This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pleiner, J. Articles by Wolzt, M. Search for Related Content PubMed PubMed Citation Articles by Pleiner, J. Articles by Wolzt, M.

FFA-Induced Endothelial Dysfunction Can Be Corrected by Vitamin C

Departments of Clinical Pharmacology (J.P., G.S., F.M., M.R., M.W.) and Department of Internal Medicine III, Endocrinology (M.B.-E., M.R.), University of Vienna, Vienna A-1090, Austria

Address all correspondence and requests for reprints to: Dr. Michael Wolzt, Department of Clinical Pharmacology, Allgemeines Krankenhaus Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: . michael.wolzt{at}univie.ac.at

Abstract

Insulin resistance is associated with an inappropriate elevation of plasma FFA and endothelial dysfunction. FFA could stimulate formation of reactive oxygen species, which could be responsible for vascular impairment. In this randomized, double-blind, cross-over study in 10 healthy volunteers (24 ± 3 yr old), forearm blood flow (FBF) responses to intraarterial acetylcholine (ACh) and glyceryl trinitrate were assessed with coadministration of vitamin C (24 mg/ml) or placebo, respectively, in the presence of increased plasma FFA induced by Intralipid/heparin infusion. The rise in plasma FFA from 320 ± 64 to 1852 ± 232 µmol/liter was associated with a reduced response of FBF to ACh by 55% (P < 0.01). During coadministration of vitamin C, the impaired responsiveness of FBF to ACh was completely reversed and not different from that observed under baseline conditions. Vitamin C did not affect plasma FFA concentrations. Glyceryl trinitrate responsiveness was unchanged during FFA elevation, with or without vitamin C. These data suggest that FFA-induced vascular oxidative stress could contribute to endothelial dysfunction in insulin-resistant patients. High concentrations of antioxidants are able to reverse the local effects of FFA on endothelium-dependent vasodilation.

INSULIN RESISTANCE, WHICH is found in conditions such as type 2 diabetes mellitus, obesity, hypertension, and dyslipidemia, is characterized by an impaired insulin-mediated glucose metabolism of the skeletal muscle (1). Inappropriate elevation of plasma FFA is seen in insulin resistance (2), and this impaired metabolism is associated with endothelial dysfunction (3).

It is generally accepted that the vascular endothelium plays an important role in regulating vascular tone, leukocyte adhesion, thrombocyte activation, and vascular remodeling because of formation of bioactive substances such as nitric oxide (NO), prostacyclin, and endothelin (4, 5). Endothelial dysfunction is thought to be a key factor in the development of cardiovascular diseases.

Recently, FFA were shown to increase the formation of reactive oxygen species (ROS) in endothelial and vascular smooth muscle cells (6). These heterogeneous groups of highly reactive compounds can interact with NO and thereby inhibit endothelium-dependent vasodilation. In vitro studies revealed that impaired endothelium-dependent relaxation by FFA was reversed by the ROS scavenger superoxide dismutase (7). Formation of ROS is therefore thought to be an important mechanism by which FFA induce endothelial dysfunction. There is, however, a lack of human experimental models or trials in patients that confirm these experimental data in vivo.

Therefore, the purpose of the present study was to test the effect of the antioxidant vitamin C on endothelium-dependent and -independent vasodilation during increased circulating concentrations of FFA in healthy subjects, employing forearm strain gauge plethysmography. The efficacy of vitamin C as an antioxidant was already shown in patients with diabetes (8), in whom it improved endothelium-dependent vasodilation, as well as in healthy humans, in whom hyperglycemia-induced vascular dysfunction was restored (9).

