Towards a blood test for heart failure: the potential use of circulating natriuretic peptides.
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Biomarkers↗
Biomedical subjects
L L Ng
Publications and source records attributed to L L Ng.
Red cell Na+/Li+ countertransport and Na+/H+ exchanger isoforms in human proximal tubules.
BACKGROUND: Increased activity of the Na+/Li+ countertransporter (SLC) is a well-recognized intermediate phenotype of hypertension and diabetic nephropathy and may indicate a predisposition to hypertension. Previous work has attempted to link this membrane transport marker to altered Na+ reabsorption in the proximal tubule. Since the Na+/H+ exchanger (NHE) isoforms 1 and 3 are expressed in the basolateral and apical membranes of the proximal tubule, respectively, we investigated the relationship between these transport proteins and red cell SLC to examine whether the peripheral blood transport phenotype is associated with altered levels of transport proteins in the proximal tubule. METHODS: Proximal tubules were prepared from human nephrectomy specimens. NHE-1 and NHE-3 were detected on Western blots by specific antibodies. Red cell SLC was also measured. RESULTS: Both NHE-1 and NHE-3 proteins were demonstrated, with molecular weights of 97 and 85 kD, respectively. SLC was very strongly correlated with the level of NHE-3 protein (r = 0.78, P < 0.001) and was negatively related to NHE-1 protein (r = -0.32). In multiple regression analysis, only NHE-3 and NHE-1 protein levels were significant predictors of red cell SLC, accounting for up to about 70% of the variance of this parameter. CONCLUSIONS: We conclude that red cell SLC may be a marker of increased NHE-3 protein expression in the proximal tubule, which may account for the blunted pressure natriuresis and predisposition to hypertension.
Adult↗
Profile of plasma N-terminal proBNP following acute myocardial infarction; correlation with left ventricular systolic dysfunction.
AIMS: The aims of this study were to describe the temporal pattern of plasma N-terminal pro-brain natriuretic peptide, to examine the optimum time of sampling and to compare plasma N-terminal pro-brain natriuretic peptide to clinical criteria in terms of identification of impaired left ventricular systolic function following acute myocardial infarction. METHODS AND RESULTS: Measurements of N-terminal pro-brain natriuretic peptide were made in 60 patients at 14-48 h, 49-72 h, 73-120 h, 121-192 h following myocardial infarction and at 6 weeks in survivors. Left ventricular wall motion index was assessed during hospitalization (WMI-1) and at 6 weeks (WMI-2). N-terminal pro-brain natriuretic peptide levels were elevated at all time points, to a greater extent in anterior compared to inferior infarction (P < 0.05). A biphasic profile of plasma concentration was observed in anterior infarction with peaks at 14-48 h and 121-192 h. This was sustained at 6 weeks. N-terminal pro- brain natriuretic peptide at 73-120 h was the best independent predictor of WMI-1 (P < 0.005). N-terminal pro-brain natriuretic peptide was higher at all times in patients who received ACE inhibitor therapy compared to those who did not (P < 0.005). N-terminal pro-brain natriuretic peptide at 73-120 h (R(2) = 17.7%, P = 0.005) and previous myocardial infarction (R(2) = 5.3%, P < 0.05) were independent predictors of poor outcome (WMI-2 < or = 1.2 or death by 6 weeks). CONCLUSIONS: A biphasic pattern of plasma N-terminal pro-brain natriuretic peptide is seen after anterior myocardial infarction. Plasma level is strongly correlated to wall motion index soon after and remote from acute myocardial infarction. Plasma N-terminal pro-brain natriuretic peptide measured later in hospitalization better predicts poor outcome following myocardial infarction than when it is measured in the immediate post infarction period.
Adult↗
Plasma N terminal pro-brain natriuretic peptide and cardiotrophin 1 are raised in unstable angina.
