scholarly journals CD31 Positive-Extracellular Vesicles from Patients with Type 2 Diabetes Shuttle a miRNA Signature Associated with Cardiovascular Complications

2020 ◽  
Author(s):  
Ada Admin ◽  
Francesco Prattichizzo ◽  
Valeria De Nigris ◽  
Jacopo Sabbatinelli ◽  
Angelica Giuliani ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Major Adverse Cardiovascular Event ◽  
Mirna Signature ◽  
Adverse Cardiovascular Event ◽  
Cross Sectional ◽  
Immunomagnetic Bead ◽  
Diagnostic Potential

Innovative biomarkers are needed to improve the management of patients with type 2 diabetes mellitus (T2DM). Blood circulating miRNAs have been proposed as a potential tool to detect T2DM complications but the lack of tissue specificity, among other reasons, has hampered their translation to clinical settings. Extracellular vesicle (EV)-shuttled miRNAs have been proposed as an alternative approach. Here, we adapted an immunomagnetic bead-based method to isolate plasma CD31 positive (<sup>+</sup>) EVs to harvest vesicles deriving from tissues relevant for T2DM complications. Surface marker characterization showed that CD31<sup>+</sup> EVs were also positive for a range of markers typical of both platelets and activated endothelial cells. After characterization, we quantified 11 candidate miRNAs associated with vascular performance and shuttled by CD31<sup>+</sup>EVs in a large (n=218), cross-sectional cohort of patients categorized as T2DM without complications, T2DM with complications, and controls. We found that 10 of the tested miRNAs are affected by T2DM, while the signature composed by miR-146a, -320a, -422a, -451a efficiently identified T2DM patients with complications. Furthermore, another CD31<sup>+</sup>EV-shuttled miRNA signature, i.e. miR-155, -320a, -342-3p, -376, and -422a, detected T2DM patients with a previous major adverse cardiovascular event. Many of these miRNAs significantly correlate with clinical variables held to play a key role in the development of complications. In addition, we show that CD31<sup>+</sup> EVs from patients with T2DM are able to promote the expression of selected inflammatory mRNAs, <i>i.e.</i> <i>CCL2</i>, <i>IL-1α</i>, and <i>TNFα</i>, when administered to endothelial cells <i>in vitro</i>. Overall, these data suggest that the miRNA cargo of plasma CD31<sup>+</sup> EVs is largely affected by T2DM and related complications, <a>encouraging further research to explore the diagnostic potential and the functional role of these alterations. </a>

scholarly journals CD31 Positive-Extracellular Vesicles from Patients with Type 2 Diabetes Shuttle a miRNA Signature Associated with Cardiovascular Complications

2020 ◽  
Author(s):  
Ada Admin ◽  
Francesco Prattichizzo ◽  
Valeria De Nigris ◽  
Jacopo Sabbatinelli ◽  
Angelica Giuliani ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Major Adverse Cardiovascular Event ◽  
Mirna Signature ◽  
Adverse Cardiovascular Event ◽  
Cross Sectional ◽  
Immunomagnetic Bead ◽  
Diagnostic Potential

Innovative biomarkers are needed to improve the management of patients with type 2 diabetes mellitus (T2DM). Blood circulating miRNAs have been proposed as a potential tool to detect T2DM complications but the lack of tissue specificity, among other reasons, has hampered their translation to clinical settings. Extracellular vesicle (EV)-shuttled miRNAs have been proposed as an alternative approach. Here, we adapted an immunomagnetic bead-based method to isolate plasma CD31 positive (<sup>+</sup>) EVs to harvest vesicles deriving from tissues relevant for T2DM complications. Surface marker characterization showed that CD31<sup>+</sup> EVs were also positive for a range of markers typical of both platelets and activated endothelial cells. After characterization, we quantified 11 candidate miRNAs associated with vascular performance and shuttled by CD31<sup>+</sup>EVs in a large (n=218), cross-sectional cohort of patients categorized as T2DM without complications, T2DM with complications, and controls. We found that 10 of the tested miRNAs are affected by T2DM, while the signature composed by miR-146a, -320a, -422a, -451a efficiently identified T2DM patients with complications. Furthermore, another CD31<sup>+</sup>EV-shuttled miRNA signature, i.e. miR-155, -320a, -342-3p, -376, and -422a, detected T2DM patients with a previous major adverse cardiovascular event. Many of these miRNAs significantly correlate with clinical variables held to play a key role in the development of complications. In addition, we show that CD31<sup>+</sup> EVs from patients with T2DM are able to promote the expression of selected inflammatory mRNAs, <i>i.e.</i> <i>CCL2</i>, <i>IL-1α</i>, and <i>TNFα</i>, when administered to endothelial cells <i>in vitro</i>. Overall, these data suggest that the miRNA cargo of plasma CD31<sup>+</sup> EVs is largely affected by T2DM and related complications, <a>encouraging further research to explore the diagnostic potential and the functional role of these alterations. </a>

