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Originally published In Press as doi:10.1194/jlr.M800015-JLR200 on January 17, 2008

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Journal of Lipid Research, Vol. 49, 847-855, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Increased methionine sulfoxide content of apoA-I in type 1 diabetes

Jonathan W. C. Brock*, Alicia J. Jenkins{dagger},§,**, Timothy J. Lyons{dagger},**, Richard L. Klein{dagger}, Eunsil Yim{dagger}{dagger}, Maria Lopes-Virella{dagger}, Rickey E. Carter{dagger}{dagger} (DCCT/EDIC) Research Group2,§§, Suzanne R. Thorpe*, John W. Baynes1,*

* Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC
{dagger} Department of Endocrinology and Medical Genetics, Medical University of South Carolina, Charleston, SC
{dagger}{dagger} Department of Epidemiology and Biostatistics, Medical University of South Carolina, Charleston, SC
§ Department of Medicine, St. Vincent's, University of Melbourne, Melbourne, Australia
§§ National Institutes of Health, Bethesda, MD
** Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK

Published, JLR Papers in Press, January 17, 2008.

2 Participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Complication (DCCT/EDIC) Research Group are listed in the Appendix. Back

1 To whom correspondence should be addressed. e-mail: john.baynes{at}sc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
Cardiovascular disease is a major cause of morbidity and premature mortality in diabetes. HDL plays an important role in limiting vascular damage by removing cholesterol and cholesteryl ester hydroperoxides from oxidized low density lipoprotein and foam cells. Methionine (Met) residues in apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, reduce peroxides in HDL lipids, forming methionine sulfoxide [Met(O)]. We examined the extent and sites of Met(O) formation in apoA-I of HDL isolated from plasma of healthy control and type 1 diabetic subjects to assess apoA-I exposure to lipid peroxides and the status of oxidative stress in the vascular compartment in diabetes. Three tryptic peptides of apoA-I contain Met residues: Q84-M86-K88, W108-M112-R116, and L144-M148-R149. These peptides and their Met(O) analogs were identified and quantified by mass spectrometry. Relative to controls, Met(O) formation was significantly increased at all three locations (Met86, Met112, and Met148) in diabetic patients. The increase in Met(O) in the diabetic group did not correlate with other biomarkers of oxidative stress, such as N{epsilon}-malondialdehyde-lysine or N{epsilon}-(carboxymethyl)lysine, in plasma or lipoproteins. The higher Met(O) content in apoA-I from diabetic patients is consistent with increased levels of lipid peroxidation products in plasma in diabetes. Using the methods developed here, future studies can address the relationship between Met(O) in apoA-I and the risk, development, or progression of the vascular complications of diabetes.

Supplementary key words apolipoprotein A-I • high density lipoprotein • oxidation • oxidative stress

Abbreviations: ACE, angiotensin-converting enzyme; AER, albumin excretion rate; apoA-I, apolipoprotein A-I; CVD, cardiovascular disease; DCCT/EDIC, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; HODE, hydroxyoctadecadienoic acid; LPO, lipid peroxide; Met, methionine; Met(O), methionine sulfoxide; PON-1, paraoxonase; Q-TOF, quadrupole time-of-flight; RA, relative area; SLO, soybean lipoxygenase; TIC, total ion chromatogram; T1DM, type 1 diabetes mellitus; XIC, extracted ion chromatogram