Materials and Methods

Study population

Ten healthy male subjects from whom informed consent was obtained before enrollment were included in this double-blind, randomized, cross-over study. Subject characteristics are shown in Table 1. All of the subjects claimed not to have ingested any prescribed medications or over-the-counter drugs containing nonsteroidal anti-inflammatory drugs from 2 wk before screening until the study was complete. The study was approved by the Ethics Committee of the University of Vienna and conforms to the principles outlined in the Declaration of Helsinki including current revisions and the Good Clinical Practice guidelines. All subjects were given a complete health examination (including physical examination, electrocardiogram, and laboratory screening) within 14 d before the first study day. Subjects were studied after overnight fasting. All studies were started between 0800 and 0900 h. Studies were conducted in a quiet room with an ambient temperature of 22 C with complete resuscitation facilities.

Two study days were scheduled for each subject with a washout period of at least 7 d. Vitamin C or placebo was administered on the two different trial days during elevated plasma FFA concentrations in random sequence. Two plastic cannulas were inserted into antecubital veins for monitoring of plasma concentrations of outcome parameters and administration of Intralipid and heparin, respectively. A very fine needle (27G needle Sterican, B. Braun, Melsungen, Germany) was inserted into the brachial artery of the nondominant arm. After a 20-min resting period, baseline forearm blood flow (FBF) measurements were done for acetylcholine (ACh) and glyceryl trinitrate (GTN), and the systemic infusion of the Intralipid/heparin emulsion was started. Vitamin C or placebo was administered into the brachial artery 110 min later, and FBF responses to intraarterial infusions of ACh and GTN were repeated after another 10 min.

Blood samples for determination of insulin, glucose, vitamin C, and FFA plasma concentrations were drawn at baseline and at timed intervals throughout the study. Blood for measurement of FFA was collected in vials containing tetrahydrolipstatin to avoid in vitro lipolysis, which could have resulted in artificially high FFA concentrations (10). After collection, blood was immediately centrifuged and plasma was stored at -80 C until further analysis.

To study direct effects of vitamin C on endothelium-dependent and -independent vasodilation, control experiments with vitamin C alone, without prior FFA elevation, were performed on a third open-label trial day in eight additional volunteers (age 26 ± 3 yr). The schedule for this third study day was identical otherwise. Clinical and metabolic characteristics of these volunteers were not different from the other study participants.

Study drugs

The iv infusion of the lipid emulsion (Intralipid 20%, 1.5 ml/min; Pharmacia \|[amp ]\| Upjohn, Inc., Vienna, Austria) plus heparin (bolus: 200 IU; constant infusion rate: 0.2 IU/kg per min; Baxter AG, Vienna, Austria) was administered to achieve systemic FFA levels typical for severely insulin-resistant subjects (3). Heparin was added to enhance breakdown of triglycerides to FFA in plasma (11). To assess endothelium-dependent vasodilation of the human forearm, increasing doses of ACh (25, 50, and 100 nmol/min, CLINALFA, Läufelfingen, Switzerland) were infused into the brachial artery. Endothelium-independent vasodilation was assessed by intraarterial infusion of GTN (4, 8, and 16 nmol/min, G. Pohl Boskamp GmbH, Hohenlockstedt, Germany). Both vasodilators were infused for 3 min per dose level, with a 15-min washout period between both drugs (12). Vitamin C (ascorbic acid, 24 mg/min, Mayerhofer GmbH, Linz, Austria) or placebo (0.9% NaCl) was administered intraarterially at an infusion rate of 1.5 ml/min (8).

FBF measurements

FBF was measured as described previously (12, 13). Briefly, strain gauges, placed on the forearms, were connected to plethysmographs (EC-6, D.E. Hokanson, Bellevue, WA) and traces analyzed using the NIVP3 software (version 5.25, Hokanson). Bilateral plethysmography was used, expressing the responses as the ratio of blood flow in the intervention arm vs. the control arm (12, 13); baseline ratio was defined as 100%. Cuffs were placed around both upper arms and inflated to 45 mm Hg by a rapid cuff inflator (AG 101, D.E. Hokanson) during the measurements to occlude venous outflow. Wrist cuffs were inflated to suprasystolic pressures during each measurement to exclude circulation of the hands. Flow measurements were recorded for 9 sec at 30-sec intervals during drug infusion.

