Endothelial dysfunction is the earliest indicator of atherosclerosis. Both type 2 diabetes mellitus (T2DM) and hyperhomocysteinemia (HHCY) are the risk factors of endothelial dysfunction. However, the combined effect of T2DM and HHCY on endothelial dysfunction is not clear. We investigated the endothelial function in T2DM patients with HHCY in this study.
Material and Methods:
Fifty newly diagnosed T2DM patients and 54 healthy subjects were recruited from Beijing Chaoyang hospital. T2DM patients were divided into two subgroups as T2DM + NHCY (n = 30) and T2DM + HHCY (n = 20) according to plasma homocysteine (HCY). HHCY was defined as plasma HCY level higher than 15 μmol/L. Endothelial function was measured by the reactive hyperemia index (RHI) with Endo PAT-2000.
Results:
Sex and age were matched between T2DM group and healthy controls. T2DM group had significantly higher HCY level (14.44 ± 4.30 vs. 12.09 ± 2.48 mmol/L, P < 0.05) and lower RHI (1.73 ± 0.50 vs. 2.05 ± 0.49, P < 0.01) than controls. In the subgroup analysis, T2DM with HHCY had significantly lower RHI than T2DM patients without HHCY (1.53 ± 0.20 vs. 1.86 ± 0.59, P < 0.05). RHI was negatively correlated with HCY (r = −0.325, P < 0.01), low-density lipoprotein cholesterol (LDL-C) (r = −0.268, P < 0.01), HbA1c (r = −0.219, P < 0.05), and HOMA-IR (r = −0.226, P < 0.05). Multiple linear regressions analysis was performed and HCY, LDL-C, HbA1c, and HOMA-IR were entered in the model. Analysis showed that HCY levels were independent negatively associated with RHI (β = −0.032, P < 0.05).
Conclusions:
T2DM patients with HHCY had poor endothelial function. Serum HCY levels were negatively associated with RHI.
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References
1.
Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet, 2010; 375:2215–2222.
2.
GuK, CowieCC, HarrisMI. Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971–1993. Diabetes Care, 1998; 21:1138–1145.
3.
TousoulisD, KampoliAM, TentolourisC, et al.The role of nitric oxide on endothelial function. Curr Vasc Pharmacol, 2012; 10:4–18.
4.
MokhtarSS, VanhouttePM, LeungSW, et al.Reduced nitric oxide-mediated relaxation and endothelial nitric oxide synthase expression in the tail arteries of streptozotocin-induced diabetic rats. Eur J Pharmacol, 2016; 773:78–84.
5.
TousoulisD, PapageorgiouN, AndroulakisE, et al.Diabetes mellitus-associated vascular impairment: Novel circulating biomarkers and therapeutic approaches. J Am Coll Cardiol, 2013; 62:667–676.
6.
RissoA, MercuriF, QuagliaroL, et al.Intermittent high glucose enhances apoptosis in human umbilical vein endothelial cells in culture. Am J Physiol Endocrinol Metab, 2001; 281: E924–E930.
7.
EndemannDH, SchiffrinEL. Endothelial dysfunction. J Am Soc Nephrol, 2004; 15:1983–1992.
8.
ClarkeR, DalyL, RobinsonK, et al.Hyperhomocysteinemia: An independent risk factor for vascular disease. New Engl J Med, 1991; 324:1149–1155.
9.
HeL, ZengH, LiF, et al.Homocysteine impairs coronary artery endothelial function by inhibiting tetrahydrobiopterin in patients with hyperhomocysteinemia. Am J Physiol Endocrinol Metab, 2010; 299:E1061–E1065.
10.
YanTT, LiQ, ZhangXH, et al.Homocysteine impaired endothelial function through compromised vascularendothelial growth factor/Akt/endothelial nitric oxide synthase signalling. Clin Exp Pharmacol Physiol, 2010; 37:1071–1077.
11.
MatthewsDR, HoskerJP, RudenskiAS, et al.Homeostasis model assessment: Insulin resistance and B-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 1995; 28:412–419.
12.
HamburgNM, KeyesMJ, LarsonMG, et al.Cross-sectional relations of digital vascular function to cardiovascular risk factors in the framingham heart study. Circulation, 2008; 117:2467–2474.
RubinshteinR, KuvinJT, SofflerM, et al.Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J, 2010; 31:1142–1148.
15.
KoskaJ, SchwartzEA, MullinMP, et al.Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes. Diabetes Care, 2010; 33:1028–1030.
16.
LøgstrupBB, HøfstenDE, ChristophersenTB, et al.Influence of abnormal glucose metabolism on coronary microvascular function after a recent myocardial infarction. JACC Cardiovasc Imaging, 2009; 2:1159–1166.