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
Oxidative stress, induced by hyperglycemia (1, 2), is implicated in the progression of cardiovascular disease (CVD) (3, 4), the leading cause of death in diabetes (5). CVD is particularly accelerated in the presence of diabetic nephropathy (6). Increased oxidation of plasma LDL (7) and accumulation of oxidatively modified LDL in macrophages in the arterial wall (8) are characteristic of the early stage of atherogenesis. HDL has a protective role against atherosclerosis: it removes lipid peroxides (LPOs) and cholesterol from oxidized LDL (9, 10) and from cell membranes through the reverse cholesterol transport pathway (11, 12). Once LPOs are absorbed by HDL, they are either transported to the liver, where they are detoxified and excreted into the bile (13–15), or they are reduced directly by HDL to hydroxylipids (16, 17). At least two HDL-bound proteins are involved with LPO detoxification, paraoxonase (PON-1) (18, 19) and apolipoprotein A-I (apoA-I) (20). PON-1 is a lactonase that protects against LDL and HDL oxidation by hydrolyzing oxidized fatty acids to lactones; plasma or serum PON-1 concentration or activity is inversely correlated with CVD and is commonly decreased in diabetes and in renal disease (21–24). ApoA-I, the major protein of HDL, is involved with the mobilization of cholesterol from oxidized LDL and macrophages of the arterial wall during reverse cholesterol transport (25) and also reduces LPOs, using methionine (Met) residues as the reductant and producing methionine sulfoxide [Met(O)] (see below).

Levine and colleagues (26) have proposed that Met residues in protein serve as endogenous antioxidants, protecting functionally important amino acids from oxidation. In apoA-I, Met appears to have the additional function of reducing LPOs. There are three Met residues on apoA-I, two of which are reported to be susceptible to oxidation by LPOs (27). These residues are oxidized at a rate parallel to the rate of reduction of cholesteryl ester hydroperoxides to cholesteryl ester hydroxide (28, 29). In apoA-I, Met86 and Met112 are thought to be important for cholesterol efflux and Met148 is believed to be involved in LCAT activation (30); oxidation of apoA-I Met residues has no effect on the affinity of HDL for cholesterol (31). Although Met(O) reductase activity is found in all cells and reverses the oxidation of Met(O) in intracellular compartments (30), this enzyme is absent from the plasma compartment (32). Thus, we hypothesized that Met(O) formation in apoA-I might serve as a biomarker for exposure of HDL to LPOs in plasma and as an integrator of oxidative stress in the vascular compartment. We describe here the quantification of oxidation of specific Met residues in apoA-I isolated from patients with type 1 diabetes mellitus (T1DM), including patients with and without renal disease, and healthy nondiabetic controls, using liquid chromatography-mass spectrometry analysis of tryptic peptides.


   EXPERIMENTAL PROCEDURES
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
Materials
Unless indicated otherwise, all chemicals were purchased from Sigma-Aldrich (St. Louis, MO). Organic solvents were of the highest purity available from Acros Chemicals (Atlanta, GA).

Study subjects
Twenty-six T1DM patients, including 13 with and 13 without nephropathy [defined as urinary albumin excretion rate (AER) > 40 mg/24 h], were selected from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) cohort (33), and 13 healthy nondiabetic controls were recruited as part of a Program Project Grant, as described previously (34). All hemoglobin A1c, conventional lipid profiles, and renal function measures were performed by the DCCT/EDIC central laboratory, as described previously (33). Urine specimens used to calculate AER were obtained in the EDIC year that preceded the collection of the serum used to measure Met(O) oxidation levels (Table 1 ). Other measures of apolipoproteins, inflammation, oxidative stress, and advanced glycation end products were performed in the authors' laboratories as described previously (34–39). Lipoprotein subclasses were measured by NMR (LipoScience, Raleigh, NC) (33).


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  		TABLE 1. Clinical characteristics of control and diabetic subjects

 
HDL isolation
HDL (d = 1.063–1.21 g/ml) was isolated from EDTA-anticoagulated plasma from fasting subjects by sequential ultracentrifugation, after removal of VLDL/intermediate density lipoprotein and LDL, as described previously (40). The HDL supernatant layer was removed, washed and concentrated, dialyzed, sterile-filtered (0.22 µm), and stored under nitrogen at –70°C in a lipoprotein preservative solution containing 2.8 mM EDTA (40). Plasma from both control and diabetic patients was collected and HDL was isolated during 1997–1999, and Met(O) was quantified in 2005. A long-term control pool, prepared by sequential ultracentrifugation in 1998, also had levels of Met(O) similar to those in freshly prepared samples of HDL from a separate group of control subjects: pool Met(O) 86:112:148 (triplicate analyses): 0.104 ± 0.037, 0.038 ± 0.004, 0.023 ± 0.002; freshly prepared controls (n = 3): 0.082 ± 0.009, 0.054 ± 0.032, 0.034 ± 0.016. The low levels of Met(O) in both controls and pools, compared with fresh samples, support the stability of these samples during storage. HDL from the same group of subjects was also prepared by the (same day) procedures of vertical spin ultracentrifugation and size exclusion chromatography [as described previously (17)], and Met(O) levels did not differ significantly from those in stored frozen samples, supporting a lack of in vitro oxidation during the more prolonged sequential ultracentrifugation procedures.

