Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels.

King, George L.; Buzney, Sheldon M.; Kahn, C. Ronald; Hetu, N; Buchwald, S; Macdonald, S G; Rand, Lawrence I.

doi:10.1172/jci110852

Cited by 223 publications

(105 citation statements)

References 20 publications

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“…Despite being functionally active in HCAECs and HCASMCs as shown by phosphorylation of protein kinase B, neither regular insulin nor insulin glargine increased DNA synthesis of HCASMCs or HCAECs. This is in accord with other studies showing little or no mitogenic effect of insulin on macrovascular cells [16][17][18][19][20]22].…”

Section: Discussionsupporting

confidence: 92%

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Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells

Staiger

Schweitzer³

et al. 2005

Diabetologia

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Aims/hypothesis: Present guidelines for the treatment of type 2 diabetes recommend HbA 1 c values of less than 7%. As beta cell function worsens during progress of the disease, insulin therapy is often necessary to achieve this ambitious goal. However, due to peripheral insulin resistance, many patients need rather high insulin dosages. In the light of the extremely high cardiovascular risk of diabetic patients, it is important to determine whether high concentrations of insulin or its frequently used analogues are harmful to the cardiovascular system. We therefore investigated the modulatory effects of regular human insulin and its analogue glargine on proliferation and apoptosis of human coronary artery endothelial cells (HCAECs) and human coronary artery smooth muscle cells (HCASMCs). Methods: Cells were treated with regular human insulin or insulin glargine. Proliferation was determined by [ 3 H]thymidine incorporation and by flow cytometric analysis of Ki-67 expression. Apoptosis was assessed by flow cytometry (cell cycle analysis and annexin V staining) and determination of caspase-3 activity. Results: HCAECs and HCASMCs treated with regular human insulin or insulin glargine did not show significant increases in DNA synthesis or Ki-67 expression. Administration of regular human insulin or insulin glargine did not modulate the extent of apoptotic events. No influence of insulin on lipoapoptotic vascular cell death could be detected.Conclusions/interpretation: Taken together, neither regular human insulin nor insulin glargine influences growth and apoptosis of human coronary artery cells in vitro. Our data do not suggest that regular human insulin or insulin glargine promote atherosclerosis through mechanisms affecting the cellularity of human coronary arteries.

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Section: Discussionsupporting

confidence: 92%

“…Vascular endothelial cells express insulin receptors as well as IGF-I receptors [21][22][23]. HUVECs contain approximately 3.5-10 times more IGF-I receptor mRNA than insulin receptor mRNA [24,25].…”

Section: Introductionmentioning

confidence: 99%

Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells

Staiger

Schweitzer³

et al. 2005

Diabetologia

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“…Other groups have previously reported the presence of GLUT-3 [35,46] and GLUT-5 [35] in brain endothelial cells. The presence of GLUT-4 has been previously reported in endothelial cells of the blood barrier (retinal and brain) [29,47,48] and in fat and muscle capillary endothelial cells [49], while it was absent in cultured cardiac [50], cultured aortic [29], and human muscle capillary endothelial cells [51]. These contradictory findings could, in part, be explained by the heterogeneity found between endothelial cells of different vascular beds and vessels of different calibres, and by the fact that endothelial cells, when cultured, have a tendency to lose the ability to express most of the GLUT and SGLT isoforms [29,30].…”

Section: Glut-2mentioning

confidence: 79%

Characterisation of glucose transporters in the intact coronary artery endothelium in rats: GLUT-2 upregulated by long-term hyperglycaemia

2004

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Aims/hypothesis. We have examined the effects of streptozotocin-induced type 1 diabetes on the expression and subcellular distribution of the classic sugar transporters (GLUT-1 to 5 and sodium-dependent glucose transporter-1 [SGLT-1]) in the endothelial cells of an en face preparation of septal coronary artery from Wistar rats. Methods. The presence of the GLUT isoforms and SGLT-1 in the endothelial cell layer was determined by immunohistochemistry using wide-field fluorescence microscopy coupled to deconvolution, and was quantified by digital image analysis. Results. We found that all of the transporters were expressed within these cells and that all except SGLT-1 were preferentially located on the abluminal side. The heaviest labelling was adjacent to the cell-to-cell junctions where the luminal and abluminal membranes are in close proximity, which may reflect a spatial organisation specialised for vectorial glucose transport across the thinnest part of the cytoplasm. Long-term hyperglycaemia, induced by streptozotocin, significantly downregulated GLUT-1, 3, 4 and 5 and dramatically upregulated GLUT-2, leaving SGLT-1 unchanged. Conclusions/interpretation. We conclude that the high susceptibility of endothelial cells to glucose toxicity may be the result of the subcellular organisation of their GLUTs and the increased expression of GLUT-2.

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“…VSMCs have been found to have insulin receptors and to exhibit insulin-induced responses. 11 It is not known, however, to what extent the increased oxidative stress and insulin resistance reflect increased VSMC migration and proliferation.…”

mentioning

confidence: 99%

Antioxidants Improve Impaired Insulin-Mediated Glucose Uptake and Prevent Migration and Proliferation of Cultured Rabbit Coronary Smooth Muscle Cells Induced by High Glucose

et al. 1999

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Background-To explore the role of intracellular oxidative stress in high glucose-induced atherogenesis, we examined the effect of probucol and/or ␣-tocopherol on the migration and growth characteristics of cultured rabbit coronary vascular smooth muscle cells (VSMCs). Methods and Results-Chronic high-glucose-medium (22.2 mmol/L) treatment increased platelet-derived growth factor (PDGF)-BB-mediated VSMC migration, [ 3 H]thymidine incorporation, and cell number compared with VSMCs treated with normal-glucose medium (5.6 mmol/Lϩ16.6 mmol/L mannose). Probucol and ␣-tocopherol significantly suppressed high glucose-induced increase in VSMC migration, cell number, and [3 H]thymidine incorporation. Probucol and ␣-tocopherol suppressed high glucose-induced elevation of the cytosolic ratio of NADH/NAD ϩ , phospholipase D, and membrane-bound protein kinase C activation. Probucol, ␣-tocopherol, and calphostin C improved the high glucose-induced suppression of insulin-mediated [ 3 H]deoxyglucose uptake. Chronic high-glucose treatment increased the oxidative stress, which was significantly suppressed by probucol, ␣-tocopherol, suramin, and calphostin C. Conclusions-These findings suggest that probucol and ␣-tocopherol may suppress high glucose-induced VSMC migration and proliferation via suppression of increases in the cytosolic ratio of free NADH/NAD ϩ , phospholipase D, and protein kinase C activation induced by high glucose, which result in reduction in intracellular oxidative stress.

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Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels.

Cited by 223 publications

References 20 publications

Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells

Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells

Characterisation of glucose transporters in the intact coronary artery endothelium in rats: GLUT-2 upregulated by long-term hyperglycaemia

Antioxidants Improve Impaired Insulin-Mediated Glucose Uptake and Prevent Migration and Proliferation of Cultured Rabbit Coronary Smooth Muscle Cells Induced by High Glucose

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