Diabetes & Metabolism Journal

Original Articles

Diabetic Retinopathy and Endothelial Dysfunction in Patients with Type 2 Diabetes Mellitus: Jae-Seung Yun, Seung-Hyun Ko, Ji-Hoon Kim, Kun-Woong Moon, Yong-Moon Park, Ki-Dong Yoo, Yu-Bae Ahn; Diabetes Metab J. 2013;37(4):262-269. Published online August 14, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.4.262

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Background

We investigated the relationship between endothelial dysfunction and diabetic retinopathy (DR) in patients with type 2 diabetes.

Methods

We used a cross-sectional design to examine 167 patients with type 2 diabetes mellitus. All patients underwent biochemical and ophthalmological examination. We assessed endothelial dysfunction by a flow-mediated vasodilation method of the brachial artery. Changes in vasodilation (flow-mediated vasodilatation, %FMD) were expressed as percent change over baseline values.

Results

The mean±standard deviation of patient age was 54.1±8.6 years. The %FMD was significantly lower in patients with DR than without DR. The prevalence of retinopathy decreased across increasing tertiles of %FMD. After adjusting for patients' age, sex, diabetes duration, use of insulin, use of antihypertensive, antiplatelet, and lipid lowering medications, systolic blood pressure, fasting plasma glucose, 2-hour plasma glucose, glycated hemoglobin, and urinary albumin excretion, participants with a reduced %FMD were more likely to have DR (odds ratio, 11.819; 95% confidence interval, 2.201 to 63.461; P=0.004, comparing the lowest and highest tertiles of %FMD).

Conclusion

Endothelial dysfunction was associated with DR, which was most apparent when the endothelial dysfunction was severe. Our study provides insights into the possible mechanism of the influence of endothelial dysfunction on the development of DR.

Citations

Citations to this article as recorded by

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The Effect of Nitric Oxide on Insulin Binding and Insulin Receptor Recycling in Bovine Aortic Endothelial Cells.: Hyuk Sang Kwon, Oak Kee Hong, Hee Soo Kim, Jung Min Lee, Sung Rae Kim, Sung Dae Moon, Sang Ah Jang, Hyun Shik Son, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2003;27(3):213-227. Published online June 1, 2003

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Abstract PDF: BACKGROUND
The coexistence of insulin resistance and endothelial dysfunction is commonly observed in a variety of metabolic and cardiovascular disorders, including athero-sclerosis and type 2 diabetes mellitus. Because nitric oxide (NO), or nitric oxide synthase (NOS), has been suggested as a significant contributing factor in the development of endothelial dysfunction and insulin resistance, reactive NO or NOS were investigated to see if they contribute to the insulin internalization pathway. METHODS: The production of NO (Nitrite), the expression of eNOS (endothelial NOS), insulin binding and the insulin receptor internalization and recycling, following 48 hours of incubation with bradykinin (BK), acetylcholine (Ach), NG-monomethyl- L-arginine (L-NMMA) and N-nitro-L-arginine methylester (L-NAME) in Bovine aortic endothelial cells (BAECs), were examined. RESULTS: The results were as follows: 1. In relation to the time course, the production of eNOS was increased, but was decreased after 8 hours of incubation. The production of eNOS in the L-NMMA and L-NAME treated groups was significantly decreased compared with that of the controls (p<0.05). 2. The specific insulin bindings to the receptors of the endothelial cells were maximized within 20 mins, and then decreased. At 20 mins, the binding rate of the L-NMMA treated group was significantly decreased compared to that of the controls. At a concentration of 0.4ng/ml of unlabelled insulin, the specific insulin binding of the L-NMMA treated group was significantly decreased compared to that of the controls (p<0.05). 3. The internalization of 125I-insulin into the endothelial cells, as assessed by the acid washing dissociation method, occurred rapidly. The internalized radioactivity of 125I-insulin, at 20 mins, was significantly increased in the BK and Ach groups compared with the controls (p<0.05). 4. The recycling of the internalized insulin receptors showed no significant differences between the study groups, but the recycling was slightly delayed compared with controls in the Ach group. CONCLUSION: In conclusion, the NO generating substances, BK and Ach, and the inhibitory substance, L-NMMA, may influence the binding and internalization of insulin-insulin receptors. Our results suggest that NO might contribute to the transcytosis of insulin in BAECs