Oxidation of HDL
Oxidized HDL was prepared using the method of Garner et al. (28). Briefly, HDL prepared from pooled plasma from a separate group of five healthy subjects (2 mg/ml, 0.3 mM Met) was incubated with soybean lipoxygenase (SLO; 4,000 U/ ml) for 12 h at 37°C in a reciprocating water bath at 30 rpm. Aliquots were taken at 0, 1, 2, 6, and 12 h. Butylated hydroxytoluene (1 mM) was added immediately, and the HDL was then delipidated as described below.

Trypsin digestion of HDL
HDL (500 µg of protein, ~2 mg/ml) was delipidated by the addition of 5 volumes of ice-cold methanol-ether (3:1), followed by centrifugation (5,000 g, 5 min); the supernatant was discarded and the protein pellet was washed with 500 µl of ice-cold ether, followed by recentrifugation. The supernatant was discarded, and the pellet was dried gently under a stream of N2, then dissolved in 300 µl of 0.6 M urea/50 mM ammonium bicarbonate, pH 7.2. Trypsin (Sigma Sequencing Grade; T8658), 4.5:100 (w/w), was added followed by incubation overnight at 37°C. Digestion was terminated by freezing at –20°C.

ESI-LC-MS
Experimental conditions for LC-MS analysis of tryptic peptides are described in detail elsewhere (41). Briefly, peptides were analyzed using an Agilent (Palo Alto, CA) Series 1100 liquid chromatograph interfaced to a Micromass (Manchester, UK) triple quadrupole (Quattro) or quadrupole time-of-flight (Q-TOF) mass spectrometer. Peptides were fractionated on an ES Industries (West Berlin, NJ) AquaSep C18 column (250 x 2 mm) using a gradient from 0.1% aqueous trifluoroacetic acid to 50% acetonitrile in water for 50 min at a flow rate of 0.2 ml/min. The mass spectrometer was set in full scan mode (200–1,800 m/z), and masses of interest were extracted using MassLynx (Micromass) software. All assays were carried out in positive ion mode. The extent of modification of Met-containing peptides, expressed as relative area (RA), was calculated by dividing the sum of the peak areas of the different charged forms of the Met(O) peptide of interest by the sum of the peak areas of the charged forms of an internal reference peptide, Q216-K226, chosen because of its strong signal and resolution from other peptides.

Statistical analyses
Data are summarized throughout as means ± SD and are plotted using SigmaPlot software (Systat Software, Inc., Point Richmond, CA). Statistical analyses were performed using the SAS System (Cary, NC). Differences between groups were analyzed using the nonparametric Mann-Whitney U-test. Correlations were analyzed by the Spearman nonparametric procedure.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
DISCUSSION
 APPENDIX
 REFERENCES
 
Clinical characteristics
Characteristics of the control and T1DM subjects are shown in Table 1. The healthy controls were comparable to the 26 diabetic patients with respect to age, body mass index, and lipid profile; however, there was significant variation in renal function within the diabetic patients by design. Compared with diabetic patients with normal renal function, the 13 diabetic patients with nephropathy (AER > 40 mg/24 h) exhibited urinary AER (mean ± SD) of 343 ± 576 versus 10 ± 6 mg/day (P < 0.01) but similar serum creatinine (1.1 ± 0.5 vs. 0.9 ± 0.1 mg/dl; P = 0.19) and glomerular filtration rate (84 ± 24 vs. 99 ± 20 ml/min/1.73 m2; P = 0.26). Of the 13 nephropathic diabetic patients, only 4 were taking angiotensin-converting enzyme (ACE) inhibitors at the time of blood collection. None of the 13 T1DM patients with an AER < 40 mg/24 h were taking ACE inhibitors. Only one diabetic subject was taking lipid-lowering drugs, an HMG-CoA reductase inhibitor. No subjects were taking antioxidant vitamin supplements.