17.
SuY, LiuXM, SunYM, et al.The relationship between endothelial dysfunction and oxidative stress in diabetes and prediabetes. Int J Clin Pract, 2008; 62:877–882.
18.
KampoliAM, TousoulisD, BriasoulisA, et al.Potential pathogenic inflammatory mechanisms of endothelial dysfunction induced by type 2 diabetes mellitus. Curr Pharm Des, 2011; 17:4147–4158.
19.
BuysschaertM, DramaisAS, WallemacqPE, et al.Hyperhomocysteinemia in type 2 diabetes: Relationship to macroangiopathy, nephropathy, and insulin resistance. Diabetes Care, 2000; 23:1816–1822.
20.
KumarJ, IngelssonE, LindL, et al.No evidence of a causal relationship between plasma homocysteine and type 2 diabetes: A Mendelian randomization study. Front Cardiovasc Med, 2015; 2:11.
21.
MazzaA, BossoneE, MazzaF, et al.Reduced serum homocysteine levels in type 2 diabetes. Nutr Metab Cardiovasc Dis, 2005; 15:118–124.
22.
McNultyH, DoweyLR, StrainJJ, et al.Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677CRT polymorphism. Circulation, 2006; 113:74–80.
23.
LiuJ, XuY, ZhangH, et al.Coronary flow velocity reserve is impaired in hypertensive patients with hyperhomocysteinemia. J Hum Hypertens, 2014; 28:743–747.
24.
ZhangZ, WeiC, ZhouY, et al.Homocysteine induces apoptosis of human umbilical vein endothelial cells via mitochondrial dysfunction and endoplasmic reticulum stress. Oxid Med Cell Longev, 2017; 2017:5736506.
25.
ZhuL, JiaF, WeiJ, et al.Salidroside protects against homocysteine-induced injury in human umbilical vein endothelial cells via the regulation of endoplasmic reticulum stress. Cardiovasc Ther, 2017; 35:33–39.
26.
WangG, WooCW, SungFL, et al.Increased monocyte adhesion to aortic endothelium in rats with hyperhomocysteinemia: Role of chemokine and adhesion molecules. Arterioscler Thromb Vasc Biol, 2002; 22:1777–1783.
27.
SethiAS, LeesDM, DouthwaiteJA, et al.Homocysteine-induced endothelin-1 release is dependent on hyperglycaemia and reactive oxygen species production in bovine aortic endothelial cells. J Vasc Res, 2006; 43:175–183.
28.
YuJ, HanJL, HeLY, et al.Low density lipoprotein cholesterol level inversely correlated with coronary flow velocity reserve in patients with Type 2 diabetes. J Geriatr Cardiol, 2013; 10:159–164.
29.
HermidaN, BalligandJL. Low-density lipoprotein-cholesterol-induced endothelial dysfunction and oxidative stress: The role of statins. Antioxid Redox Signal, 2014; 20:1216–1237.
30.
YokoyamaI, OhtakeT, MomomuraS, et al.Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis. Circulation, 1996; 94:3232–3238.
31.
HeinWH, KuoL. LDLs impair vasomotor function of the coronary microcirculation: Role of superoxide anions. Circ Res, 1998; 83:404–414.
32.
SheuWHH, ChenYT, LeeWJ. Improvement in endothelial dysfunction with LDL cholesterol level <80 mg/dL in type 2 diabetes mellites. Diabetes Care, 2001; 24:1499–1501.
33.
TreasureCB, KleinJL, WeintraubWS, et al.Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med, 1995; 332:481–487.
34.
LiY, ZhangH, JiangC, et al.Hyperhomocysteinemia promotes insulin resistance by inducing endoplasmic reticulum stress in adipose tissue. J Biol Chem, 2013; 288:9583–9592.
35.
NajibS, Sanchez-MargaletV. Homocysteinethiolactone inhibits insulin signaling and glutathione has a protective effect. J Mol Endocrinol, 2001; 27:85–91.
36.
JanusA, Szahidewicz-KrupskaE, MazurG, et al.Insulin resistance and endothelial dysfunction constitute a common therapeutic target in cardiometabolic disorders. Mediat Inflamm, 2016; 2016:3634948.
37.
MatsudaM, DeFronzoR. Insulin sensitivity indices obtained from oral glucose tolerance testing. Comparison with the euglycemic insulin clamp. Diabetes Care, 1999; 22:1462–1470.
38.
BrunJF, RaynaudE, MercierJ. Homeostasis model assessment and related simplified evaluations of insulin sensitivity from fasting insulin and glucose. Diabetes Care, 2000; 23:1037–1038.
39.
MariA, PaciniG, MurphyE, et al.A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care, 2001; 24:539–548.