The Effect of alpha-lipoic Acid on Endothelial Dysfunction Induced by Intralipid Infusion in Healthy Volunteers.: Dong Wook Lee, Mi Jung Kim, Hye Soon Kim, Tae Sung Yun, Ho Chan Cho, Sang Jun Lee, Seung Ho Hur, Kyo Cheol Mun, Yong Won Cho, Jae Hoon Bae, In Kyu Lee; Korean Diabetes J. 2002;26(5):336-346. Published online October 1, 2002

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Abstract PDF: BACKGROUND
Endothelial dysfunciton has been proposed as an early manifestation of atherogenesis. Recently, emerging evidence suggests that hypertriglyceridemia and elevated free fatty acid are important risk factors in the development of atherosclerosis, probably through an increased oxidative stress. To clarify the hypothesis, we evaluated the effect of alpha-lipoic acid (ALA) on the endothelial dysfunction induced by intralipid infusion in healthy volunteers. METHODS: Hypertriglyceridemia and elevated free fatty acids was induced by infusion of intralipid. FMD (Flow-mediated dilation) of the brachial artery was investigated noninvasively by a high-resolution ultrasound technique in 13 young, healthy men without risk factors for coronary heart disease. RESULTS: Plasma triglyceride, free fatty acid and the superoxide anion were increased from 61.7+/-28.8 to 332.6+/-202.5 mg/dL, from 330.7+/-131.1 to 1267.0+/-486.2 microEq/L and from 6.6+/-2.2 to 8.7+/-1.5 X 10(-7)nmol/10(6)cells/30min (vs. basal p<0.001), respectively, following infusion of the intralipid. The FMD was decreased from 10.1+/-3.3 to 7.7+/-3.7% (vs. basal p<0.01) following infusion of the intralipid. After treatment with ALA, the increase in the FMD and the decrease in superoxide anion were significant. CONCLUSION: Acute hypertriglyceridemia, induced by intralipid infusion, is implicated in endothelial dysfunction. This endothelial dysfunction was reversed by treatment with ALA. These results suggest that chronic and repeated hypertriglyceridemia may play important roles in the development of atherosclerosis probably by increasing oxidative stress.

The Effect of Alpha-lipoic Acid on Endothelial Dysfunction in Postmenopausal Uncomplicated Type 2 Diabetes.: Ho Chan Cho, Sang Jun Lee, Mi Jung Kim, Hye Sun Kim, Tae Sung Yun, Sung Jae Kim, Sang Hyon Kim, Seung Ho Hur, Kyo Chul Moon, Jae Hoon Bae, In Kyu Lee; Korean Diabetes J. 2002;26(4):242-252. Published online August 1, 2002

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Abstract PDF: BACKGROUND
Recently, increased oxidative stress has been proposed as a major cause of vascular complications of patients with diabetes mellitus. Increased generation of oxygen free radicals in patients with diabetes mellitus could deplete cellular antioxidants and inactivate endothelial dependent vasodilating factor (EDRF), such as nitric oxide (NO). The purpose of this study was to evaluate whether the antioxidant alpha-lipoic acid (ALA) is effective in endothelial dysfunction of brachial artery, which induced by increased oxidative stress in postmenopausal diabetic women using high resolution ultrasound technique and initial reaction time (IRT) measurement. METHODS: We enrolled 11 menopausal women (mean age, 56.5+/-5.1 years) with uncomplicated type 2 diabetes. All patients were taking 1200 mg of ALA (Thioctacid(R), Bukwang, Korea). We measured of superoxide anion (O2-) in neutrophils as a marker of oxidative stress. Flow-mediated dilation (FMD) was measured using a high-resolution ultrasound. RESULTS: After treatment of ALA, fasting blood glucose was decreased significantly, the endothelium-dependent vasodilation of the brachial artery was increased, and O2- production was also decreased significantly. CONCLUSION: These results show that short term ALA treatment could improve the endothelial dysfunction in patients with type 2 diabetes mellitus. This improvement might be related with the antioxidants effect of ALA.