Characterization of Met- and Met(O)-containing peptides of apoA-I
ApoA-I contains three Met residues, Met86, Met112, and Met148, which are located on three different tryptic peptides (Table 2 ). To determine the site specificity of Met oxidation, apoA-I isolated from a healthy subject was digested with trypsin and the peptides were analyzed by reverse-phase HPLC in-line with an ESI tandem mass spectrometer (Quattro or Q-TOF). Figure 1 shows a typical total ion chromatogram (TIC) of peptides from apoA-I, on the Quattro, using a full-scan analysis between 200 and 1,800 Da.


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  		TABLE 2. Mass-charge ratios of the charged forms of unmodified and oxidized apolipoprotein A-I tryptic peptides

 

Figure 1
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  		Fig. 1. Typical ESI-LC-MS chromatogram of HDL tryptic peptides. HDL isolated from a type 1 diabetes mellitus (T1DM) subject was delipidated, digested with trypsin, fractionated by reverse-phase LC, and analyzed on a Quattro mass spectrometer set in survey mode (200–1,800 m/z). The methionine (Met)-containing peptides Q84-M86-K88, L144-M148-K149, and W108-M112-R116 elute at 3.3, 24.4, and 27.5 min, respectively.

 
ESI-LC-MS produces multiply charged species (i.e., +1, +2, and +3), with each species contributing to the TIC. To quantify the peptides of interest, each multiply charged species was extracted from the TIC using MassLynx software, giving an extracted ion chromatogram (XIC). Figure 2 shows a typical XIC for the three charged species of the nonoxidized peptide W108-M112-R116. All peptides of interest had multiple charged forms that were extracted. Figure 3 shows a series of typical XICs for the +2 charged species of the nonoxidized and oxidized peptides Q84-M86-K88, L144-M148-K149, and W108-M112-R116. The Met(O) peptides eluted ~3 min earlier than the nonoxidized (native) form, which is attributable to increased hydrophilicity of Met(O), compared with Met. All of the Met(O) peptides were detectable in this and other samples of HDL from control and diabetic subjects.


Figure 2
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  		Fig. 2. Typical extracted ion chromatograms (XICs) of peptide W108-M112-R116. XICs are shown for the +1 (1,284 m/z) (A), +2 (642 m/z) (B), and +3 (429 m/z) (C) charge states of peptide W108-M112-R116, for the sample shown in Fig. 1, with an elution time of 27.5 min.

 

Figure 3
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  		Fig. 3. Typical XICs of the +2 charge state of the nonoxidized and oxidized peptides Q84-M86-K88, W108-M112-R116, and L144-M148-R149. XICs are shown for the +2 charge state of the peptides Q84-M86-K88, W108-M112-R116, and L144-M148-R149 (A–C) and the +2 charge state of the peptides Q84-Met(O)86-K88, W108-Met(O)112-R116, and L144-Met(O)148-R149 (D–F) from the sample shown in Fig. 1. The methionine sulfoxide [Met(O)] peptides eluted on average 3 min earlier than the nonoxidized (Met) peptides.

 
To confirm the assignment of the charged species, the Met and Met(O) peptides were sequenced using the Q-TOF mass spectrometer. Figure 4 shows representative sequencing spectra of the nonoxidized and oxidized W108-M112-R116 peptide. The insets represent sequencing bars showing the masses for each y and b ion. A complete series of y ions and immonium ions was obtained for both peptides. There was a neutral loss of 64 amu for all y ions containing Met(O), indicative of a loss of methyl sulfoxide from Met(O) (Fig. 4B).