scholarly journals Serum IL-6 and sIL-6R in type 2 diabetes contribute to impaired capillary-like network formation

2019 ◽  
Vol 127 (2) ◽  
pp. 385-392
Author(s):  
Rian Q. Landers-Ramos ◽  
Jacob B. Blumenthal ◽  
Steven J. Prior
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Glucose Tolerance ◽  
Interleukin 6 ◽  
Network Formation ◽  
Normal Glucose Tolerance ◽  
Normal Glucose

We hypothesized that the serum from individuals with type 2 diabetes mellitus (T2DM) and impaired glucose tolerance (IGT) would reduce in vitro capillary-like network formation compared with normal glucose tolerance (NGT) serum and that this would occur along with higher serum concentrations of inflammatory cytokines and lower concentrations of angiogenic growth factors. Subjects were sedentary, older (55–65 yr) adults with NGT, IGT, or T2DM ( n = 10/group) matched for body mass index. Human retroviral telomerized endothelial cells (HRVT-ECs) or coronary artery endothelial cells (CECs) were used in a capillary-like network formation assay using endothelial basal medium supplemented with 7.5% serum. Quantification of HRVT-EC network length indicated that serum from the T2DM group resulted in 32 and 35% lower network formation than when using serum from the NGT and IGT groups, respectively ( P < 0.05). Serum from T2DM subjects resulted in CEC network formation that was 11 and 8% lower than when using serum from NGT and IGT subjects, respectively ( P < 0.05). Analysis of serum cytokines indicated that IL-6 was 41% and 49% higher in the IGT and T2DM groups, respectively, compared with the NGT group ( P < 0.05) and there was a trend for higher soluble interleukin-6 receptor (sIL-6R; P = 0.06) and IL-8 ( P = 0.08) in the T2DM serum compared with NGT. The use of recombinant IL-6 and sIL-6R at concentrations detected in the T2DM serum also reduced capillary network formation compared with NGT concentrations ( P < 0.05). These results suggest that IL-6 and sIL-6R present in the serum of T2DM individuals impair in vitro endothelial cell function across different cell lines. Our findings may have implications for the microvascular complications associated with T2DM. NEW & NOTEWORTHY Higher concentrations of serum factors, specifically Interleukin-6 and its soluble receptor found in individuals with type 2 diabetes (T2DM) appear to impair endothelial cell capillary-like network formation compared with those present in serum from individuals with impaired glucose tolerance and normal glucose tolerance. This may have implications for the vascular complications associated with T2DM.

Vitamin D and Insulin Action and Secretion –An Overview of Current Understanding and Future Perspectives

2010 ◽  
Vol 6 (2) ◽  
pp. 13 ◽  
Author(s):  
Hanne L Gulseth ◽  
Cecilie Wium ◽  
Kåre I Birkeland ◽  
◽  
◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Vitamin D ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Current Knowledge ◽  
Vitamin D Status ◽  
Cross Sectional ◽  
Indirect Measures

Impaired vitamin D status has been linked to the development of type 2 diabetes. This review summarises the current knowledge of the effects of vitamin D on insulin action and secretion. Animal andin vitrostudies suggest an effect of vitamin D on insulin action and secretion. The effects of vitamin D status in humans are not as clear, however, and cross-sectional data on insulin sensitivity and secretion are inconclusive. Intervention studies are few and often suffer from inadequate design including short duration, low sample power, low dose of vitamin D or use of indirect measures of insulin sensitivity and secretion. Despite some plausible biological mechanisms for an effect of vitamin D on both insulin secretion and action, more evidence is needed to decide whether vitamin D plays an important role in the pathophysiology of type 2 diabetes.

scholarly journals Association of high density lipoprotein levels with advancing age in type 2 diabetes patients in Tertiary Hospital.