OBJECTIVE: To compare circulating concentrations of N terminal pro-brain natriuretic peptide (N-BNP) and cardiotrophin 1 in stable and unstable angina. DESIGN AND SETTING: Observational study in a teaching hospital. PATIENTS: 15 patients with unstable angina, 10 patients with stable angina, and 15 controls. MAIN OUTCOME MEASURES: Resting plasma N-BNP and cardiotrophin 1 concentrations. RESULTS: N-BNP concentration (median (range)) was 714 fmol/ml (177-3217 fmol/ml) in unstable angina, 169.5 fmol/ml (105.7-399.5 fmol/ml) in stable angina (p = 0.005 v unstable angina), and 150.5 fmol/ml (104. 7-236.9 fmol/ml) in controls (p < 0.0001 v unstable angina; NS v stable angina). Cardiotrophin 1 concentration was 142.5 fmol/ml (42. 2-527.4 fmol/ml) in unstable angina, 73.2 fmol/ml (41.5-102.1 fmol/ml) in stable angina (p < 0.05 v unstable angina), and 27 fmol/ml (6.9-54.1 fmol/ml) in controls (p < 0.0005 v stable angina; p < 0.0001 v unstable angina). Log cardiotrophin 1 correlated with log N-BNP in unstable angina (r = 0.93, p < 0.0001). CONCLUSIONS: Both circulating N-BNP and cardiotrophin 1 are raised in unstable angina, while cardiotrophin 1 alone is raised in stable angina. The role of cardiotrophin 1 and the relation between cardiotrophin 1 and N-BNP in myocardial ischaemia remain to be defined.
Aged↗
Antiproliferative effect of UTP on human arterial and venous smooth muscle cells.
We have investigated the hypothesis that responses associated with proliferation are regulated by extracellular nucleotides such as ATP and UTP in cultured human vascular smooth muscle cells (VSMC) derived from internal mammary artery (IMA) and saphenous vein (SV). Platelet-derived growth factor (PDGF), ATP, and UTP each generated an increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)) in both IMA- and SV-derived cells in the absence of detectable inositol 1,4,5-trisphosphate production. ATP alone had no effect on [(3)H]thymidine incorporation into DNA, but with a submaximal concentration of PDGF it raised [(3)H]thymidine incorporation in SV- but not IMA-derived cells. UTP alone also was without effect on [(3)H]thymidine incorporation or cell number. However, in both SV- and IMA-derived cells, UTP reduced the PDGF-stimulated [(3)H]thymidine response and PDGF-stimulated cell proliferation. This cannot be explained by an inhibitory effect on the p42/p44 mitogen-activated protein kinase (MAPK) cascade, since this response to PDGF was not attenuated by UTP. We conclude that, in human VSMC of both arterial and venous origin, UTP acts as an anti-proliferative regulator.
Adenosine Triphosphate↗
Na+/H+ exchanger activity and phosphorylation in temperature-sensitive immortalized proximal tubule cell lines derived from the spontaneously hypertensive rat.
Freshly isolated proximal tubules from the spontaneously hypertensive rat (SHR) demonstrate elevated Na(+)/H(+) exchanger (NHE) activity, but the underlying mechanism is unclear. Because of the difficulties in preparing sufficient numbers of proximal tubule cells for detailed biochemical studies, we have generated cell lines from SHR and Wistar-Kyoto rat (WKY) proximal tubule cells. Cell lines were obtained by transforming the cells with an origin-defective mutant of simian virus 40 encoding a heat-labile T antigen (tsA58 transformant). Such cells proliferate at the permissive temperature of 33 degrees C, but growth is abolished at the restrictive temperature of 39 degrees C. The predominant NHE isoform expressed was isoform 1, as determined by sensitivity to HOE-694 (3-methylsulphonyl-4-piperidinobenzoyl guanidine) and Western blotting using specific polyclonal antisera to NHE-1. NHE-3 protein was also present. Northern blots of poly(A) mRNA extracts of the cell lines revealed a low abundance of transcripts for NHE-2, -3 and -4, with no systematic difference between the lines. Although the intracellular pH was similar in the SHR and WKY lines, HOE-694-sensitive H(+) efflux due to NHE-1 was substantially elevated in SHR lines compared with WKY lines (95.0+/-2.8 and 39. 9+/-5.7 mmol.min(-1).l(-1) respectively; P<0.001; n=6). H(+) efflux due to non-Na(+)-dependent mechanisms were similar in lines from the two strains. Western blotting revealed that NHE-1 density was also very similar in SHR and WKY lines, and subcellular fractionation of homogenates indicated that NHE-1 was localized predominantly to plasma membranes. Thus the turnover number of NHE-1 was increased. Immunoprecipitation of (32)P-labelled phosphoproteins from these lines demonstrated an approximately 2-fold higher degree of phosphorylation of NHE-1 in SHR compared with WKY lines. These cell lines form a useful model for defining the biochemical mechanisms leading to the NHE-1 phenotype in the SHR kidney, in addition to investigations of other SHR phenotypic markers.