Figure 4
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  		Fig. 4. Sequencing spectra of the nonoxidized and oxidized peptide W108-M112-R116. Sequencing spectra of the +2 ion of peptides W108-M112-R116 (A) and W108-Met(O)112-R116 (B). All y ions and immonium ions are represented. All y ions containing Met(O) (y5–y8) have a neutral loss of methyl sulfoxide (–64 m/z), indicative of Met(O). Insets show amino acid sequences of peptides W108-M112-R116 and W108-Met(O)112-R116, showing the theoretical masses of the b and y ions.

 
Site specificity of Met oxidation on apoA-I during in vitro oxidation of HDL
To determine the site specificity of Met(O) formation on apoA-I, we treated isolated HDL with SLO to generate LPOs with concomitant oxidation of Met, followed by analysis of tryptic peptides on the Quattro mass spectrometer. As indicated by the increase in RA values, all three of the Met residues on apoA-I were susceptible to oxidation by LPOs (Fig. 5 ), with the order of increase in RA for Met112 > Met148 > Met86. There was a slight lag phase in Met oxidation, most apparent for the oxidation of Met112 and Met148, probably because HDL contains {alpha}-tocopherol, which would temporarily protect against Met oxidation.


Figure 5
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  		Fig. 5. Analysis of the site specificity of Met oxidation on apolipoprotein A-I (apoA-I) in lipoxygenase-treated HDL. Met(O)112 is the predominant site of oxidation during lipoxygenase treatment of HDL, followed by Met148 and Met86. Relative area (RA) values (means ± SD; n = 3) are calculated relative to the reference peptide Q216-K226, as described in Experimental Procedures.

 
Extent of Met(O) formation on apoA-I in HDL isolated from control and diabetic subjects
HDL isolated from T1DM patients and nondiabetic controls (Table 1) was analyzed to determine whether Met(O) was increased in T1DM versus control subjects. Met(O) was detectable in apoA-I from healthy nondiabetic individuals, with the RA for W108-Met(O)112-R116 {approx} L144-Met(O)148-K149 >> Q84-Met(O)86-K88 (Fig. 6 ), in reasonable agreement with the in vitro data for the zero-time sample (Fig. 5). The RAs for all three of the Met(O) peptides were increased significantly in diabetic subjects compared with nondiabetic controls (Fig. 6); there was also a strong correlation between the RA values for Met(O)112 and Met(O)148 (Fig. 7 ), comparable to that observed in LPO-treated HDL (Fig. 5; r2 = 0.84).


Figure 6
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  		Fig. 6. Met(O) concentration is significantly increased in apoA-I peptides from T1DM patients. HDL isolated from healthy subjects (n = 13) and T1DM subjects (n = 26) was delipidated and digested with trypsin for ESI-LC-MS analysis. Data are expressed relative to the peptide Q216-K226 (see Experimental Procedures). Data are means ± SD; statistical analysis was performed by Dunn's (nonparametric) test (* P = 0.01 vs. healthy control; # P < 0.01 vs. healthy control).

 

Figure 7
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  		Fig. 7. Correlation between Met(O)112 and Met(O)148 formation on apoA-I. Met(O)112 and Met(O)148 oxidation are strongly correlated in HDL from T1DM patients, indicating an overall increase in oxidative damage to the HDL particle. Met(O)112 is the predominant site of oxidation in T1DM. Two-tailed P < 0.0001 with a 99% confidence interval is shown (n = 39).

