The effect of the accessory proteins, soluble CD14 and lipopolysaccharide-binding protein on Toll-like receptor 4 activity in human monocytes and adipocytes.

BACKGROUND: There is a growinge body of evidence pointing towards an important role for Toll-like receptors (TLR) especially TLR4 in obesity and metabolic syndrome. OBJECTIVE: Owing to the paucity of data on the effect of the accessory proteins, lipopolysaccharide (LPS)-binding protein (LBP) and soluble CD14 (sCD14) on TLR4 activation, the present study was undertaken to examine the effect of sCD14 and LBP on TLR4 activation in pivotal cells of meta-inflammation, monocytes and adipocytes. METHODS: The dose-response effects of sCD14 and LBP on TLR4 protein abundance in monocytes obtained from normal human volunteers was determined by flow cytometry and in human-differentiated adipocytes by western blotting. Additionally, the nuclear factor-kappaB (NF-κB) p65 and downstream biomediators interleukin (IL)-1ß, IL-8, IL-6 and tumor necrosis factor (TNF)-α were measured in the cell culture supernatants by ELISA (enzyme-linked immunosorbent assay). RESULTS: In LPS-primed monocytes, sCD14 but not LBP, augments both TLR4 abundance and inflammatory biomediators (IL-1ß, IL-8, IL-6 and TNF-α).sCD14 also showed a similar effect in LPS-primed human adipocytes by augmenting TLR4 protein expression and activity in terms of NF-κB p65 and downstream biomediators (IL-1ß, IL-8, IL-6 and TNF-α). LBP at the highest concentration only promoted secretion of IL-8 and TNF-α. However in both monocytes and adipocytes, the effect of sCD14 was superior to LBP. CONCLUSIONS: In the present report, we make the novel observation that sCD14 compared with LBP, offers a preferred target to ameliorate TLR especially TLR4-induced inflammation and insulin resistance in human obesity and metabolic syndrome.

Small interfering-RNA to protein kinase C-delta reduces the proinflammatory effects of human C-reactive protein in biobreeding diabetic rats.

Type 1 diabetes (T1DM) is a proinflammatory state characterized by increased C-reactive protein (CRP) levels. Previously we reported that human CRP accentuated macrophage activity in spontaneously diabetic biobreeding (BB) rats and also increased protein kinase C (PKC) delta. Hence we tested the effect of molecular inhibition of PKC delta on plasma and macrophage proinflammatory biomarkers using small interfering (si)RNA to PKC delta. Prior to administration of human CRP, daily for 3 days to diabetic rats, scrambled siRNA or siRNA to PKC delta was also delivered for the 3 days, and the animals were sacrificed on day 4. Peritoneal macrophages and plasma were obtained. Compared to scrambled siRNA, siRNA to PKC delta resulted in a significant decrease in biomediators of inflammation in plasma and from macrophages (IL-1, TNF-alpha, IL-6, MCP-1, KC/IL-8, and PAI -1). However, siRNA to PKC delta has no effect on superoxide release from macrophages. In conclusion, our novel data suggests that siRNA to PKC delta attenuates the proinflammatory effect of human CRP in spontaneously diabetic BB rats and could have implications with regard to attenuating inflammation and vascular complications in T1DM.

Low vitamin D levels in Northern American adults with the metabolic syndrome.

Metabolic syndrome (MetS), is a constellation of cardiometabolic disease risk factors, that affects 1 in 3 US adults and predisposes to increased risks for both diabetes and cardiovascular disease. While epidemiological studies show low vitamin D [(25(OH)D] levels in MetS, there is sparse data on vitamin D status in MetS patients in North America. Thus, the aim of our study was to examine plasma vitamin D concentration among adults with MetS in Northern California (sunny climate), but without diabetes or cardiovascular disease. 25(OH)D levels were significantly decreased in MetS compared to controls. 8 % of controls and 30% of MetS North American adult subjects were deficient in 25(OH)D (<20 ng/ml; p=0.0236, Controls vs. MetS). There were no significant differences between the groups with respect to blood sampling in winter and summer months, total calcium and phosphate, and creatinine levels. Vitamin D levels were significantly inversely correlated with fasting glucose (r=-0.29, p=0.04) and HOMA (r=-0.34, p=0.04). Future studies of vitamin D supplementation in these subjects on subsequent risk of diabetes will prove instructive with respect to potential health claims in these high risk patients with MetS.