The Effect of Acute Hyperglycemia on Endothelial Function in Type 2 Diabetes.: Sang Jun Lee, Dong Wook Lee, In Kyu Lee; Korean Diabetes J. 2000;24(5):574-586. Published online January 1, 2001

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Abstract: BACKGROUND
Multiple studies in patients with diabetes demonstrate impaired endothelial-dependent vasodilation. But the mechanisms of vascular dysfunction in type 2 diabetes are still controversial. Some risk factors, such as dyslipidemia, hypertension and obesity, are commonly associated with type 2 diabetes. These risk factor may cause endothelial dysfunction. And hyperglycemia may have a specific role in the increased risk of vascular complications in diabetes but it remains unclear. The purpose of this study was to examine whether endothelial dysfunction occurs when acute hyperglycemia is induced by oral glucose loading. METHOD: Using the high-resolution ultrasound, we measured flow-mediated vasodilation (endothelial dependent vasodilation: FMD) during oral glucose tolerance test in 11 men (mean age: 59+/-5 years) with type 2 diabetes without chronic diabetic complications. For statistical analysis, we used paired t-test, generalized linear method (GLM) to compare FMD before and after glucose loading. RESULT: Flow-mediated vasodilation was diminished after glucose loading (13.2+/- 6.4%, 7.3+/-3.3*%, 12.8+/-5.6%, in fasting, at 1- and 2-h, respectively; *p<0.001 vs fasting). Superoxide anion formation by neutrophils was increased after glucose loading (4.65+/-2.8, 6.17+/-2.2, in fasting, at 1-h respectively: p<0.05 vs fasting)( 10-7nmol/106cells/30min). Endothelial independent vasodilation was not significantly affected by glucose loading. The concentration of triglyceride were not changed after glucose loading. CONCLUSION: This study shows that acute hyperglycemia induced by 75 gm oral glucose intake results in endothelial dysfunction. These results suggest that prolonged and repeated hyperglycemia may play an important role in the developement and progression of vascular complication in diabetes.

Solyble ICAM-1 and BCAM-1 in Patients with NIDDM.: Young Min Kim, Yong Gi Kim, Seok Man Son, In Ju Kim, Seok Dong Yoo, Young Keun Choi, Chang Won Lee, Jun Hyup Ahn; Korean Diabetes J. 1999;23(3):315-325. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The development of vascular complications in diabetic patients changess their quality of life, as well as shortens their life expectancy. It has been recently discovered that the expressions of the cell adhesion molecules initiate vascular complications and have major effects on the progress of atherosclerosis. We measured soluble forms of intercelluar adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1), the immunoglobulin superfamily members of the cell adhesion molecules concerning firm adhesion and transendothelial migration during leukocyte- endothelial cell interactions to clarify their concentrations and their relation with glycemic control and plasma lipoproteins as well as differences in concentration according to the presence of diabetic microvascular complcations in non-insulin dependent diabetes mellitus (NIDDM) patients. METHODS: Serum sICAM-1and sVCAM-1 levels were measured by commercial ELISA kits in 35 NIDDM patients without overt macrovascular complications of diabetes or acute inflammation and 10 normal controls matched with body mass index and plasma lipoprotein levels. The mean age of the patient group and control group was 55.82+3.43 years and 46.30+15.15 years, respectively. Clinical characteristics and laboratory parameters such as fasting plasma glucose, HbAplasma lipoproteins and status of diabetic microvascular complications were evaluated and their relations with the levels of sICAM-1 and sVCAM-1 were analyzed. RESULTS: 1) The level of sICAM-1 in NIDDM patients was significantly higher than that of normal controls (15.79+6.21 ng/mL vs. 11.98+2.35, p<0.05). sVCAM-1 showed the trend in elevation in NIDDM patients, but had no statistical significance (p=0.053). 2) The level of soluble ICAM-1 was positively correlated with HbAlc>, and plasma triglyceride levels (r=0.38, p<0.05, r=0.36, p<0.05, respectively) and negatively correlated with HDL (r=-0.44, p<0.01) in the patient group. There were no differences in their age, sex, and the presence of hypertension with the levels of sICAM-1 and no relation between sICAM-1 level and body mass index, plasma total cholesterol, Lp (a), fasting plasma glucose, fasting plasma C-peptide levels. Plasma LDL was partially correlated with the level of sICAM-1, but failed to reveal statistical significance. sVCAM-1 level was not correlated with any parameters discussed above, but had a tendency of correlation with HbAlc level (r=0.31, p=0.06). 3) No significant correlation was noted between the levels of sICAM-1 or sVCAM-1 and the duration of diabetes. 4) Both sICAM-1 and sVCAM-1 levels were significantly higher in patients with diabetic nephropathy when compared to patients without nephropathy (21.58+7.11 ng/mL vs. 14.06+4.84 ng/mL, p<0.05, 37.51+16.91 ng/mL vs. 22.26+8.89 ng/mL, p<0.05, respectively, but such differences were not noted when patients were classifed according to the presence of retinopathy or neuropathy. 5) Both sICAM-1and sVCAM-1 levels did not correlate in the patient group or in the normal control group. CONCLUSION: These findings suggest that enhanced expression of the the endothelial cell adhesion molecules in diabetic patients can be explained by endothelial dysfunction caused by persistent hyperglycemia and dyslipidemia. Furthermore, it can be suggested that endothelial dysfunction may be initiated by diabetes itself and can be deteriorated by combined dyslipidemia. From the result of the elevated concentrations of sICAM-1 and sVCAM-1 in patients with diabetic nephropathy, we can suggest that the elevation of these cell adhesion molecules may be useful as markers in diabetic nephropathy. More selective and prospective studies are necessary in order to reveal thesignificance of these cell adhesion molecules in the pathogenesis of diabetic vascular complications.