 
Correlation between Met(O) on apoA-I and risk markers for CVD
There were no statistically significant correlations between the RAs for Met(O) peptides and urinary AER, serum creatinine, or glomerular filtration rate. Met(O) levels also did not differ significantly between diabetic subjects with or without nephropathy or between subjects taking or not taking ACE inhibitors or HMG-CoA reductase inhibitors (data not shown). This does not exclude Met(O) as an independent risk factor for CVD, so a cross-sectional analysis was also performed between Met(O) peptide RAs and potential mediators of CVD, including other markers of oxidative stress and inflammation [C-reactive protein, soluble vascular cell adhesion molecule-1, soluble intracellular adhesion molecule, soluble E-selectin, smoking, LDL susceptibility to in vitro oxidation (oxidizibility), and serum PON-1 activity]. No statistically significant correlations were found between these measures and RAs for Met(O) peptides (data not shown). As there are several size-based HDL subclasses, the relationship between Met(O) RAs and NMR-determined HDL profile (including HDL particle number, mean HDL size, concentration of five HDL subclasses, and ratio of large to small HDL) was also assessed. Again, there was no correlation found between Met(O) formation on apoA-I and these measurements. Nor was there any correlation with measures of plasma antioxidant status (albumin, bilirubin, urate, PON activity, or iron concentration) or levels of advanced glycation and lipoxidation end products [N{epsilon}-(carboxymethyl)lysine, N{epsilon}-(carboxyethyl)lysine, hydroxynonenal-lysine, malondialdehyde-lysine, or pentosidine] in plasma, LDL, or HDL. The clinical CVD status of the patients is not yet available, so the predictive value of Met(O) in apoA-I or of other biomarkers for CVD cannot be assessed at this time.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
APPENDIX
 REFERENCES
 
In this study, we used LC-MS/MS to measure the oxidation of specific Met residues in apoA-I. This protein has three Met residues, Met86, Met112, and Met148. The relative rates of oxidation of the three peptides containing these Met residues are in agreement with earlier work based on chromatographic separation of intact apoA-I molecules containing Met(O)112 or Met(O)148 (42), which also identified Met112 as the primary site of oxidation of HDL that had been chemically oxidized with chloramine-T. In other studies, Met86 was identified as the major site of oxidation of apoA-I initiated by the aqueous peroxyl radical generator 2,2'-azo-bis-(2-amidinopropane)dihydrochloride. Thus, although the differences in relative rates of oxidation of these Met residues are attributable to differences in oxidant and methodology, in the present study the oxidation of Met residues in apoA-I by SLO-generated LPOs is consistent with the relative extents of oxidation of Met residues in apoA-I isolated from human plasma (Fig. 5 vs. Fig. 6).

In in vitro studies with SLO-generated LPOs (Fig. 5) and among the diabetic subjects (Fig. 7), there was a strong correlation between the extent of oxidation of Met112 and Met148, suggesting oxidation by LPOs, both in vitro and in vivo. The greater oxidation of Met112 compared with Met148 may be attributed to structural features of the protein, such as exposure of the Met residues to bound lipids or sites of docking with cellular or protein donors of LPOs. Recent studies by Shao et al. (43) indicate that Met112 oxidation in HDL may also be enhanced by the MxxY motif in the protein. In this case, Met may protect tyrosine from chlorination by serving as a sacrificial antioxidant, reducing HOCl, a product of myeloperoxidase in macrophages. During reverse cholesterol transport, HDL interacts with foam cells, which are laden with oxidized LDL, and this interaction could also expose apoA-I to HOCl as well as to LPOs, both of which may drive the oxidation of Met112.

If LPOs were the primary source of apoA-I oxidation, hydroxylipids, such as 9- or 13-hydroxyoctadecadienoic acids (HODEs) or cholesterol oxides, might increase in HDL in diabetes. Jira et al. (44, 45), in fact, have reported increases in HODEs in LDL in diseases associated with increased oxidative stress, such as rheumatoid arthritis (44) and atherosclerosis (45). In obese type 2 diabetic patients, plasma 9- and 13-HODE levels are decreased by troglitazone therapy (46), but no information is available regarding plasma or lipoprotein-related HODE concentrations in T1DM. However, Ferderbar et al. (47) recently reported significant increases in total cholesterol oxides and 7-hydroxycholesterol in plasma of children and young adults with T1DM, even in the absence of hypercholesterolemia. Martin-Gallan et al. (48) have also reported increased levels of LPOs and the lipid peroxidation product, malondialdehyde, in plasma of T1DM patients, independent of complication status. Thus, although little information is available regarding levels of HODEs in patients with diabetes, there is some evidence for increased cholesterol oxidation and oxidative stress in T1DM, even in the absence of dyslipidemia or complications. These results are consistent with increased peroxidation of lipids in diabetes and suggest that measurement of Met(O) in apoA-I in HDL, which has an average half-life of ~5 days in plasma (49), may provide a useful intermediate-term index of exposure to oxidative stress in diabetes.