Increased levels of ligands of Toll-like receptors 2 and 4 in type 1 diabetes.

AIMS/HYPOTHESIS: Type 1 diabetes is a proinflammatory state characterised by increased levels of circulating biomarkers of inflammation and monocyte activity. We have shown increased Toll-like receptor 2 (TLR2) and TLR4 expression and signalling in monocytes from type 1 diabetic patients. Several endogenous ligands of TLR2 and TLR4 have been identified; however, there is a paucity of data on levels of these endogenous ligands in diabetes. Thus, the aim of this study was to examine circulating levels of exogenous/endogenous ligands of TLR2 and TLR4 in type 1 diabetic patients and to compare these with the levels in matched healthy controls. METHODS: Healthy controls (n = 37) and type 1 diabetic patients (n = 34) were recruited, and a fasting blood sample was obtained. Circulating levels of endotoxin, heat-shock protein 60 (Hsp60), high-mobility group box 1 (HMGB1) and growth arrest-specific 6 (GAS6) proteins were assessed by ELISA, and TLR2 and TLR4 expression was determined by flow cytometry. RESULTS: Levels of the classical TLR4 ligand, endotoxin, were significantly elevated in type 1 diabetic patients compared with those in matched controls. Hsp60 and HMGB1 concentrations were also significantly increased in the patients (p < 0.01 and p < 0.001, respectively). No significant differences were observed in GAS6. CONCLUSIONS/INTERPRETATION: We report the novel observation that levels of ligands of TLR2 and TLR4 are significantly elevated in type 1 diabetes, and this, in concert with hyperglycaemia, accounts for the increase in TLR2 and TLR4 activity, underscoring the proinflammatory state of type 1 diabetes.

Nontraditional risk factors for cardiovascular disease in diabetes.

People with type 2 diabetes are disproportionately affected by cardiovascular disease (CVD), compared with those without diabetes. Traditional risk factors do not fully explain this excess risk, and other "nontraditional" risk factors may be important. This review will highlight the importance of nontraditional risk factors for CVD in the setting of type 2 diabetes and discuss their role in the pathogenesis of the excess CVD morbidity and mortality in these patients. We will also discuss the impact of various therapies used in patients with diabetes on nontraditional risk factors.

Preservation of the endogenous antioxidants in low density lipoprotein by ascorbate but not probucol during oxidative modification.

Several lines of evidence indicate that the oxidative modification of low density lipoproteins (LDL) may provide an important link between plasma LDL and the genesis of the atherosclerotic lesion. Ascorbate is an important water-soluble, chain-breaking antioxidant in humans. Probucol, a lipid-soluble antioxidant drug has been shown to retard the progression of atherosclerosis. The aim of the present study was to compare the effects of probucol and physiologic levels of ascorbate on the oxidative modification of LDL in both a cell-free (2.5 microM Cu++ in phosphate-buffered saline) and cellular system (human monocyte macrophages in Ham's F-10 medium). Both ascorbate and probucol inhibited the oxidative modification of LDL in both systems to a similar degree as evidenced by the thiobarbituric acid-reacting substance activity, electrophoretic mobility, and degradation by macrophages. However, whereas co-incubation with physiologic levels of ascorbate resulted in a substantial preservation of the alpha-tocopherol, gamma-tocopherol, and beta-carotene of the LDL, probucol in concentrations ranging from 10 to 80 microM failed to protect these antioxidants. Thus, in addition to being as potent as probucol in inhibiting the oxidation of LDL, ascorbate in contrast preserves the endogenous antioxidants in the LDL.

The effects of alpha tocopherol supplementation on monocyte function. Decreased lipid oxidation, interleukin 1 beta secretion, and monocyte adhesion to endothelium.

