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No detectable differential microRNA expression between non-atherosclerotic arteries of type 2 diabetic patients (treated or untreated with metformin) and non-diabetic patients.

ABSTRACT: BACKGROUND:Type 2 diabetes mellitus (T2DM) is an independent risk factor of cardiovascular disease (CVD), however, the underlying mechanisms are largely unknown. Using non-atherosclerotic internal thoracic arteries (ITAs) obtained from coronary artery bypass grafting, we previously identified a distinct elevation in the level of proteins comprising the arterial basement membrane in T2DM patients not treated with metformin. Altered transcription of genes encoding these proteins has not been observed, indicating alternative mechanisms of dysregulation. METHODS:In this study we screened for differential expression of arterial microRNAs (miRNAs) in T2DM patients to test the hypothesis that the arterial protein signature of diabetic patients is associated with dysregulation at the miRNA level, and further to lay the foundation for novel hypotheses addressing the increased CVD risk of T2DM patients. MiRNA isolated from fresh frozen ITAs [from 18 T2DM- (10 of which were subject to metformin treatment) and 30 non-diabetes mellitus (non-DM) patients] were analyzed by microarray, and miRNAs isolated from formalin-fixated paraffin-embedded (FFPE) ITAs were analyzed by quantitative PCR (qPCR) in an independent study group [26 T2DM- (15 of which were subject to metformin treatment) and 26 non-DM patients] to determine expression levels of miRNAs in a pre-defined panel of 12 miRNAs. RESULTS:Unexpectedly, no miRNAs were found to be affected by T2DM status in either of the two study groups. CONCLUSIONS:Our data suggest that alternatives to microRNA dysregulation underlie T2DM-associated protein changes in non-atherosclerotic arteries.

SUBMITTER: Steffensen LB

PROVIDER: S-EPMC5958402 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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No detectable differential microRNA expression between non-atherosclerotic arteries of type 2 diabetic patients (treated or untreated with metformin) and non-diabetic patients.

Steffensen Lasse Bach LB Feddersen Søren S Preil Simone Rørdam SR Rasmussen Lars Melholt LM

Cardiovascular diabetology 20180517 1

<h4>Background</h4>Type 2 diabetes mellitus (T2DM) is an independent risk factor of cardiovascular disease (CVD), however, the underlying mechanisms are largely unknown. Using non-atherosclerotic internal thoracic arteries (ITAs) obtained from coronary artery bypass grafting, we previously identified a distinct elevation in the level of proteins comprising the arterial basement membrane in T2DM patients not treated with metformin. Altered transcription of genes encoding these proteins has not be ...[more]

PMID: 29773082

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Project description:BackgroundThe association between prolong metformin usage and B12 deficiency has been documented. However, the prevalence estimates of metformin-induced vitamin B12 deficiency showed substantial disparity among studies due to varied study definitions of vitamin B12 deficiency. Metformin blocks the calcium dependent absorption of the vitamin B12-Intrinsic Factor complex at the terminal ileum. Lack of intrinsic factor due to the presence of auto-antibodies to parietal cells (IFA) could lead to vitamin B12 deficiency and subsequently cause peripheral neuropathy. We investigated the prevalence of vitamin B12 deficiency using more sensitive, combined markers of vitamin B12 status (4cB12) and the immuno-biochemical mediators of vitamin B12 deficiency.MethodsIn this observational study, 200 consecutive consenting metformin-treated T2DM patients, aged 35 and above, attending the diabetic clinic at KATH were recruited. Vitamin B12 deficiency was classified based on the Fedosov age-normalized wellness quotient. Anthropometric measurement was taken as well as blood samples for immunological and biochemical mediators. Peripheral neuropathy was assessed using the Michigan Neuropathy Screening Instrument (MNSI). Statistical analysis was performed using the R Language for Statistical Computing.ResultsUsing the combined indicator (4cB12), the prevalence of metformin induced vitamin B12 deficiency was 40.5% whilst the prevalence of MNSI-Q and MNSI-PE diabetic neuropathy was 32.5% and 6.5% respectively. Participants with vitamin B12 deficiency had significantly higher levels of IFA, GPA, TNF-α, TC, LDL and albumin compared to those with normal vitamin B12 levels (p < 0.05). Correlation analysis revealed a statistically significant negative association between 4cB12 and the immunological markers [IFA (rs = -0.301, p<0.0001), GPA (rs = -0.244, p = 0.001), TNF-α (rs = -0.242, p = 0.001) and IL-6 (rs = -0.145, p = 0.041)]. Likewise, 4cB12 was negatively associated with TC (rs = -0.203, p = 0.004) and LDL (rs = -0.222, p = 0.002) but positively correlated with HDL (rs = 0.196, p = 0.005).ConclusionVitamin B12 deficiency and diabetic neuropathy are very high among metformin-treated T2DM patients and it is associated with increased GPA, IFA, TNF-α and cardiometabolic risk factors (higher LDL and TC and lower HDL). Upon verification of these findings in a prospective case-control study, it may be beneficial to include periodic measurement of Vitamin B12 using the more sensitive combined indicators (4cB 12) in the management of patients with T2DM treated with metformin in Ghana.

Project description:INTRODUCTION:People living with HIV (PLWH) on antiretroviral therapy (ART) do not progress to AIDS. However, they still suffer from an increased risk of inflammation-associated complications. HIV persists in long-lived CD4+ T?cells, which form the major viral reservoir. The persistence of this reservoir despite long-term ART is the major hurdle to curing HIV. Importantly, the size of the HIV reservoir is larger in individuals who start ART late in the course of infection and have a low CD4+/CD8+ ratio. HIV reservoir size is also linked to the levels of persistent inflammation on ART. Thus, novel strategies to reduce immune inflammation and improve the host response to control the HIV reservoir would be a valuable addition to current ART. Among the different strategies under investigation is metformin, a widely used antidiabetic drug that was recently shown to modulate T-cell activation and inflammation. Treatment of non-diabetic individuals with metformin controls inflammation by improving glucose metabolism and by regulating intracellular immunometabolic checkpoints such as the adenosin 5 monophosphate activated protein kinase and mammalian target of rapamycin, in association with microbiota modification. METHODS AND ANALYSIS:22 PLWH on ART for more than 3 years, at high risk of inflammation or the development of non-AIDS events (low CD4+/CD8+ ratio) will be recruited in a clinical single-arm pilot study. We will test whether supplementing ART with metformin in non-diabetic HIV-infected individuals can reduce the size of the HIV reservoir as determined by various virological assays. The expected outcome of this study is a reduction in both the size of the HIV reservoir and inflammation following the addition of metformin to ART, thus paving the way towards HIV eradication. ETHICS AND DISSEMINATION:Ethical approval: McGill university Health Centre committee number MP-37-2016-2456. Canadian Canadian Institutes of Health Research/Canadian HIV Trials Network (CTN) protocol CTNPT027. Results will be made available through publication in peer-reviewed journals and through the CTN website. TRIAL REGISTRATION NUMBER:NCT02659306.

Dataset Information

No detectable differential microRNA expression between non-atherosclerotic arteries of type 2 diabetic patients (treated or untreated with metformin) and non-diabetic patients.

Publications

No detectable differential microRNA expression between non-atherosclerotic arteries of type 2 diabetic patients (treated or untreated with metformin) and non-diabetic patients.

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