Biochemical assays

Glucose concentration was determined using the glucose oxidase method (glucose analyzer II, Beckmann Instruments, Fullerton, CA) (14, 15). Plasma concentrations of FFA were measured using enzymatic methods as described previously (14, 15). Insulin concentrations were determined using a double-antibody RIA (Diagnostics Systems Laboratories, Inc., Webster, TX). Vitamin C plasma concentrations were measured by the ascorbate oxidase method on a clinical chemistry analyzer (Roche/Hitachi 911, Basel, Switzerland).

Statistical analysis

Systemic hemodynamics and metabolic parameters were expressed as absolute values or percentage changes from baseline. FBF measurements were expressed as changes over baseline. The effects of ACh and GTN at baseline and following Intralipid/heparin administration were assessed by ANOVA for repeated measurements using the Statistica software package (release 4.5, StatSoft Inc., Tulsa, OK). Metabolic parameters were compared after log transformation using t test. A P value of 0.05 or less was considered significant. Values are expressed as means ± SEM unless indicated otherwise.

Results

All infusions were well tolerated and no adverse events were reported. Systemic hemodynamics and metabolic parameters were comparable between the trial days at baseline. Intralipid/heparin infusion caused a small increase in systolic and diastolic blood pressure from 123 ± 14 and 64 ± 12 mm Hg at baseline to 130 ± 15 and 75 ± 9 mm Hg, respectively, on both study days (P < 0.05, no significant difference between study days). No change in pulse rate was noted.

Effect of FFA and vitamin C on metabolic parameters

A summary of changes in metabolic parameters on both study days is given in Table 2. Administration of the Intralipid/heparin emulsion increased plasma FFA concentrations by approximately 6-fold (P < 0.001), with maximum concentrations at the end of infusion and no significant difference between the trial days. Glucose or insulin concentrations were not affected during Intralipid/heparin infusion on both trial days. Systemic vitamin C levels increased to 684% ± 199% after local intraarterial infusion of vitamin C (P < 0.001), and a slight nonsignificant decrease in vitamin C levels were observed under placebo conditions.

Baseline FBF was comparable between both study days. Administration of Intralipid/heparin was associated with a slight but significant increase in FBF from 4.5 ± 0.1 to 4.8 ± 0.1 ml/100 ml/min (P < 0.05), with no differences between both trial days.

Endothelium-dependent vasodilation to ACh was comparable at baseline on both trial days. Exogenously increased FFA concentrations significantly reduced the responses of FBF to ACh, which was not affected by infusion of placebo (Fig. 1). Intraarterial administration of vitamin C, which had no effect on baseline FBF, completely reversed the reduced responsiveness to ACh (Fig. 1).

View larger version (22K): [in this window] [in a new window]   Figure 1. Endothelium-dependent (ACh, top) and endothelium-independent (GTN, bottom) vasodilation at baseline (left) on the two trial days (-•- and --, respectively). During systemic Intralipid/heparin administration (right), vitamin C (--), or placebo (--) was infused into the brachial artery. The ratio of FBF [ratio (%): intervention vs. control arm, baseline defined as 100%] is expressed as mean ± SEM n = 10; *, P < 0.05; **, P < 0.01 (ANOVA).

Endothelium-dependent and -independent effects of vitamin C alone

Vitamin C alone increased systemic vitamin C levels from 66.1 ± 5.8 to 445.5 ± 36.2 µmol/liter (P < 0.001) but had no effect on baseline FBF or endothelium-dependent or -independent vasodilation (data not shown). No change in systemic hemodynamics or metabolic parameters was observed in this control experiment.

Discussion

This is the first study demonstrating in humans in vivo that the acute detrimental vascular action of elevated FFA on endothelial function can be abrogated by high local concentrations of the potent antioxidant vitamin C, which had no effects alone and did not affect circulating FFA concentrations. This indicates that oxidative stress might play a crucial role in the acute development of endothelial dysfunction induced by a rise in FFA.