Despite the evidence for increased oxidative stress in diabetes (2–4, 50), in the present study diabetic patients with nephropathy, which is thought to increase oxidative stress and CVD risk (50–52), did not show a statistically significant increase in Met oxidation. Relative to control subjects, Met(O) was increased in the HDL of all diabetic subjects (irrespective of nephropathy status). In contrast, in a recent study of skin collagen, Met(O) levels were increased in diabetic patients with complications but did not differ significantly between complication-free diabetic patients and controls (39). The studies of Met(O) in apoA-I and collagen are not readily compared because of differences in patient populations and the complications evaluated: there were fewer patients with renal complications and more with retinal complications in the collagen study. Nonetheless, both of these studies indicate that extracellular proteins are exposed to increased oxidative stress in T1DM.

Differences in the oxidation of Met in apoA-I and collagen may result from differences in location (plasma vs. extracellular matrix), the different half-lives of the lipoproteins and collagen (days for apoA-I, years for collagen), or the nature of the oxidant (LPOs in apoA-I vs. water-soluble or cell-derived oxidants in the extracellular matrix). It is also possible that alterations in lipoprotein metabolism in diabetes may obscure differences in oxidative stress in diabetic patients with or without complications. In the present, small cross-sectional study, we found no evidence of differences in lipemia, apoprotein composition, or lipoprotein size distribution between the nephropathic and nonnephropathic groups of patients, nor any statistically significant correlations with Met(O), but in a larger cross-sectional study of DCCT/EDIC subjects, in which Met(O) was not quantified, we found multiple differences in lipoproteins between such groups (34). Coronary artery disease is the major cause of morbidity and mortality in T1DM patients, and HDL oxidation, as indicated by the increased Met (O) in diabetic compared with healthy subjects, may contribute to accelerated atherosclerosis. Even young people with T1DM without clinically evident complications have increased carotid intima medial thickness and coronary artery atheroma, as detected by intravascular ultrasound (53–55). Atherosclerosis may also contribute to the increased levels of circulating HDL oxidation products by providing a source of pro-oxidants; thus, future research will examine the association of Met(O) in apoA-I and measures of CVD. Potential modulators that might also be evaluated in future clinical studies, in addition to antioxidants, include ACE inhibitors, angiotensin receptor blockers (56–58), and HMG-CoA reductase inhibitors (59), which are more likely to be used by patients with complications and which have antioxidant effects.

The entire DCCT/EDIC cohort of patients is being followed to address the predictors of diabetes complications. HDL quality could modulate diabetes-associated microvascular and macrovascular damage. If HDL oxidation proves to be pathogenically important, then it may also be a therapeutic target and Met(O) levels measured by careful and specific methodology may prove to be a useful surrogate end point to assist in the goal of reducing the burden of vascular complications in diabetes.


   APPENDIX
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 APPENDIX
REFERENCES
 