Animals↗
Elevated circulating cardiotrophin-1 in heart failure: relationship with parameters of left ventricular systolic dysfunction.
Cardiotrophin-1 (CT-1) is a cytokine that has been implicated as a factor involved in myocardial remodelling. The objective of the present study was to establish the relationship between circulating levels of CT-1 and measures of left ventricular size and systolic function in patients with heart failure. We recruited 15 normal subjects [six male; median age 60 years (range 30-79 years)] and 15 patients [11 male; median age 66 years (range 43-84 years)] with a clinical diagnosis of heart failure and echocardiographic left ventricular systolic dysfunction (LVSD). Echocardiographic variables (left ventricular wall motion index, end-diastolic and -systolic volumes, stroke volume, fractional shortening) and plasma CT-1 levels were determined. In patients with LVSD [median wall motion index 0.6 (range 0.3-1.4)], CT-1 was elevated [median 110.4 fmol/ml (range 33-516 fmol/ml)] compared with controls [wall motion index 2 in all cases; median CT-1 level 34.2 fmol/ml (range 6.9-54.1 fmol/ml); P<0.0001]. Log CT-1 was correlated with log wall motion index (r=-0.76, P<0.0001), log left ventricular end-systolic volume (r=0.54, P<0.05), stroke volume (r=-0.60, P=0.007) and log fractional shortening (r=-0.70, P=0.001). In a multivariate model of the predictors of log wall motion index, the only significant predictor was log CT-1 (R(2)=56%, P=0.006). This is the first assessment of the relationship between plasma CT-1 levels and the degree of LVSD in humans, and demonstrates that CT-1 is elevated in heart failure in relation to the severity of LVSD.
Adult↗
An immunoluminometric assay for cardiotrophin-1: a newly identified cytokine is present in normal human plasma and is increased in heart failure.
Cardiotrophin-1, a member of the interleukin-6 related cytokine family which acts via the glycoprotein 130 signalling pathway, may be involved in the process of ventricular remodelling. Its presence in human plasma has never been reported. We have devised a non-radioactive immunoluminometric sensitive and specific assay for CT-1 based on a competitive ligand binding principle. The chemiluminescent label 4-(2-succinimidyl-oxycarbonylethyl)phenyl-10-methylacridinium 9-carboxylate fluorosulfonate was used to label a peptide representing a domain in the middle section of CT-1. Assay of this domain of CT-1 (amino acids 105-120) in patients with heart failure revealed elevated CT-1 values median 87 [range 74.3-182.8] fmol/ml) compared to normal controls (CT-1 median 29.55 [range 6.9-48.3] fmol/ml, P<0.0005). The molecular weight of human CT-1 was estimated to be 26.7 kD from sodium dodecyl sulphate polyacrylamide gel electrophoresis. This is the first quantitative assessment of CT-1 in humans. Furthermore, this is the first demonstration of significant elevation of plasma CT-1 in patients with heart failure.
Aged↗
Exon repetition in mRNA.
The production of different transcripts (transcript heterogeneity) is a feature of many genes that may result in phenotypic variation. Several mechanisms, that occur at both the DNA and RNA level have been shown to contribute to this transcript heterogeneity in mammals, all of which involve either the rearrangement of sequences within a genome or the use of alternative signals in linear, contiguous DNA or RNA. Here we describe tissue-specific repetition of selective exons in transcripts of a rat gene (SA) with a normal exon-intron organization. We conclude that nonlinear mRNA processing can generate tissue-specific transcripts.
Animals↗
Plasma N-terminal pro-brain natriuretic peptide and the ECG in the assessment of left-ventricular systolic dysfunction in a high risk population.
