Type 2 diabetes mellitus is associated with an imbalance in circulating endothelial and smooth muscle progenitor cell numbers

Ark, Joris van; Moser, Jill; Lexis, Chris P. H.; Bekkema, F.; Pop, Ioana; Horst, van der; Zeebregts, Clark J.; Goor, van Harry; Wolffenbuttel, Bruce H. R.; Hillebrands, Jan-Luuk

doi:10.1007/s00125-012-2590-5

Cited by 52 publications

(35 citation statements)

References 24 publications

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“…Individuals included are a subset of subjects on which we recently reported [13]. Patients were assigned to the following groups: diabetes, no MVD (n = 11); diabetes with CAD (n = 12); diabetes with PAD (n = 12); no diabetes with CAD (n = 13); and no diabetes with PAD (n = 14).…”

Section: Methodsmentioning

confidence: 99%

Circulating alpha-klotho levels are not disturbed in patients with type 2 diabetes with and without macrovascular disease in the absence of nephropathy

Ark

Hammes

Dijk

et al. 2013

Cardiovasc Diabetol

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BackgroundDiabetes is associated with a high incidence of macrovascular disease (MVD), including peripheral and coronary artery disease. Circulating soluble-Klotho (sKlotho) is produced in the kidney and is a putative anti-aging and vasculoprotective hormone. Reduced Klotho levels may therefore increase cardiovascular risk in diabetes. We investigated if sKlotho levels are decreased in type 2 diabetes and associate with MVD in the absence of diabetic nephropathy, and whether hyperglycemia affects renal Klotho production in vitro and in vivo.MethodssKlotho levels were determined with ELISA in diabetic and non-diabetic patients with and without MVD, and healthy control subjects. Human renal tubular epithelial cells (TECs) were isolated and exposed to high glucose levels (15 and 30 mM) in vitro and Klotho levels were measured with qPCR and quantitative immunofluorescence. Klotho mRNA expression was quantified in kidneys obtained from long term (3 and 8 months) diabetic Ins2Akita mice and normoglycemic control mice.ResultsNo significant differences in sKlotho levels were observed between diabetic patients with and without MVD (527 (433–704) pg/mL, n = 35), non-diabetic MVD patients (517 (349–571) pg/mL, n = 27), and healthy control subjects (435 (346–663) pg/mL, n = 15). High glucose (15 and 30 mM) did not alter Klotho expression in TECs. Long-term hyperglycemia in diabetic Ins2Akita mice (characterized by increased HbA1c levels [12.9 ± 0.3% (3 months) and 11.3 ± 2.0% (8 months)], p < 0.05 vs. non-diabetic mice) did not affect renal Klotho mRNA expression.ConclusionsThese data indicate that sKlotho levels are not affected in type 2 diabetes patients with and without MVD. Furthermore, hyperglycemia per se does not affect renal Klotho production. As type 2 diabetes does not alter sKlotho levels, sKlotho does not seem to play a major role in the pathogenesis of MVD in type 2 diabetes.

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Section: Methodsmentioning

confidence: 99%

Circulating alpha-klotho levels are not disturbed in patients with type 2 diabetes with and without macrovascular disease in the absence of nephropathy

Ark

Hammes

Dijk

et al. 2013

Cardiovasc Diabetol

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“…22 Moreover, decreased secretion of NO and vascular endothelial growth factor (VEGF), reduced activity of superoxide dismutase, and impaired function, such as migration and tube formation, are observed in activated late EPCs after exposure to a hyperglycemic condition 23 or advanced glycation end products. 24 Reduced number and function of EPCs are also more prevalent in patients with type 1 and type 2 DM with diabetic nephropathy [25][26][27][28] and macrovascular 26,[29][30][31][32][33] complications and correlate with the degree of atherosclerosis. 34 These observations suggest that the burden of DM-related cardiovascular complications correlates with the number and function of EPCs: alterations in EPCs may contribute to the development and progression of atherosclerosis in patients with DM.…”

Section: Yiu and Tse Diabetes Mellitus And Endothelial Progenitor Celmentioning

confidence: 99%

Specific Role of Impaired Glucose Metabolism and Diabetes Mellitus in Endothelial Progenitor Cell Characteristics and Function

