Pathogenetic Loop Between Diabetes and Cell Senescence

Testa, Roberto; Ceriello, Antonio

doi:10.2337/dc07-1534

Cited by 23 publications

(17 citation statements)

References 19 publications

(18 reference statements)

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“…Since accumulation of senescent cells in the elderly seems to be a detrimental factor in aging and age-related disorders [11], and differences in circulating miRNAs have been detected in a variety of age-associated diseases [12-15], it is conceivable that the conditions interfering with miRNA synthesis and/or release are related both to aging and disease processes. Interestingly, comparison of the miRNAs involved in cellular senescence with those involved in age-associated diseases showed that these in vitro and in vivo conditions share several miRNAs [16-18].…”

Section: Introductionmentioning

confidence: 99%

Age- and glycemia-related miR-126-3p levels in plasma and endothelial cells

Olivieri

Bonafè

Spazzafumo

et al. 2014

Aging

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108

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Circulating miR-126-3p levels were determined in 136 healthy subjects (CTRs) aged 20-90 years and 193 patients with type-2 diabetes mellitus (T2DMs) aged 40-80 years, to explore the combined effect of age and glycemic state on miR-126-3p expression. Moreover, intra/extracellular miR-126-3p levels were measured in human endothelial cells (HUVECs) undergoing senescence under normo/hyper-glycemic conditions.Plasma miR-126-3p was significantly higher in the oldest compared with the youngest CTRs (<45 vs. >75 years; relative expression: 0.27±0.29 vs. 0.48±0.39, p=0.047). Age-based comparison between CTRs and T2DM demonstrated significantly different miR-126-3p levels only in the oldest (0.48±0.39 vs. 0.22±0.23, p<0.005). After multiple adjustments, miR-126-3p levels were seen to be lower in patients with poor glycemic control, compared with age-matched CTRs.The age-related increase in plasma miR-126-3p found in CTRs was paralleled by a 5/6-fold increase in intra/extracellular miR-126-3p in in vitro-cultured HUVECs undergoing senescence. Notably, significant down-regulation of SPRED-1 protein, a validated miR-126-3p target, was found in senescent HUVECs. Moreover, miR-126-3p expression was down-regulated in intermediate-age HUVECs grown in high-glucose medium until senescence.Aging/senescence-associated miR-126-3p up-regulation is likely a senescence-associated compensatory mechanism that is blunted when endothelial cells are exposed to high glucose levels, a phenomenon that probably occurs in vivo in T2DM patients.

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Section: Introductionmentioning

confidence: 99%

Age- and glycemia-related miR-126-3p levels in plasma and endothelial cells

Olivieri

Bonafè

Spazzafumo

et al. 2014

Aging

Self Cite

108

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“…In this context, a variety of evidence suggests that cellular senescence is involved in obesity [63] and development of type 2 diabetes [64]. Moreover, in the vessel wall, Cu bound primarily to Cp can contribute to local redox-dependent reactions [65–67] that might be involved in promoting a senescent phenotype.…”

Section: Discussionmentioning

confidence: 99%

Effect of 6-month caloric restriction on Cu bound to ceruloplasmin in adult overweight subjects

Piacenza¹,

Malavolta²,

Basso³

et al. 2015

The Journal of Nutritional Biochemistry

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In a randomized clinical trial of calorie restriction (CR), we demonstrated that important cardiovascular disease (CVD) biomarkers were favorably influenced by CR alone and in conjunction with physical exercise. The aim of this study was to examine the effects of CR with or without exercise on Copper bound to Ceruloplasmin (CuCp), a well-known biomarker for CVD, in overweight men and women enrolled in the CALERIE phase 1 study. Forty-six individuals were randomized to one of four groups for 6 months: control: healthy weight maintenance; CR: 25% CR from baseline energy requirements; CR + exercise: 12.5% CR and 12.5% through aerobic exercise; low calorie diet: low calorie diet until 15% reduction in body weight followed by weight maintenance diet. CuCp was determined in fasting blood samples by an HPLC-ICP-MS methodology and compared with changes in body composition and markers of CVD. After 6 months, CR combined with exercise induced a decrease in plasma concentration of CuCp. CuCp was inversely correlated with insulin sensitivity (Si) at baseline and after 6 months of intervention. A cluster analysis showed that the percent change of weight after 6 months of intervention was the most important variable that could discriminate the intervention groups. The percent change of CuCp was the only other variable selected by the analysis. Decreased CuCp in overweight subjects by CR combined with exercise suggest a positive effect of this intervention on metabolic health. Further studies to explain the relationship between weight loss and CuCp and its relevance for cardiovascular health are needed.

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“…Recently, the senescence of EPCs has been assumed as an important cause/consequence of diabetes and its complications [18], the reasons of which lie in that hyperglycemia in vivo could product free radicals and generate oxidative stress, triggering cellular senescence in DM. However, the mechanisms remain largely unknown.…”

Section: The Mechanisms Of Epcs Dysfunction In Dmmentioning

confidence: 99%

The possible role of ribosomal protein S6 kinase 4 in the senescence of endothelial progenitor cells in diabetes mellitus

Yin

Fan

Huang

et al. 2012

Cardiovasc Diabetol

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BackgroundThe decrease and dysfunction of endothelial progenitor cells (EPCs) has been assumed as an important cause/consequence of diabetes mellitus (DM) and its complications, in which the senescence of EPCs induced by hyperglycemia may play an immensurable role. However, the mechanisms of EPCs senescence has not been fully investigated. Recently, ribosomal protein S6 kinase 4 (RSK4), a member of serine/threomine (Ser/Thr) kinase family and p53-related gene, is reported to regulate the replicative and stress-induced senescence of different cells.Presentation of the hypothesisThese above lead to consideration of an evidence-based hypothesis that RSK4 may serve as a mediator of EPCs senescence in DM.Testing the hypothesisEPCs of healthy subjects and DM patients are isolated from peripheral blood and incubated with high glucose (HG). Then, the EPCs senescence would be detected by senescence associated β-galactosides (SA-β-gal) staining. Meanwhile, the RSK4 expression is assessed by RT-PCR and western blot. Moreover, overexpressing or RNA interfering of RSK4 in EPCs to investigate the relationship between RSK4 expression and the senescence of EPCs are necessary to substantiate this hypothesis. Also, studies on possible upstream and downstream factors of RSK4 would be explored to reveal the RSK4-mediated senescence pathway in EPCs.Implications of the hypothesisIf proved, this hypothesis will provide another mediator of EPCs senescence, and may establish a novel pathogenesis for DM and further benefit to the management of DM.

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Pathogenetic Loop Between Diabetes and Cell Senescence

Cited by 23 publications

References 19 publications

Age- and glycemia-related miR-126-3p levels in plasma and endothelial cells

Age- and glycemia-related miR-126-3p levels in plasma and endothelial cells

Effect of 6-month caloric restriction on Cu bound to ceruloplasmin in adult overweight subjects

The possible role of ribosomal protein S6 kinase 4 in the senescence of endothelial progenitor cells in diabetes mellitus

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