2019 ◽  
Vol 26 (09) ◽  
pp. 1471-1476
Author(s):  
Shahzad Alam Khan ◽  
Iqra Imtiaz
Keyword(s):  
Type 2 Diabetes ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
P Value ◽  
Diabetic Patients ◽  
Adverse Cardiovascular Event ◽  
Type 2 Diabetic Patients ◽  
Cross Sectional ◽  
Low Hdl

Background: HDL particles have several biological functions. Low levels of HDL-cholesterol are responsible for atherosclerotic disease. Type 2 diabetes is a metabolic disease of chronic etiology and low HDL‐cholesterol is frequent finding in diabetics. Levels of HDL with advancing age are inconsistent, few study show decline in HDL with increasing age while others show vice versa results. Objectives: Objective of this study was to establish an association between low HDL levels with advancing age in type 2 diabetic patients. Study Design: Cross sectional descriptive study. Setting: Diabetes Outpatient Department Nishtar Hospital Multan. Period: 6 months extending from March 2018 to August 2018. Materials and Methods: 145 patients with newly or previously diagnosed type 2 diabetes mellitus, age >35 years were considered for the study. Those diabetics who had family history of dyslipidemias (to rule out familial hyperlipidemias) were excluded. Study was started after acquiring permission from ethical committee. All the patients were evaluated for the HDL levels by getting a fasting lipid assay. Results: Out of 145 cases 78 (53.6%) were males while remaining 67 (46.4%) were female. Mean age of the patients was 57.27 + 6.91 years. Mean HDL level was 37.82 + 8.42. It was seen that HDL is low in 116/145 (80%) patients. Those diabetic patients who were < 60 (91 cases), HDL was noticed to be low in 67/91(73.62%) patients. Among patients >60 years (54 cases), HDL was identified to be low in 49/54(90.7%) patients. P-value was found out to be 0.012 Conclusion: Due to falling levels of HDL with advancing age in diabetic patients, there is increase in cardiovascular events in elderly diabetic patients. So the measures which tend to increase HDL level will also give protection against adverse cardiovascular event in elderly diabetics.

scholarly journals Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Lindsay E. Clegg ◽  
Robert C. Penland ◽  
Srinivas Bachina ◽  
David W. Boulton ◽  
Marcus Thuresson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mixed Model ◽  
Cox Regression ◽  
Sglt2 Inhibitor ◽  
Major Adverse Cardiovascular Event ◽  
Cardiovascular Outcomes ◽  
Open Label ◽  
Adverse Cardiovascular Event ◽  
Renal Outcomes

Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. Methods In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. Results In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39–1.17) and EQW alone (0.85, 0.48–1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16–0.90) and compared with EQW (0.41, 0.17–0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94–2.94 mL/min/1.73 m2/year) and EQW alone (+ 2.38, 1.40–3.35 mL/min/1.73 m2/year). Conclusions This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.

scholarly journals Association between Serum Zinc and Calcification Propensity (T50) in Patients with Type 2 Diabetes Mellitus and In Vitro Effect of Exogenous Zinc on T50

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 337
Author(s):  
Shinya Nakatani ◽  
Katsuhito Mori ◽  
Mika Sonoda ◽  
Kozo Nishide ◽  
Hideki Uedono ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Serum Zinc ◽  
In Vitro Test ◽  
Physiological Concentration ◽  
Cross Sectional ◽  
Vitro Effect