Yiu

Tse

2014

ATVB

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Abstract-The disease burden of diabetes mellitus (DM) and its associated cardiovascular complications represent a growing and major global health problem. Recent studies suggest that circulating exogenous endothelial progenitor cells (EPCs) play an important role in endothelial repair and neovascularization at sites of injury or ischemia. 1 This has been attributed to the occurrence of endothelial dysfunction that leads to the initiation and progression of atherosclerotic vascular disease 2 and impaired neovascularization after ischemia induced by hyperglycemia. 3,4 In patients with impaired glucose metabolism and DM, the vascular endothelium is challenged by inflammation, reactive oxygen species, and deletion of endothelial nitric oxide synthase (eNOS) with resultant endothelial dysfunction.2,5-7 The depletion and dysfunction of the circulating endothelial progenitor cells (EPCs) are thought to underlie the endothelial dysfunction in DM. In this review, the possible mechanisms, functional consequences, and the potential therapeutic approach for impaired EPCs in DM are discussed. A systematic literature search for full-text papers in the English language was performed using MEDLINE, Embase, and the Cochrane library through to February 2014. In the search phrases used, the following terms were combined with the phrase AND Diabetes: endothelial progenitor cells, cardiovascular disease, myocardial infarction, and stroke.

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“…Outgrowth of smooth muscle progenitor cells from PBMCs in diabetic patients does not appear to be balanced by the outgrowth of CACs [100], implying a differentiation drift towards smooth muscle at the expense of the endothelial phenotype. In the same study, however, the level of putative CD14 + CD105 + smooth muscle progenitors was increased in non-diabetic patients with peripheral arterial disease, but was not associated with diabetes [100]. Although putative smooth muscle progenitor cells have been isolated from peripheral blood and BM [35], whether BM-derived cells contribute to smooth muscle hyperplasia in atherosclerotic plaques is still debated.…”

Section: Monocyte-macrophage Polarisationmentioning

confidence: 95%

“…It also promotes the differentiation of BM progenitor cells toward the smooth muscle phenotype [99]. Outgrowth of smooth muscle progenitor cells from PBMCs in diabetic patients does not appear to be balanced by the outgrowth of CACs [100], implying a differentiation drift towards smooth muscle at the expense of the endothelial phenotype. In the same study, however, the level of putative CD14 + CD105 + smooth muscle progenitors was increased in non-diabetic patients with peripheral arterial disease, but was not associated with diabetes [100].…”

Section: Monocyte-macrophage Polarisationmentioning

confidence: 99%

A reappraisal of the role of circulating (progenitor) cells in the pathobiology of diabetic complications

Fadini

2013

Diabetologia

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Traditionally, the development of diabetic complications has been attributed to the biochemical pathways driving hyperglycaemic cell damage, while reparatory mechanisms have been long overlooked. A more comprehensive view of the balance between damage and repair suggests that an impaired regenerative capacity of bone marrow (BM)-derived cells strongly contributes to defective re-endothelisation and neoangiogenesis in diabetes. Although recent technological advances have redefined the biology and function of endothelial progenitor cells (EPCs), interest in BM-derived vasculotropic cells in the setting of diabetes and its complications remains high. Several circulating cell types of haematopoietic and non-haematopoietic origin are affected by diabetes and are potentially involved in the pathobiology of chronic complications. In addition to classical EPCs, these include circulating (pro-)angiogenic cells, polarised monocytes/macrophages (M1 and M2), myeloid calcifying cells and smooth muscle progenitor cells, having disparate roles in vascular biology. In parallel with the study of elusive progenitor cell phenotypes, it has been recognised that diabetes induces a profound remodelling of the BM stem cell niche. The alteration of circulating (progenitor) cells in the BM is now believed to be the link among distant end-organ complications. The field is rapidly evolving and interest is shifting from specific cell populations to the complex network of interactions that orchestrate trafficking of circulating vasculotropic cells.

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Type 2 diabetes mellitus is associated with an imbalance in circulating endothelial and smooth muscle progenitor cell numbers

Cited by 52 publications

References 24 publications

Circulating alpha-klotho levels are not disturbed in patients with type 2 diabetes with and without macrovascular disease in the absence of nephropathy

Circulating alpha-klotho levels are not disturbed in patients with type 2 diabetes with and without macrovascular disease in the absence of nephropathy

Specific Role of Impaired Glucose Metabolism and Diabetes Mellitus in Endothelial Progenitor Cell Characteristics and Function

A reappraisal of the role of circulating (progenitor) cells in the pathobiology of diabetic complications

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