Low levels of alpha tocopherol are related to a higher incidence of cardiovascular disease and increased intake appears to afford protection against cardiovascular disease. In addition to decreasing LDL oxidation, alpha tocopherol may exert intracellular effects on cells crucial in atherogenesis, such as monocytes. Hence, the aim of this study was to test the effect of alpha tocopherol supplementation on monocyte function relevant to atherogenesis. Monocyte function was assessed in 21 healthy subjects at baseline, after 8 wk of supplementation with d-alpha tocopherol (1,200 IU/d) and after a 6-wk washout phase. The release of reactive oxygen species (superoxide anion, hydrogen peroxide), lipid oxidation, release of the potentially atherogenic cytokine, interleukin 1 beta, and monocyte-endothelial adhesion were studied in the resting state and after activation of the monocytes with lipopolysaccharide at 0, 8, and 14 wk. There was a 2.5-fold increase in plasma lipid-standardized and monocyte alpha tocopherol levels in the supplemented phase. After alpha tocopherol supplementation, there were significant decreases in release of reactive oxygen species, lipid oxidation, IL-1 beta secretion, and monocyte-endothelial cell adhesion, both in resting and activated cells compared with baseline and washout phases. Studies with the protein kinase C inhibitor, Calphostin C, suggest that the inhibition of reactive oxygen species release and lipid oxidation is due to an inhibition of protein kinase C activity by alpha tocopherol. Thus, this study provides novel evidence for an intracellular effect of alpha tocopherol in monocytes that is antiatherogenic.

Increased fibrosis and angiogenesis in subcutaneous gluteal adipose tissue in nascent metabolic syndrome.

AIMS: Metabolic syndrome (MetS) is globally a common disorder that predisposes to both diabetes and cardiovascular disease (CVD). There is a paucity of data on fibrosis and angiogenesis in adipose tissue (AT) in patients with nascent MetS uncomplicated by diabetes or CVD. Hence, we assayed various indices of fibrosis and angiogenesis in subcutaneous AT (SAT). METHODS: In both patients with MetS and matched controls, we determined fibrosis and the densities of CD31, VEGF and Angiopoietin (Angio) 2 and 1 by immunohistochemistry in gluteal SAT. RESULTS: The fibrosis score was significantly increased in SAT of Met S. Also, both CD31 and VEGF densities were significantly increased. Surprisingly, Angio-2 was not increased and the ratio of Angio2:1 was decreased. Both indices of fibrosis and angiogenesis correlated with biomediators of inflammation. CONCLUSIONS: In conclusion, we report increased fibrosis and paradoxical increased angiogenesis in gluteal SAT and speculate that the increased angiogenesis is a protective mechanism in mitigating further adipose tissue dysregulation in this depot.

Heterozygosity for the mouse Apex gene results in phenotypes associated with oxidative stress.

Apurinic/apyrimidinic endonuclease is a key enzyme in the process of base excision repair, required for the repair of spontaneous base damage that arises as a result of oxidative damage to DNA. In mice, this endonuclease is coded by the Apex gene, disruption of which is incompatible with embryonic life. Here we confirm the embryonic lethality of Apex-null mice and report the phenotypic characterization of mice that are heterozygous mutants for the Apex gene (Apex+/-). We show that Apex heterozygous mutant cells and animals are abnormally sensitive to increased oxidative stress. Additionally, such animals manifest elevated levels of oxidative stress markers in serum, and we show that dietary supplementation with antioxidants restores these to normal levels. Apex+/- embryos and pups manifest reduced survival that can also be partially rescued by dietary supplementation with antioxidants. These results are consistent with a proposed role for this enzyme in protection against the deleterious effects of oxidative stress and raise the possibility that humans with heterozygous mutations in the homologous HAP1 gene may be at increased risk for the phenotypic consequences of oxidative stress in cells.

beta-Carotene inhibits the oxidative modification of low-density lipoprotein.

Several lines of evidence indicate that oxidized LDL (Ox-LDL) may promote atherogenesis. Hence, the role of antioxidants in the prevention of LDL oxidation needs to be determined. beta-Carotene, in addition to being an efficient quencher of singlet oxygen, can also function as a radical-trapping antioxidant. Since previous studies have failed to show that beta-carotene inhibits LDL oxidation, we re-examined its effect on the oxidative modification of LDL. For these studies, LDL was oxidized in both a cell-free (2.5 microM Cu2+ in PBS) and a cellular system (human monocyte macrophages in Ham's F-10 medium). beta-Carotene inhibited the oxidative modification of LDL in both systems as evidenced by a decrease in the lipid peroxide content (thiobarbituric-acid-reacting substances activity), the negative charge of LDL (electrophoretic mobility) and the formation of conjugated dienes. By inhibiting LDL oxidation, beta-carotene substantially decreased its degradation by macrophages. beta-Carotene (2 microM) was more potent than alpha-tocopherol (40 microM) in inhibiting LDL oxidation. Thus, beta-carotene, like ascorbate and alpha-tocopherol, inhibits LDL oxidation and might have an important role in the prevention of atherosclerosis.