Effect of Oxidezed LDL in Insulin Binding, Internalization and Recycling of Insulin Receptor in Cultured Bovine Aortic Endothelial Cells.: Sung Dae Moon, Bong Yun Cha, Hye Soo Kim, Sang Ah Jang, Yu Bae An, Ki Ho Song, Je Ho Han, Soon Jib You, Kun Ho Yoon, Moo Il Kang, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 1999;23(3):243-255. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Endothelial dysfunction is perhaps one of the earliest manifestations of atherosclerosis. This abnormality is in part due to altered membrane signal transduction in endothelial cells. Oxidized LDL that is atherogenic may induce endothelial dysfunction, and its presence has been documented in atherosclerotic vessels. Many studies have shown that oxidized LDL inhibits signaling pathways mediated by inhibitory GTP-binding proteins (Gi- protein). It is also known that G-protein is involved in insulin recycling on cultured human umbilical vein endothelial cells. Therefore, to determine the effect of oxidized LDL on endothelial cells: insulin binding, internalization, and the recycling of insulin receptors were assessed in cultured bovine aortic endothelial cells treated with native LDL, oxidized LDL, and in some cells pretreated with pertussis toxin before the incubation with oxidized LDL. METHOD: Native LDL (density 1.019 1.063 g/mL) was obtained from using the rapid single discontinuous density gradient ultracentrifugation of plasma samples from a single donor. Oxidized LDL was prepared by exposing samples of native LDL to CuSO4 (5 uM) at 37't for 24 hours. Endothelial cells at 80% confluence were treated with the indicated concentrations of native LDL, oxidized LDL, and some cells were pretreated with pertussis toxin for 6 hrs before the incubation with oxidized LDL. These cells were incubated for 24 72 hours. RESULTS: 1. Binding of (125)I-insulin(0.17nM) to endothelial cells treated with increasing concentrations of oxidized LDL shows dose-dependent decrease. There were significant differences in insulin binding between native LDL and oxidized LDL-treated cells (p<0.05). Binding of 'I-insulin (0.17 nM) to endothelial cells treated with increasing culture time of oxidized LDL shows more decreased than that of native LDL significantly (p<0.05). And oxidized LDL had additive effect, but not significant, with pertussis toxin on the specific (125)I-insulin binding to bovine aortic endothelial cells. 2. Internalization of insulin receptors reached rapidly to its maximal level around 30min at 37'C. At 60 min, oxidized-LDL treated cells was less increased in internalization of insulin receptors than that of native LDL treated cells [59.1+1.9% of total cell associated insulin (mean+SE) vs. 67.5+1.1%, p<0.05]. There were additive effects, but not significant differences, between oxidized LDL and pretreated with pertussis toxin before the incubation with oxidized LDL. 3. After 30 min of incubation with unlabeled insulin (33 nM), insulin binding in oxidized LDL treated cells was significantly higher compared to native LDL treated cells (69.0+2.5% of control values vs. 63.7+1.2%, p<0.05), suggesting that oxidized-LDL decreased internalization of insulin receptors. And during the process of recycling, there were significant differences in insulin receptor recycling between the oxidized LDL and native LDL treated cells, but oxidized LDL had an additive effect, but not significant, with pertussis toxin on insulin receptor recycling to the bovine aortic endothelial cells. CONCLUSION: 1. The findings in this study suggest that oxidized LDL may play a causative role to produce the insulin resistance by inhibiting insulin binding, internalization and recycling of insulin receptor in cultured bovine aortic endothelial cells 2. This study suggests that the effect of oxidized LDL to the bovine aortic endothelial cells in insulin binding and receptor-mediated transcytosis is caused by inhibiting pertussis toxin sensitive Gi-protein.