Zinc inhibits vascular calcification in vivo and in vitro. Patients with type 2 diabetes mellitus show hypozincemia and are at an elevated risk of cardiovascular events. Recently, an in vitro test (T50-test) was developed for determination of serum calcification propensity and a shorter T50 means a higher calcification propensity. This cross-sectional study investigated the association between serum zinc and T50 in 132 type 2 diabetes mellitus patients with various kidney functions. Furthermore, the effect of exogenous zinc on T50 was also investigated in vitro using separately pooled serum samples obtained from healthy volunteers and patients with hemodialysis. We measured T50 levels using the established nephelometric method. The median (interquartile range) levels of T50 and serum zinc were 306 (269 to 332) min, and 80.0 (70.1 to 89.8) µg/dL, respectively. Serum zinc level showed a weak, but positive correlation with T50 (rs = 0.219, p = 0.012). This association remained significant in multivariable-adjusted analysis, and was independent of known factors including phosphate, calcium, and magnesium. Kidney function and glycemic control were not significantly associated with T50. Finally, in vitro experiments showed that addition of a physiological concentration of exogenous zinc chloride significantly increased serum T50. Our results indicate that serum zinc is an independent factor with a potential role in suppressing calcification propensity in serum.

scholarly journals Significance of Soluble CD93 in Type 2 Diabetes as a Biomarker for Diabetic Nephropathy: Integrated Results from Human and Rodent Studies

2020 ◽  
Vol 9 (5) ◽  
pp. 1394
Author(s):  
Minyoung Lee ◽  
Ho Seon Park ◽  
Min Yeong Choi ◽  
Hak Zoo Kim ◽  
Sung Jin Moon ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Diabetic Nephropathy ◽  
Soluble Form ◽  
Human Umbilical Cord ◽  
Inflammatory Conditions ◽  
Cluster Of Differentiation

Cluster of differentiation 93 (CD93) is a glycoprotein expressed in activated endothelial cells. The extracellular portion of CD93 can be secreted as a soluble form (sCD93) under inflammatory conditions. As diabetic nephropathy (DN) is a well-known inflammatory disease, we hypothesized that sCD93 would be a new biomarker for DN. We prospectively enrolled 97 patients with type 2 diabetes and evaluated the association between serum sCD93 and DN prevalence. The association between CD93 and development of DN was investigated using human umbilical cord endothelial cells (HUVECs) in vitro and diabetic db/db mice in vivo. Subjects with higher sCD93 levels had a lower estimated glomerular filtration rate (eGFR). The sCD93 level was an independent determinant of both the albumin-to-creatinine ratio (ACR) and the eGFR. The risk of prevalent DN was higher in the high sCD93 group (adjusted odds ratio 7.212, 95% confidence interval 1.244–41.796, p = 0.028). In vitro, CD93 was highly expressed in HUVECs and both CD93 expression and secretion were upregulated after lipopolysaccharides (LPS) stimulation. In vivo, peritoneal and urine sCD93 levels and the renal glomerular expression of CD93 were significantly higher in the db/db mice than in the control db/m+ mice. These results suggest the potential of sCD93 as a candidate biomarker associated with DN.

scholarly journals Sodium-glucose cotransporter 2 inhibitor effects on cardiovascular outcomes in chronic kidney disease

2020 ◽  
Vol 35 (Supplement_1) ◽  
pp. i43-i47 ◽  
Author(s):  
Oshini Shivakumar ◽  
Naveed Sattar ◽  
David C Wheeler
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Major Adverse Cardiovascular Event ◽  
Sglt2 Inhibitors ◽  
Adverse Cardiovascular Event ◽  
Sodium Glucose Cotransporter ◽  
Patients With Heart Failure

Abstract Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events, specifically those related to heart failure in patients with type 2 diabetes. Reductions in major adverse cardiovascular event (MACE) outcomes are also observed, but confined largely to patients who have prior cardiovascular disease. Cardiovascular outcome benefits extend to patients with type 2 diabetes and reduced estimated glomerular filtration (eGFR) rate down to 30 mL/min/1.73 m2 and to patients with heart failure but without diabetes. Ongoing trials are exploring whether patients with chronic kidney disease (CKD) but without diabetes will gain similar benefits from this class of agents. Although some safety concerns have emerged, it seems likely that SGLT2 inhibitors will be used more widely in CKD patients to reduce their cardiovascular risk.