Identification of two new LDL-receptor mutations causing homozygous familial hypercholesterolemia in a South African of Indian origin.

South Africans of Indian origin have a high frequency of Familial Hypercholesterolemia (FH). Fibroblasts from a South African Indian FH homozygote, D, expressed about 30% of the normal number of LDL receptors. These receptors showed defective LDL binding. Sequence and haplotype analysis revealed that D had two different mutant LDL receptor alleles: FH Durban-1 is a point mutation [asp69(GAT) to tyr(TAT)] in ligand-binding repeat 2 and FH Durban-2 is a point mutation [glu119(GAG) to lys(AAG)] in ligand-binding repeat three of the LDL receptor. Single-strand conformational polymorphism analysis, which was used in the initial detection of these mutations, was also employed for subsequent population screening assays. These mutations were not detected in any of the South African Indian FH or hypercholesterolemic patients that were screened.

Low-density lipoprotein postsecretory modification, monocyte function, and circulating adhesion molecules in type 2 diabetic patients with and without macrovascular complications: the effect of alpha-tocopherol supplementation.

BACKGROUND: Although diabetes confers an increased propensity toward accelerated atherogenesis, data are lacking on monocyte activity in type 2 diabetic patients with (DM2-MV) and without (DM2) macrovascular disease compared with control subjects. Thus, we tested whether (1) postsecretory modifications of LDL (glycation and oxidation), monocyte proatherogenic activity, and circulating levels of soluble cell adhesion molecules (sCAMs) are more pronounced in DM2-MV than in DM2 and control subjects and (2) RRR-alpha-tocopherol (AT) therapy, 1200 IU/d for 3 months, has a similar effect in the 3 groups (n=25 per group). METHODS AND RESULTS: Although LDL glycation was increased in both diabetic groups compared with control subjects, AT therapy had no significant effect on glycation. AT therapy significantly decreased LDL oxidizability in all 3 groups. Diabetic monocytes released significantly more superoxide anion (O(2)(-)) and interleukin-1beta (IL-1beta) and exhibited greater adhesion to endothelium than control subjects. AT therapy significantly decreased the release of O(2)(-), IL-1beta, tumor necrosis factor-alpha, and monocyte-endothelium adhesion in all 3 groups. There was no significant difference between the 2 diabetic groups for any of the above parameters. sICAM levels were significantly elevated in both diabetic groups compared with controls. AT therapy resulted in a significant decrease in sCAMs. CONCLUSIONS: This is the first demonstration of increased IL-1beta secretion and increased adhesion of monocytes to endothelium from normotriglyceridemic diabetic subjects and of decreased monocyte activity and sCAMs with AT therapy in diabetic subjects with and without macrovasculopathy.

Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels.

BACKGROUND: Prospective studies indicate that baseline levels of C-reactive protein (CRP), the prototypic marker of inflammation, are associated with an increased risk for cardiovascular events. Limited studies have examined therapies that influence high-sensitive CRP (hs-CRP) levels, especially in hyperlipidemic patients. Thus, we tested the effects of 3 hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), simvastatin (20 mg/d), pravastatin (40 mg/d), and atorvastatin (10 mg/d), on levels of hs-CRP in a randomized, double-blind, crossover trial of 22 patients with combined hyperlipidemia (LDL cholesterol >130 mg/dL and triglycerides of 200 to 600 mg/dL). METHODS AND RESULTS: After 6 weeks of an American Heart Association Step 1 diet, fasting blood samples were drawn at baseline and after 6 weeks of therapy with each drug. hs-CRP levels were significantly decreased after treatment with all 3 statins compared with baseline (median values: baseline, 2.6 mg/L; atorvastatin, 1.7 mg/L; simvastatin, 1.7 mg/L; and pravastatin, 1.9 mg/L; P<0.025). The reductions obtained with the 3 statins were similar. In addition, there was no significant effect on either plasma interleukin-6 or interleukin-6 soluble receptor levels. There was no relationship between reductions in hs-CRP and LDL cholesterol. CONCLUSIONS: Pravastatin, simvastatin, and atorvastatin significantly decreased levels of hs-CRP. These data support an anti-inflammatory effect of these drugs.