Participants of the DCCT/EDIC Research Group
Albert Einstein College of Medicine: H. Shamoon, H. Duffy, S. Engel, and H. Engel; Case Western Reserve University: S. Genuth (study co-chairman), W. Dahms, L. Mayer, S. Pendegras, H. Zegarra, D. Miller, and L. Singerman; Cornell University Medical Center: D. Brillion, M. Lackaye, M. Heinemann, F. Rahhal, V. Reppuci, and T. Lee; Henry Ford Health System: F. Whitehouse, D. Kruger, and J. D. Carey; International Diabetes Center: R. Bergenstal, M. Johnson, D. Kendall, M. Spencer, D. Noller, K. Morgan, and D. Etzwiler; Joslin Diabetes Center: A. Jacobson, E. Golden, D. Soroko, G. Sharuk, P. Arrigg, and J. Doyle; Massachusetts General Hospital: D. Nathan (study co-chairman), S. Fritz, J. Godine, C. McKitrick, and P. Lou; Mayo Foundation: J. Service, G. Ziegler, and J. Pach; Medical University of South Carolina: J. Colwell, D. Wood, R. Mayfield, K. Hermayer, M. Szpiech, T. Lyons, J. Parker, A. Farr, S. Elsing, and T. Thompson; Northwestern University: M. Molitch, B. Schaefer, L. Jampol, D. Weinberg, and A. Lyon; University of California, San Diego: O. Kolterman, G. Lorenzi, and M. Goldbaum; University of Iowa: W. Sivitz, M. Bayless, R. Zeither, T. Weingeist, E. Stone, H. Culver Boidt, K. Gehies, and S. Russell; University of Maryland School of Medicine: D. Counts, A. Kowarski, D. Ostrowski, T. Donner, S. Steidl, and B. Jones; University of Michigan: W. Herman, D. Greene, C. Martin, M. J. Stevens, A. K. Vine, and S. Elner; University of Minnesota: J. Bantle, B. Rogness, T. Olsen, E. Steuer, and S. Kaushel; University of Missouri: D. Goldstein, S. Hitt, J. Giangiacomo, and L. D. Ormerod; University of New Mexico: D. Schade, J. Canady, M. Schluster, A. Das, and D. Hornbeck; University of Pennsylvania: S. Schwartz, B. J. Maschak-Carey, L. Baker, and S. Braunstein; University of Pittsburgh: T. Orchard, N. Silvers, T. Songer, B. Doft, S. Olson, R. L. Bergren, and M. Fineman; University of South Florida: J. Malone, H. Wetz, C. Berger, R. Gstalder, and P. R. Pavan; University of Tennessee: M. Bryer-Ash, A. Kitabchi, H. Lambeth, M. B. Murphy, S. Moser, and D. Meyer; University of Texas Southwestern University Medical Center: P. Raskin, S. Strowig, A. Edwards, J. Alappatt, C. Wilson, and S. Park; University of Toronto: B. Zinman, A. Barnie, S. Mac-Lean, R. Devenyi, M. Mandelcorn, and M. Brent; University of Washington: J. Palmer, S. Catton, J. Kinyoun, and L. Van Ottingham; University of Western Ontario: J. Dupre, J. Harth, C. Canny, and D. Nicolle; Vanderbilt University: M. May, R. Lorenz, J. Lipps, L. Survant, S. Feman, and Tawansy; Washington University, St. Louis: N. White, J. Santiago, L. Levandoski, I. Boniuk, G. Grand, M. Thomas, D. Burgess, D. Joseph, and K. Blinder; Yale University School of Medicine: W. Tamborlane, P. Gatcomb, and K. Stroessel; Clinical Coordinating Center (Case Western Reserve University): B. Dahms, R. Trail, and J. Quin; Data Coordinating Center (The George Washington University, Biostatistics Center): J. Lachin, P. Cleary, D. Kenny, J. Backlund, L. Diminick, A. Henry, K. Klump, and D. Lamas; Molecular Risk Factors Program Project (Medical University of South Carolina): W. T. Garvey, T. J. Lyons, A. Jenkins, R. Klein, M. Lopes-Virella, G. Virella, A. A. Jaffa, D. Zheng, D. Lackland, D. McGee, and R. K. Mayfield.


   ACKNOWLEDGMENTS
 
This work was supported by National Institutes of Health Grant DK-19971, the Juvenile Diabetes Research Foundation, and the American Diabetes Association. The authors acknowledge the support of Dr. Daniel T. Lackland and Dr. M. Brent McHenry at the Medical University of South Carolina for assistance with study design, Dr. James D. Otvos of LipoScience, Inc. (Raleigh, NC), for NMR analyses, and Karina Moller, Zina Valaydon, and Connie Karschimkus for lipoprotein preparation.

Manuscript received April 30, 2007 and in revised form January 11, 2008.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
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