Diabetes & Metabolism Journal

Original Articles

Study on the Mechanism of Neutrophil Adhesion to Retinal Capillary Endothelial Cells under High Glucose Condition.: Seok Man Son, Young Sil Lee, Chang Won Lee, Seok Dong Yoo, In Ju Kim, Yong Ki Kim; Korean Diabetes J. 2001;25(1):35-49. Published online February 1, 2001

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Abstract PDF: BACKGROUND
Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and occlusion. Capillary occlusion is the result of microvascular thrombi in which erythrocytes, platelets and leukocytes each may play a major role. Thus, we investigated the pathogenesis of leukocyte stasis by exposing bovine retinal capillary endothelial cells (BRCECs) for high glucose concentration. METHODS: We examined the adhesion of neutrophils to BRCECs incubated in media containing 5.5-30 mmol/L D-glucose for 24 hours. We also measured the expression of E-selectin on endothelial cells and the activation of NF(nuclear transcription factor)-kappaB in nuclear fractions of endothelial cells by using electrophoretic mobility shift assay. RESULTS: We observed that 30 mmol/L D-glucose significantly increased the adhesion of neutrophils to BRCECs (12.5% vs. 3.0%, p<0.01) and migration of neutrophil across cultured BRCEC monolayers (41.0% vs. 21.0%, p<0.05) in respect to 5.5 mmol/L D-glucose. The expression of E-selectin was increased incubated with 30 mmol/L D-glucose compared with 5.5 mmol/L D-glucose (1.45 OD vs. 0.54 OD, p<0.01). Electrophoretic mobility shift assay of nuclear extracts of BRCECs exposed for 24 h to 30 mmol/L D-glucose revealed an intense NF-kappaB activation compared with cells cultured in 5.5 mmol/L D-glucose (8.72x104 countsxmm2 vs.1.88x104 countsxmm2, p<0.01). CONCLUSION: These results suggest that high glucose concentration promote neutrophil adhesion to the BRCECs through upregulation of cell surface expression of E-selectin, possibly depending on NF-kappaB activation and may have implications for the induction of microvasculopathy of diabetic retinopathy.

Effect of High Glucose Concentration on Expression of Adhesion Molecules in Endothelial Cells.: In Ju Kim, Seok Man Son, Min Ki Lee, Hee Jeong, Yong Ki Kim; Korean Diabetes J. 1998;22(3):280-289. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Accelerated atherosclerotic vascular disease is the leading cause of mortality in patients with diabetes mellitus. Endothelial dysfunction, monocytes, and platelets are well known pathogenic factors in atherogenesis. Changes in the neutrophils and endothelial cells, an important early events in all inflammatory process, may contribute to the atherogenesis at early stage, but the significance of this process is not established yet. So we investigated the effects of glucose on the expression of adhesion molecules in endothelial cells, which retlects the change in endothelial-neutrophil adhesive interactions.METHODS: The human umbilical vein endothelial cells(HUVECs) are purchased from American Type Culture Collection. The cells were incubated upto 24 hours to evaluate the expression of E-selectin, PECAM-1, and P-selectin on the cell surface using whole cell ELISA method and soluble P-selectin under different glucose concentration(5.5, 15, and 30 mmol/L). Neutrophil adherence was also measured hy incubation of isolated human neutrophils with monolayers of HUVECs under same different glucose concentration. RESULTS: After 24h incubation with a various concentration of glucose, neutrophil adherence to high concentration of glucose(15 and 30mmol/L)- treated endothelium was significantly increased(5.0 +0.4 and 10.4+0.5%, respectively) compared with adhesion to low concentration of glucose(5.5mmol/ L)-treated endothelium(2.9.+0.4%). Incubation of HUVECs for 24 h in 30mmol/L glucose increased absorbance of E-selectin to 1.36+0.16(P<0.01) and reduced that of P-selectin to 0.56+0.04 compared with the results of respective control culture in 5.5mmol/L glucose(p<0.01), but not changed PECAM-1 expression. In addition, 24 h exposure of HUVECs to 30mmol/L glucose decreased soluble P-selectin concentration to 0.33+0.06ng/mL(P<0.01). CONCLUSION: The results of this study demonstrate that high concentration of glucose stimulates neutrophil adhesion to endothelial cells in association with increased expression of E-selectin. These results suggest that high glucose can directly affect interaction between neutrophil and endothelial cell through a adhesion molecule, especially E-selectin dependent mechanism. Further study should be necessary to investigate the significance of this phenomenon.

Soluble P-selectin, E-selectin, and VCAM-1 as Markers of Vascular Endothelial Damage in Diabetic Patients with Microangiopathy.: Young Sun Kim, Dong Won Byun, Kyo Il Seo, Myung Hi Yoo, Guk Bae Kim, Seong Soo Koong; Korean Diabetes J. 1998;22(1):35-46. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Vascular complications of diabetic patients are common and are known as the major cause of death. Hyperglycemia has been supposed to be the leading cause of vascular complications by unknown mechanisms. In recent reports, hyperglycemia stimulated the expression of leukocyte-endothelial adhesion molecules in the endothelial cells, and increased plasma concentrations of their soluble forms. The aim of this study was to evaluate the role of plasma concentrations of soluble P-selectin(sP-selectin), soluble E-selectin(sE-selectin), and soluble VCAM-1(sVCAM-1) in diabetic patients with microvascular complications as markers of vascular endothelial damage. METHODS: In this study, plasma levels of sP-selection, sE-selectin and sVCAM-1 were determined by ELISA in 39 diabetic patients and 25 normal conirols. RESULTS: The concentrations of sP-selectin, sE-selectin, and sVCAM-1 in diabetic group were significantly higher than those in control group. The concentrations of sP-selectin and sE-selectin decreased sigruficantly after contol of hyperglycemia in diabetic group, but sVCAM-1 level was not altered by treatment. In diabetic group with microvascular complications, the concentrations of sP-selectin and sE-selectin significantly were elevated as compared with the diabetic group without microvascular complication, but the concentration of sVCAM-l was not different between the two groups. In diabetic group, the levels of sP-selectin, sE-selcctin, and sVCAM-1 were not correlated with the concentration of C-peptide, HbA1, triglyceride, total cholesterol, HDL-cholesterol and LDL-cholesterol. There was no difference between control group and diabetic group in terms of age and sex. There were not any differences of sP-selectin, sE-selectin, and sVCAM-1 concentration according to the duration of diabetes and the presence of hypertension. CONCLUSION: Hyperglycemia might stimulated the expression of P-selectin, E-selectin, and VCAM-1 in the endothelial cells and increased the plasma levels of their soluble forms. sP-selectin and sE-selectin could be used as indicators of ongoing vascular dysfunction in diabetes as well as a dynamic surrogate marker for the effectiveness of therapeutic interventions.

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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