Processing of insulin by bovine endothelial cells in culture. Internalization without degradation.

Insulin binding and processing was studied in monolayer cultures of bovine aortic endothelial cells. Specific 125I-insulin binding was both time and temperature dependent. Maximum binding at 37 degrees C occurred at 90 min, and was 3.8%/mg protein and, at 15 degrees C, 7%/mg protein at 4 h. 125I-insulin was crosslinked to its receptor using disuccinimidyl suberate (DSS), and the structure of the receptor complex was identified by SDS-polyacrylamide gel electrophoresis and autoradiography; a major band with Mr = 145,000 was identified, which corresponds to the alpha-subunit of the insulin receptor reported in other tissues. Receptor-bound insulin was internalized, and both the rate and the amount of internalization were temperature dependent. The rate of internalization was slowest at 4 degrees C, and fastest at 37 degrees C, and the maximum amount of 125I-insulin internalized in 120 min was 16% at 4 degrees C, 45% at 15 degrees C, and 81% at 37 degrees C. Despite the high rate of internalization, endothelial cells do not appear to degrade insulin significantly, as determined by gel chromatography and TCA solubility (7% at 4 h) of media-associated radioactivity. In addition, the majority of internalized insulin (75%) was released by 60 min, largely as intact insulin. Chloroquine treatment at high concentration did not exert any major effect on insulin binding or degradation within the first 60 min, but thereafter produced a marked increase in cell-associated radioactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of low-dose aspirin on serum C-reactive protein and thromboxane B2 concentrations: a placebo-controlled study using a highly sensitive C-reactive protein assay.

OBJECTIVES: We performed a placebo-controlled study to evaluate the effect of low-dose aspirin on serum C-reactive protein (CRP) levels. BACKGROUND: Elevated circulating concentrations of CRP, an inflammatory marker, increase the risk of thrombotic cardiovascular diseases such as myocardial infarction (MI). Moreover, low-dose aspirin therapy has been reported to be more effective in preventing MI in men with higher CRP levels than it is in those with lower levels, raising the possibility that aspirin prevents thrombosis by reducing vascular inflammation. The effect of low-dose aspirin therapy on serum CRP levels in men has been addressed recently, but the results of the two studies conflict. METHODS: Effects of aspirin (81 mg every day or 325, 81 or 40 mg every-third-day given for 31 days) on serum CRP, using a highly-sensitive assay, and on serum platelet-cyclo-oxygenase (COX)-1-derived thromboxane (Tx) B2 concentrations were studied simultaneously in 57 healthy volunteers (30 men and 27 women). RESULTS: Trough platelet COX-1-derived serum Tx B2 concentrations decreased by 100% with daily aspirin and by 90%, 84% and 78% with 325, 81 and 40 mg aspirin every-third-day (p < 0.001). However, there were no significant changes in serum CRP levels from baseline with daily low-dose aspirin therapy, with any of the every-third-day aspirin regimens or with placebo treatment. CONCLUSIONS: Low doses of aspirin that markedly inhibit platelet COX-1 activity, as manifested by a profound decline in platelet-derived serum Tx B2 concentrations, have no detectable effect on serum CRP levels in healthy men and women.

Effect of statin therapy on remnant lipoprotein cholesterol levels in patients with combined hyperlipidemia.

Clinical trials with statins have demonstrated significant reductions in cardiovascular events. Remnant lipoproteins are independent predictors of cardiovascular events. Because of the paucity of data on the effect of statins on remnant lipoproteins, we tested the effect of pravastatin, simvastatin, and atorvastatin on remnant lipoprotein cholesterol (RLP-C) levels in a randomized crossover study in patients with combined hyperlipidemia. After a 6-week diet phase, patients (n=22) were randomized to pravastatin (40 mg/d), simvastatin (20 mg/d), or atorvastatin (10 mg/d) for 6 weeks, with a 3-week washout between each drug. All 3 drugs significantly decreased total and low density lipoprotein (LDL) cholesterol (P<0.001). Mean reduction in LDL cholesterol with pravastatin, simvastatin, and atorvastatin was 21%, 29%, and 32%, respectively. None of the drugs affected high density lipoprotein cholesterol levels. Median levels of triglycerides were significantly reduced with simvastatin (26%, P=0.001) and atorvastatin (24%, P=0.0001) but not with pravastatin (9%, P=0.18). Non-high density lipoprotein cholesterol decreased significantly with all 3 statins (20%, 29%, and 32% with pravastatin, simvastatin, and atorvastatin, respectively; P<0.001). Median RLP-C levels were significantly reduced with simvastatin (6%, P<0.05) and atorvastatin (25.9%, P<0.001) but not with pravastatin (2.9%, P=0.58). Thus, atorvastatin and simvastatin, in addition to reducing LDL cholesterol and triglyceride levels, significantly reduced RLP-C levels. This could be another potential mechanism to explain their cardiovascular benefits.