AIMS: To examine the value of N-terminal pro-brain natriuretic peptide, abnormal electrocardiogram and other baseline clinical and laboratory variables in identifying patients with left ventricular systolic dysfunction in a high risk population. METHODS AND RESULTS: We studied 243 patients (129 male, median age 73 years, range 20-94) referred for echocardiography. The relationship between left ventricular wall motion index and log N-terminal pro-brain natriuretic peptide, log creatinine, electrocardiogram, age, history of hypertension, history of ischaemic heart disease, gender, valvular disease and current drug therapy was examined using regression analysis. There was a strong correlation between N-terminal pro-brain natriuretic peptide and left ventricular wall motion index for the whole population (r=-0.624, P<0.001) and in those receiving diuretic +/- angiotensin converting enzyme inhibitor (r= -0.661, P<0.005) and in those receiving neither (r=-0.584, P<0. 005). On multiple regression analysis, log N-terminal pro-brain natriuretic peptide (P<0.001), age (P=0.015), current diuretic (P=0. 002) or angiotensin converting enzyme inhibitor use (P=0.001) and male gender (P=0.026) were independently associated with a low left ventricular wall motion index. Log N-terminal pro-brain natriuretic peptide alone (R(2)=39%) was a better predictor of left ventricular wall motion index than any other single or combination of factors. Plasma N-terminal pro-brain natriuretic peptide>275 pmol l(-1)predicted left ventricular wall motion index < or =1.2 with a sensitivity of 93.8%, a specificity of 55% and a negative predictive value of 93%. Left ventricular function was impaired in 18/36 patients with a normal electrocardiogram, in all of whom N-terminal pro-brain natriuretic peptide was >275 fmol ml(-1). CONCLUSION: Of the variables studies, N-terminal pro-brain natriuretic peptide had the strongest correlation with reduced left ventricular wall motion index. The electrocardiogram had a poor predictive value for left ventricular systolic dysfunction in this population. Plasma N-terminal pro-brain natriuretic peptide can usefully predict patients with a reduced left ventricular wall motion index in whom echocardiographic examination may be appropriate.
Adult↗
Measurement of calcium and movement in heart cells.
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Animals↗
An immunoluminometric assay for N-terminal pro-brain natriuretic peptide: development of a test for left ventricular dysfunction.
Measurement of plasma levels of brain natriuretic peptide (BNP) has been used to assess left ventricular dysfunction and prognosis. Levels of the N-terminus of the precursor of BNP (NT-proBNP) have been reported to be elevated to a greater extent than BNP in left ventricular dysfunction. We have devised a non-radioactive sensitive and specific assay for NT-proBNP based on a competitive ligand binding principle. The chemiluminescent label 4-(2-succinimidyloxycarbonylethyl)phenyl-10-methylacridinium 9-carboxylate fluorosulphonate was used to label peptides representing domains in the middle and C-terminal sections of NT-proBNP. Assay of the C-terminal section of NT-proBNP (amino acids 65-76) in patients with proven left ventricular dysfunction [left ventricular wall motion index median 0.9 (range 0.3-1.4)] revealed elevated values [median 639 (386-911) fmol/ml] compared with normal controls [left ventricular wall motion index of 2 in all, NT-proBNP median 159 (120-245) fmol/ml, P<0.001]. Measurement of the middle section of NT-proBNP (amino acids 37-49) was not a discriminating test. It is thus possible to derivatize small peptides with a methyl acridinium label and preserve immunodetection with specific antibodies. Such methodology may allow non-radioactive immunoluminometric assays to be devised.
Adult↗
Assessment of the stability of N-terminal pro-brain natriuretic peptide in vitro: implications for assessment of left ventricular dysfunction.
Plasma concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) are raised in patients with left ventricular dysfunction. Measurement of this peptide has a potential diagnostic role in the identification and assessment of patients with heart failure. The stability of this peptide over time periods and conditions pertaining to routine clinical practice has not been reported previously. Blood samples were obtained from 15 subjects. One aliquot was processed immediately, and the remaining portions of the blood samples were stored for 24 h or 48 h at room temperature or on ice prior to processing. Plasma concentrations of NT-proBNP were measured with a novel immunoluminometric assay developed within our laboratory. Mean plasma concentrations of NT-proBNP were not significantly different whether blood samples were centrifuged immediately and stored at -70 degrees C or kept at room temperature or on ice for 24 h or 48 h. The mean percentage differences from baseline (reference standard) were +5.2% (95% confidence interval +18.2 to -7.8%) and +0.8% (+15.2 to -13.7%) after storage for 24 h at room temperature or on ice respectively, and +8.9% (+24.2 to -6. 5%) and +3.2% (+15.1 to -0.9%) for storage for 48 h at room temperature or on ice respectively. Pearson correlation coefficients for baseline NT-proBNP concentrations compared with levels at 48 h at room temperature or on ice were r=0.89 and r=0.83 respectively (both P<0.0001). Thus NT-proBNP extracted from plasma samples treated with EDTA and aprotinin is stable under conditions relevant to clinical practice.
