Effect of metformin on the high-density lipoprotein proteome in youth with type 1 diabetes.
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ABSTRACT: Background
Youth with type 1 diabetes (T1D) have normal or elevated High-Density Lipoprotein Cholesterol (HDL-C), however, the function of HDL, partly mediated by the HDL proteome, may be impaired. Metformin can be used as an adjunct therapy in youth with T1D, but its effects on the HDL proteome are unknown.Objective
To determine the effect of metformin on the HDL proteome.Subjects
Youth (12-20 years old) with T1D who had a BMI > 90th percentile, HbA1c > 8.0% and Tanner stage 5.Methods
Double-blinded, placebo-controlled randomized sub-study. We examined the effects of metformin (n = 25) or placebo (n = 10) after 6 months on HDL proteome. Changes in HDL proteins were measured by data-independent acquisition (DIA) mass spectrometry and compared between treatment groups. As a secondary outcome, associations between proteins of interest and the most studied function of HDL, the cholesterol efflux capacity (CEC), was examined.Results
The relative abundance of 84 HDL-associated proteins were measured. Two proteins were significantly affected by metformin treatment, peptidoglycan recognition protein 2 (PGRP2; +23.4%, p = .0058) and alpha-2-macroglobulin (A2MG; +29.8%, p = .049). Metformin did not significantly affect CEC. Changes in affected HDL proteins did not correlate with CEC.Conclusions
Despite having little effect on HDL-C, metformin increased PGRP2 and A2MG protein on HDL in youth with T1D, but had no significant effect on CEC. Further studies are needed to understand the impact of PGRP2 and A2MG on other HDL functions.
SUBMITTER: Gourgari E
PROVIDER: S-EPMC8279605 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:(1) Background: high-density lipoproteins (HDLs) exhibit antioxidant and anti-inflammatory properties that play an important role in preventing the development of atherosclerotic lesions and possibly also diabetes. In turn, both type 1 diabetes (T1D) and type 2 diabetes (T2D) are susceptible to having deleterious effects on these HDL functions. The objectives of the present review are to expound upon the antioxidant and anti-inflammatory functions of HDLs in both diabetes in the setting of atherosclerotic cardiovascular diseases and discuss the contributions of these HDL functions to the onset of diabetes. (2) Methods: this narrative review is based on the literature available from the PubMed database. (3) Results: several antioxidant functions of HDLs, such as paraoxonase-1 activity, are compromised in T2D, thereby facilitating the pro-atherogenic effects of oxidized low-density lipoproteins. In addition, HDLs exhibit diminished ability to inhibit pro-inflammatory pathways in the vessels of individuals with T2D. Although the literature is less extensive, recent evidence suggests defective antiatherogenic properties of HDL particles in T1D. Lastly, substantial evidence indicates that HDLs play a role in the onset of diabetes by modulating glucose metabolism. (4) Conclusions and perspectives: impaired HDL antioxidant and anti-inflammatory functions present intriguing targets for mitigating cardiovascular risk in individuals with diabetes. Further investigations are needed to clarify the influence of glycaemic control and nephropathy on HDL functionality in patients with T1D. Furthermore, exploring the effects on HDL functionality of novel antidiabetic drugs used in the management of T2D may provide intriguing insights for future research.
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Project description:BackgroundThe association of serum high-density lipoprotein cholesterol (HDL-C) with microalbuminuria in type 2 diabetes mellitus (T2DM) remains controversial. Therefore, a cross-sectional study was conducted on patients with T2DM to investigate the relationship of HDL-C with microalbuminuria.MethodsA total of 524 participants with T2DM were recruited in this cross-sectional study. The patients were divided into four groups according to serum HDL-C quartile. A nonparametric test was employed to assess the relationships across quartiles with clinical parameters and demographics. Multivariate logistic regression analysis was further performed.ResultsOf the 524 patients, 138 (26.3%) were found to have microalbuminuria by urinary albumin excretion rate determination. Serum HDL-C levels in microalbuminuria group were significantly lower than those in non-microalbuminuria group (1.04 (0.90-1.21) vs. 1.10 (0.94-1.31) mmol/L, P = 0.002). The nonparametric test for trend showed that the prevalence of microalbuminuria was significantly reduced for subjects of the fourth quartile of HDL-C compared to the first to third quartile (13.5% vs. 33.1%, 28.6%, 29.4%, P = 0.001). Multivariate logistic regression showed that subjects within the highest quartile of HDL-C had lower odds of microalbuminuria than those within the lowest quartile of HDL-C (OR = 0.17, 95% CI 0.15-0.52, P = 0.004).ConclusionsHigher levels of serum HDL-C were associated with decreased rates of microalbuminuria in T2DM patients.
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Project description:Boosting low high-density lipoprotein (HDL) levels is a current strategy for preventing clinical events that result from cardiovascular disease. We previously showed that HDL(3) of subjects with coronary artery disease is enriched in apolipoprotein E and that the lipoprotein carries a distinct protein cargo. This observation suggests that altered protein composition might affect the antiatherogenic and antiinflammatory properties of HDL. We hypothesized that an intervention that increases HDL levels-combined statin and niacin therapy-might reverse these changes.HDL(3) isolated from 6 coronary artery disease subjects before and 1 year after combination therapy was analyzed by liquid chromatography-Fourier transform-mass spectrometry. Alterations in protein composition were detected by spectral counting and confirmed with extracted ion chromatograms. We found that combination therapy decreased the abundance of apolipoprotein E in HDL(3) while increasing the abundance of other macrophage proteins implicated in reverse cholesterol transport. Treatment-induced decreases in apolipoprotein E levels of HDL(3) were validated biochemically in a second group of 18 coronary artery disease subjects. Interestingly, the changes in HDL(3) proteome with niacin/statin treatment resulted in a protein composition that more closely resembled that of HDL(3) in healthy control subjects.Combined statin and niacin therapy partially reverses the changes in the protein composition seen in HDL(3) in coronary artery disease subjects. Our observations raise the possibility that quantifying the HDL proteome could provide insights into the therapeutic efficacy of antiatherosclerotic interventions.
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Project description:Toyoshima MTK. Proteomics and functionality of high-density lipoprotein subfractions and subclinical cardiovascular disease in type 1 diabetes mellitus. Faculdade de Medicina, Universidade de Sao Paulo 2021.
2021-08-13 | MSV000087986 | MassIVE