Elevated Levels of Soluble E-selectin and P-selectin in Patients with NIDDM.: Seok Dong Yoo, In Joo Kim, Yong Ki Kim; Korean Diabetes J. 1998;22(1):23-34. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Although there is wide spread agreement that patients with NIDDM are at increased risk of the premature development of atherosclerosis, it is not totally clear why this is so. This may be related to the interaction of blood leukocytes with vascular endothelium resulting from a loss of normal metabolic control. The adherence of leukocytes to the endothelium is at least partly mcdiated by cell adhesion molecules. In this study, we evaluated the level of soluble E-selectin and P-selectin in blood of normal controls and patients with NIDDM, and studied its relation to glycemic control and identifiable factors influencing the level of soluble E-selectin and P-selectin. METHODS: Serum soluble E-selectin and plasma soluble P-selectin levels were measured by ELISA method in 24 NIDDM patients without macrovascullar disease and 14 normal controls matched with age, sex and body mass index. Clinical characteristics and laboratory findings such as fasting plasma glucose, HbA1c and lipid profile were evaluated, and their relation with the levels of E-selectin and P-selectin was analized. RESULTS: 1) The levels of E-selectin and P-selectin in NIDDM patients were significantly higher than those of normal controls(55.69+21.97 vs. 42.11+13.57ng/ mL, P<0.05 for E-selectin, 41.60+20.90 vs. 27.16 +7.12ng/mL, P 0.01 for P-selectin). 2) The levels of E-selectin and P-selectin were positively correlated with the fasting plasma glucose level(r=0.400 P<0,05 for E-selectin, r=0.456 P<0.01 for P-selectin). They were also positively correlated with the levels of serum triglyceride(r=0.531 P<0.01 for E-selectin, r=0.415 P =0.05 for P-selectin) but not with the levels of serum total cholesterol, LDL and HDL cholestrol in NIDDM patients. 3) No significant correlation was noted between the levels of E-selectin or P-selectin and the duration of NIDDM. And the levels were not different according to the type of treatment. 4) E-selectin level, not P-selectin level, was significantly higher in the patients with nephropathy when compared to the patients without nephropathy. But such difference was not noted when the patients were classified according to the presence of retinopathy or neuropathy. 5) E-selectin level was positively correlated with P-selectin level in both NIDDM patients and normal controls(r=0.52, P<0.01). CONCLUSION: These findings suggest that endothelial dysfunction, revealed by increased cellular adhesion molecules, could play a role in the pathogenesis of diabetic atherosclerotic vascular disorders in NIDDM patients with increased fasting plasma glucose control and hypertriglyceridemia. In addition, elevated soluble E-selectin and P-selectin level in blood might be used as a marker of diabetic nephropathy.

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