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Circulating angiogenic stem cells in type 2 diabetes are associated with glycemic control and endothelial dysfunction.

ABSTRACT: Circulating angiogenic cells (CACs) of various described phenotypes participate in the regeneration of the damaged endothelium, but the abundance of these cells is highly influenced by external cues including diabetes. It is not entirely clear which CAC populations are most reflective of endothelial function nor which are impacted by diabetes. To answer these questions, we enrolled a human cohort with variable CVD risk and determined relationships between stratified levels of CACs and indices of diabetes and vascular function. We also determined associations between CAC functional markers and diabetes and identified pro-angiogenic molecules which are impacted by diabetes. We found that subjects with low levels of CD34+/AC133+/CD31+/CD45dim cells (CAC-3) had a significantly higher incidence of diabetes (p = 0.004), higher HbA1c levels (p = 0.049) and higher CVD risk scores. Furthermore, there was an association between low CAC-3 levels and impaired vascular function (p = 0.023). These cells from diabetics had reduced levels of CXCR4 and VEGFR2, while diabetics had higher levels of certain cytokines and pro-angiogenic molecules. These results suggest that quantitative and functional defects of CD34+/AC133+/CD31+/CD45dim cells are associated with diabetes and vascular impairment and that this cell type may be a prognostic indicator of CVD and vascular dysfunction.

SUBMITTER: Zafar N

PROVIDER: S-EPMC6188890 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Circulating angiogenic stem cells in type 2 diabetes are associated with glycemic control and endothelial dysfunction.

Zafar Nagma N Krishnasamy Sathya S SS Shah Jasmit J Rai Shesh N SN Riggs Daniel W DW Bhatnagar Aruni A O'Toole Timothy E TE

PloS one 20181015 10

Circulating angiogenic cells (CACs) of various described phenotypes participate in the regeneration of the damaged endothelium, but the abundance of these cells is highly influenced by external cues including diabetes. It is not entirely clear which CAC populations are most reflective of endothelial function nor which are impacted by diabetes. To answer these questions, we enrolled a human cohort with variable CVD risk and determined relationships between stratified levels of CACs and indices of ...[more]

PMID: 30321232

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Project description:Abstract Background An emerging field of research concerns the deleterious effects of type 2 diabetes mellitus (T2DM) on bone. Our group has previously reported a hemoglobin A1c (A1c) threshold of 7% where bone impairment occurs as reflected by reduction in bone turnover markers and deterioration in bone microarchitecture and strength. However, whether poor glycemic control is also associated with underlying derangements in cellular flux remains unclear. Methods Analysis of the baseline data from 42 consecutive men aged 35-65 enrolled in a clinical trial (NCT03887936) at the Michael E DeBakey VA Medical Center, Houston, TX, who were able to provide the outcomes of interest. Inclusion criteria were average fasting morning testosterone from 2 measurements of <300 ng/dl, T2DM and BMI<35 kg/m2. The following variables were assessed: A1c by high performance liquid chromatography; testosterone and estradiol by LC/MS; bone turnover markers and sex hormone binding globulin by ELISA; quantification of osteoblast (OB) progenitors and osteoclast (OC) precursors by flow cytometry; areal bone mineral density (aBMD) and body composition by DXA; and bone microarchitecture and strength by high resolution peripheral quantitative computerized tomography. Results Participants with poorly controlled T2DM (A1c>7%) had significantly lower percent of OB progenitors in circulation than those with A1c≤7% (1.12 ± 0. 079% v 1.47 ± 0.11% of non-B non-T non-NK cells, p=0. 02) when controlling for age, duration of T2DM, free testosterone, and 25-hydroxyvitamin D levels. Higher levels of free testosterone were associated with smaller percentage of OB progenitors (r = -0.31, p = 0. 05). Although the percent of OC precursors in circulation (cells that were dual CD14CD11b+, CD14MCSFR+, or CD14CD120b+) was not significantly related to A1c, it was positively associated with percent of OB progenitors in peripheral blood (r = 0.34, p = 0. 03; r = 0.35, p = 0. 02; r = 0.39, p = 0. 01) respectively. There was a significant positive association between OB progenitors and visceral adipose tissue (VAT) volume (r=0.41, p=0. 009). Although there was no association between osteoblast progenitors and osteocalcin levels (product of mature OBs), osteocalcin negatively correlated with VAT (r=-0.47, p=0. 002). There was no association between OB progenitors and OC precursors with aBMD or bone microarchitecture parameters. Conclusions Poor glycemic control is associated with fewer circulating OB progenitors, as was higher free testosterone levels while the converse was true for VAT. It is possible that the former harms cell viability, while the latter two affect differentiation of OB progenitors into mature OB's; with testosterone promoting, and visceral adipose tissue (via unknown mediators) retarding maturation as suggested by the negative association between osteocalcin and VAT. The positive association between OB progenitors with circulating OC precursors is consistent with the physiologic crosstalk between OB and OC which appears to be preserved in patients with T2D. Presentation: No date and time listed

Project description:The development of type-2 diabetes mellitus (T2DM) and its complications is largely due to the complex interaction between genetic factors and environmental influences, mainly dietary habits and lifestyle, which can either accelerate or slow down disease progression. Recent findings suggest the potential involvement of epigenetic mechanisms as a crucial interface between the effects of genetic predisposition and environmental factors. The common denominator of environmental factors promoting T2DM development and progression is that they trigger an inflammatory response, promoting inflammation-mediated insulin resistance and endothelial dysfunction. Proinflammatory stimuli, including hyperglycemia, oxidative stress, and other inflammatory mediators, can affect epigenetic mechanisms, altering the expression of specific genes in target cells without changes in underlying DNA sequences. DNA methylation and post-translational histone modifications (PTHMs) are the most extensively investigated epigenetic mechanisms. Over the past few years, non-coding RNA, including microRNAs (miRNAs), have also emerged as key players in gene expression modulation. MiRNAs can be actively released or shed by cells in the bloodstream and taken up in active form by receiving cells, acting as efficient systemic communication tools. The miRNAs involved in modulation of inflammatory pathways (inflammamiRs), such as miR-146a, and those highly expressed in endothelial lineages and hematopoietic progenitor cells (angiomiRs), such as miR-126, are the most extensively studied circulating miRNAs in T2DM. However, data on circulating miRNA signatures associated with specific diabetic complications are still lacking. Since immune cells and endothelial cells are primarily involved in the vascular complications of T2DM, their relative contribution to circulating miRNA signatures needs to be elucidated. An integrated approach encompassing different epigenetic mechanisms would have the potential to provide new mechanistic insights into the genesis of diabetes and its severe vascular complications and identify a panel of epigenetic markers with diagnostic/prognostic and therapeutic relevance.

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Circulating angiogenic stem cells in type 2 diabetes are associated with glycemic control and endothelial dysfunction.

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Circulating angiogenic stem cells in type 2 diabetes are associated with glycemic control and endothelial dysfunction.

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