol/mol (6.5%) is associated with endothelial dysfunction. An HbA1c level of 48–52 mmol/mol (6.5–6.9%) may be appropriate for maintenance of endothelial function.

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