scholarly journals Zinc As A Factor Affecting Serum Calcification Propensity in Patients With Type 2 Diabetes Mellitus

2020 ◽  
Author(s):  
Shinya Nakatani ◽  
Katsuhito Mori ◽  
Mika Sonoda ◽  
Kozo Nishide ◽  
Hideki Uedono ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Serum Zinc ◽  
Zinc Level ◽  
Physiological Concentration ◽  
Cross Sectional

Abstract Background: Zinc inhibits vascular calcification in vivo and in vitro. Patients with type 2 diabetes mellitus show hypozincemia and are at an elevated risk of cardiovascular events. Recently, the in vitro test (T50-test) was developed for the determination of serum calcification propensity. This cross-sectional study investigated the association between serum zinc and T50 in type 2 diabetes mellitus patients and the effect of zinc on T50in vitro.Methods: The subjects were 132 type 2 diabetes mellitus patients with various kidney function. We measured T50 levels by the established nephelometric method.Results: The median (interquartile range) levels of T50 and serum zinc were 306 (269 to 332) min, and 80.0 (70.1 to 89.8) µg/dL, respectively. Serum zinc level was significantly and positively correlated with T50 (rs = 0.219, p = 0.012). This association remained significant in multivariable-adjusted analysis, and was independent of known factors including phosphate, calcium, and magnesium. Renal function and glycemic control were not significantly associated with T50. Finally, addition of physiological concentration of exogenous zinc chloride significantly increased the serum T50 in vitro.Conclusions: This is the first report to investigate the association between serum calcification propensity and zinc levels in type 2 diabetes mellitus patients. Our data suggest that serum zinc is an independent factor that inhibits serum calcification propensity.

scholarly journals Type 2 Diabetes-Driven Alterations in Bone Healing and Angiogenesis

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Seungyup Sun ◽  
Fazal Ur Rehman Bhatti ◽  
Ushashi C. Dadwal ◽  
Deepa Sheik Pran Babu ◽  
Anthony J. Perugini III ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Fracture Healing ◽  
Bone Healing ◽  
The United States ◽  
Tube Formation ◽  
Metabolic Phenotype ◽  
Endothelial Cell Function

Background and Hypothesis: Type 2 diabetes (T2D) is prevalent in the United States. T2D patients are at risk for impaired fracture healing due to decreased angiogenesis, which is required for successful bone regeneration. Bone morphogenetic protein-2 (BMP-2) is often used to help orthopedic surgeons with bone healing in difficult cases. Here, we begin characterizing the mechanism by which T2D alters bone healing with or without BMP-2 treatment. We hypothesize that T2D impairs fracture healing by decreasing angiogenesis and endothelial cell function. Project Methods: Using Tie2-CreER;Td-Tomato mice (Tie2CreERT+), we established a high fat diet (HFD)-induced T2D mouse model to compare with control low fat diet (LFD)-fed mice. Mice underwent testing to confirm the T2D-like metabolic phenotype, underwent a femoral critical-size defect surgery that was treated with either saline or BMP-2, and were then assessed biweekly by X-ray imaging over the course of 12 weeks. Finally, bone marrow-derived endothelial cells were collected from these mice to assess changes in endothelial colony and tube formation in vitro. Results: Results showed that the HFD mice acquired the T2D metabolic phenotype. Fracture healing was impaired in the HFD mice, even with BMP-2 treatment. The isolation of BMECs was confirmed by visualization of fluorescent Tie2+ cells. Unexpectedly, in vitro tube formation assays indicated that HFD improved vessel-like formation properties. BMP-2 treatment appeared to improve some vessel-like formation properties compared to control treatment. Conclusion and Potential Impact: This study is ongoing. Further data will need to be collected to better characterize differences in bone healing and angiogenesis in the healing femurs. Still, these data reveal the mechanisms by which T2D impairs bone healing and demonstrate the important difference between examining endothelial cells in vitro vs. in vivo. Future investigations will examine if thrombopoietin, which our group has previously shown to improve both fracture healing and angiogenesis, may be a more effective treatment than BMP-2 in this model.

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