Adult↗
Uptake mechanisms for ascorbate and dehydroascorbate in lymphoblasts from diabetic nephropathy and hypertensive patients.
In diabetic nephropathy and hypertension, a major cause of mortality is from cardiovascular disease. Since low levels of antioxidants such as vitamin C have been associated with such complications, we have examined the uptake mechanisms for ascorbic acid (AA) and dehydroascorbic acid (DHA) in lymphoblasts from normal control subjects (CON), normoalbuminuric insulin-dependent diabetic (IDDM) patients (DCON), patients with IDDM and nephropathy (DN) and hypertensive patients (HT) using mass assays of uptake and measuring AA using high-performance liquid chromatography. Precautions were taken to prevent oxidation of AA and to take into account the instability of DHA in buffers. DHA uptake was the major mechanism in all four groups of subjects, and the Vmax (maximal uptake rate) was significantly lower in the DN cells (24.7 +/- 1.0 nmol [95% confidence intervals CI 22.5, 26.3] 10(6) cells(-1) h(-1)) compared to CON and DCON cells (33.9 +/- 2.1 [95% CI 29.4, 38.4] and 37.0 +/- 2.2 [95% CI 32.2, 41.8] nmol 10(6) cells(-1) h(-1), respectively, p < 0.001 for both). DHA Vmax was also lower in the HT group (23.2 +/- 1.1 [95% CI 20.7, 25.7] nmol 10(6) cells(-1) h(-1)) compared to the CON group (p < 0.001). There were no significant differences in the Km or passive membrane permeability for DHA or the AA uptake. DHA uptake showed a negative correlation to systolic blood pressure (r(s) = -0.49, p < 0.001). These findings suggest that impaired DHA uptake may be one component of the phenotype expressed by DN cells that may persist in culture. Impaired DHA uptake in vivo, especially in the presence of hyperglycaemia, leads to impaired regeneration of AA and depletion of anti-oxidant defences, exposing such individuals to increased risk of cardiovascular disease.
Adult↗
Identification of mRNA transcripts and immunohistochemical localization of Na/H exchanger isoforms in gerbil inner ear.
Recent physiological and pharmacological studies have implicated involvement of the Na/H exchanger (NHE) in regulating inner ear ion homeostasis, but the cellular distribution of this membrane transporter remains unknown. Here reverse transcription and the polymerase chain reaction (RT-PCR) were employed to screen adult gerbil inner ears for mRNA transcripts encoding the four best characterized isoforms of NHE. PCR products spanning selected segments of NHE mRNAs were cloned and sequenced. The putative housekeeping gene NHE-1 was found to be expressed and the 459 bp product shared 98.7% amino acid homology with rat sequence. NHE-2, NHE-3 and NHE-4 cDNA transcripts likewise were detected and the PCR products shared 100, 99.4 and 88.9% amino acid homology, respectively, with their rat counterparts. In addition, the cellular distribution of NHE isoforms 1 and 3 was mapped in the gerbil inner ear by immunostaining with polyclonal antisera against rat antigens. In the cochlea, the antiserum against NHE-1 reacted strongly at the basolateral membrane of strial marginal cells as well as with inner and outer hair cells and spiral ganglion neurons. Less intense staining for NHE-1 was present in subpopulations of fibrocytes in the spiral limbus and in inferior and superior areas of the spiral ligament. In the vestibular system dark and transitional cells expressed abundant NHE-1 as did hair cells and vestibular ganglia neurons. Immunostaining with the antiserum against NHE-3 was limited to the apical surface of marginal cells in the stria vascularis. Based on these data, NHE-1 likely functions primarily to maintain intracellular pH levels in cells where it is found in high abundance. NHE-3, on the other hand, possibly participates in the vectorial transcellular movement of Na+ by strial marginal cells thus helping to maintain the extremely low Na+ level in cochlear endolymph.
Animals↗
Evidence that P2Y4 nucleotide receptors are involved in the regulation of rat aortic smooth muscle cells by UTP and ATP.