Obesity does not modulate insulin secretion in Indian patients with non-insulin-dependent diabetes in the young.

The insulin response to a 100-g oral glucose load was studied in 40 obese (percent desirable weight greater than or equal to 120%) and 40 nonobese (less than 120%) age- and sex-matched Indian patients with non-insulin-dependent diabetes in the young. There were no significant differences between the obese and nonobese patients with respect to their insulin and glucose responses. Thus, it appears that obesity does not exert a significant modulating effect on insulin secretion in patients with fasting hyperglycemia.

Nephropathy in Indian patients with non-insulin-dependent diabetes in the young.

In 85 patients diagnosed as having non-insulin-dependent diabetes in the young (NIDDY), 6 were found to have nephropathy. The duration of diabetes ranged from 2 to 17 yr; 5 of the 6 patients had retinopathy as evidenced by fluoroscein angiography (3 with proliferative changes). All 6 patients had a 24-h urinary protein excretion greater than 0.5 g and a glomerular filtration rate less than 80 ml/min. Serum beta 2-microglobulin levels were increased in all 6 patients, while only 3 had increased serum creatinine levels.

Acute insulin response to glucagon, tolbutamide, and glucose in non-insulin-dependent diabetes of the young.

Acute insulin release in response to maximal intravenous doses of glucose (0.5 g/kg), tolbutamide (1 g), and glucagon (1 mg) was studied in 10 subjects with non-insulin-dependent diabetes of the young (NIDDY) and 10 age-, sex-, and weight-matched controls. Diabetic subjects had attenuated insulinemic responses to all three stimuli, in comparison with control subjects. However, insulin responses to glucagon and tolbutamide were higher than those obtained with intravenous glucose. This study demonstrates that the pancreatic beta-cell is more responsive to nonglucose secretagogues than to glucose stimuli in individuals with NIDDY.

Plasma oxidizability in subjects with normal glucose tolerance, impaired glucose tolerance, and NIDDM.

OBJECTIVE: Several lines of evidence support an atherogenic role for oxidized low-density lipoprotein (LDL). Studies on LDL oxidation in diabetes to date have examined LDL isolated from plasma, but have failed to evaluate the other pro- and antioxidant factors present in vivo, the balance of which could be crucial in determining the susceptibility of LDL to lipid peroxidation. RESEARCH DESIGN AND METHODS: We examined the oxidizability of plasma from Mexican-Americans in the San Antonio Heart Study. The oxidizability of plasma in 75 subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and non-insulin-dependent diabetes mellitus (NIDDM) was studied after co-incubation with a free radical initiator, 2,2'-azobis-2-amidinopropane hydrochloride (AAPH). Lipid peroxide (LPO) levels were measured by a modified fluorimetric assay. RESULTS: Baseline LPO levels (mumol/l; means +/- SE) were similar in the three glucose tolerance categories (NGT, 1.99 +/- 0.07; IGT, 1.88 +/- 0.07; NIDDM, 1.97 +/- 0.07; P = 0.521). However, after incubation with AAPH (NGT, 4.30 +/- 0.20; IGT, 4.45 +/- 0.20; NIDDM, 5.35 +/- 0.20; P = 0.003), the diabetic plasma had significantly greater amounts of LPOs compared with the other two groups. There was no significant difference in LPOs between the NGT and IGT groups. The statistical significance of increased oxidizability of the diabetic plasma persisted after exclusion of patients who smoked cigarettes (n = 15) or who had vascular disease (n = 4). CONCLUSIONS: In conclusion, this study shows that the plasma of Mexican-American subjects with NIDDM is more prone to lipid peroxidation than that of non-Hispanic whites.