1. Previous studies have shown that ATP and UTP are able to stimulate phospholipase C (PLC) and proliferation in cultured aortic smooth muscle cells. Here we set out to characterize the receptor responsible, and investigate a possible role for p42 and p44 mitogen activated protein kinase (MAPK) in the proliferative response. 2. The phospholipase C response of spontaneously hypertensive rat (SHR) derived aortic smooth muscle cells in culture showed that the response to ATP was partial compared to the response to UTP. 3. Further studies characterized the responses of the SHR derived cells. UTP was the only full agonist with the SHR cells; UDP gave a partial response while ADP, 2-methythio-ATP and alpha,beta-methylene ATP were essentially ineffective. The response to UDP was almost lost in the presence of hexokinase, consistent with this being due to extracellular conversion to UTP. These observations are inconsistent with the response being mediated by either P2Y1 or P2Y6 receptors. 4. When increasing concentrations of ATP were present with a maximally effective concentration of UTP, the size of the response diminished, consistent with UTP and ATP acting at a single population of receptors for which ATP was a partial agonist. This is inconsistent with a response mainly at P2Y2 receptors. 5. 1321N1 cells transfected with human P2Y4 receptors gave a similar agonist response profile, with ATP being partial compared to UTP, loss of response to UDP with hexokinase treatment, and with the response to UTP diminishing in the presence of increasing concentrations of ATP. 6. Use of the reverse transcriptase-polymerase chain reaction confirmed the presence of mRNA encoding P2Y4 receptors in SHR derived vascular smooth muscle cells. Transcripts for P2Y2, P2Y4 and P2Y6 receptors, but not P2Y1 receptors, were detected. 7. Stimulation of SHR derived cells with UTP enhanced the tyrosine phosphorylation of both p42 and p44 MAPK, and the incorporation of [3H]-thymidine into DNA. Both these responses were diminished in the presence of an inhibitor of activation of MAPK. 8 These results lead to the conclusion that in SHR derived cultured aortic smooth muscle cells, PLC responses to extracellular UTP and ATP are predominantly at P2Y4 receptors, and suggest that these receptors are coupled to mitogenesis via p42/p44 MAPK.
Adenosine Triphosphate↗
Sodium proton exchanger (NHE) isoforms--potential relevance to hypertension and its complications.
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Animals↗
Two distinct uptake mechanisms for ascorbate and dehydroascorbate in human lymphoblasts and their interaction with glucose.
In diabetes, a major cause of mortality is from cardiovascular causes, and low levels of antioxidants such as vitamin C have been associated with such complications. Leucocyte ascorbic acid status can reflect total body stores but the mechanisms that mediate the uptake of ascorbic acid (AA) or dehydroascorbic acid (DHA) in human lymphoid cells are undefined. We have investigated the uptake of AA and DHA with mass assays in human lymphoblasts by using HPLC, with precautions to prevent the oxidation of AA and to take into account the instability of DHA in buffers. Human lymphoblasts exhibit distinct uptake mechanisms for both AA and DHA, with Vmax values of 1.35+/-0.14 and 29.0+/-5.8 nmol/h per 10(6) cells and Km values of 23.5+/-6 and 104+/-84 microM respectively. The AA uptake was Na+-dependent and inhibitable with ouabain, whereas DHA uptake was independent of Na+ and ouabain-insensitive. Both uptake mechanisms were inhibited by phloretin or cytochalasin B. AA uptake was decreased significantly (by 13+/-2%) only at extracellular glucose concentrations of 20 mM (P<0.05). In contrast, glucose competitively inhibited DHA uptake with a Ki of 2.2 mM so that DHA uptake was decreased by glucose even in the physiological range. Phorbol esters stimulated AA but not DHA uptake; this was abolished in the presence of extracellular reductant, indicating that AA was converted to DHA before uptake occurred. Prolonged increased glucose levels (20 mM) led to a decrease in the Vmax of DHA uptake. At concentrations of plasma AA or DHA, the AA uptake mechanism might be nearly half-saturated but the DHA mechanism has enormous spare capacity. This allows for cellular uptake and regeneration of AA from DHA derived from oxidative stress. In diabetes, high glucose levels might impair DHA uptake acutely by competitive inhibition or by down-regulation of uptake with chronic glucose exposure, leading to an impaired ability to store and recycle oxidized AA.
Ascorbic Acid↗