FFA and vascular dysfunction

The exogenous infusion of Intralipid/heparin emulsion markedly increased plasma FFA concentrations. This elevation was comparable with former experiments at our (14, 15) and other institutions (11, 16, 17). In these studies it has been demonstrated that exogenous FFA administration does not influence plasma triglyceride concentrations. There was also little effect of increased FFA on circulating insulin concentrations, which is in agreement with some other (11, 16) but not all studies (17). Administration of the lipid emulsion mediated an increase in basal FBF, which is in accordance with previous trials (11, 16, 17). The reason for regional hyperperfusion in the forearm is poorly understood and may be owing to alterations on the L-arginine/NO pathway (18). However, this had no effect on GTN-mediated vasodilation alone or with placebo, rendering a confounding role of altered baseline blood flow unlikely for our experimental setup.

In contrast, endothelial response to ACh was substantially impaired during plasma FFA elevation. FFA have been found to attenuate endothelium-dependent relaxation of precontracted rabbit aortic rings (7) and endothelium-dependent vasodilation in healthy humans (11, 16, 17). Comparable with former studies (11), elevated plasma FFA caused a modest rise in systolic and diastolic blood pressure. This has been explained by reduced NO bioactivity or increased sensitivity of the vasculature to vasoconstrictors (19).

Several mechanisms have been proposed by which FFA could influence endothelium-dependent vasodilation. First, plasma FFA elevation lowers circulating levels of most amino acids including L-arginine (20), which may reduce the substrate for NO formation. In vitro, however, supplementation of high doses of L-Arginine did not improve lipoprotein-induced endothelial dysfunction (21). Direct inhibition of the NO synthesis by FFA has also been reported (22).

Kreutzenberg et al. (17) have investigated the role of cyclooxygenase and chain length of FFA in the development of endothelial dysfunction in humans. Their conclusion, however, was that neither inhibition of cyclooxygenase nor chain length of FFA influences the impaired endothelium-dependent vasodilation. It was further demonstrated that insulin can reverse endothelial dysfunction induced by exogenously administered lipids in healthy subjects (16). However, insulin concentrations were nearly unchanged in our experiments, and it is doubtful that this effect is also seen in insulin-resistant patients because they are also resistant to the vasodilatory action of insulin (23).

Vitamin C as an antioxidant

A more likely explanation for the mechanism underlying endothelial dysfunction by FFA is the increased formation of ROS, mainly superoxide anions, in vascular cells (6, 24). The most important source of ROS by FFA in intact arteries seems to be an activation of NAD(P)H oxidase, rather than arachidonic acid-metabolizing enzymes, xanthine oxidase, or mitochondrial sources (6, 25). Unfortunately, specific nicotinamide adenine dinucleotide phosphate antagonists or superoxide dismutase mimetics are not available for human use at the moment. Therefore, we have used an indirect intervention to reduce oxidative stress by administration of vitamin C, which was shown to be an efficient antioxidant in many clinical and in vitro studies (8, 9, 26).

In unsupplemented individuals vitamin C plasma concentrations of 30–60 µmol/liter were reported (27), which is in line with our baseline levels. Infusion of 24 mg/min of vitamin C for 10 min as used in our experiments yields a local forearm concentration of up to 10 mmol/liter. In vitro, this concentration of vitamin C was necessary to prevent the reaction between superoxide anions and NO (28). It is, however, doubtful that local infusion of vitamin C at lower concentrations or oral administration of vitamin C would have resulted in the same improvement of endothelium-dependent relaxation (29). This significant limitation of an oral therapy regimen with vitamin C has to be considered for clinical trials in patients.

Conclusion

In summary, we have demonstrated that an acutely impaired endothelial function by elevated FFA concentrations can be counteracted by an antioxidant therapy using vitamin C in vivo. Clinical strategies to reduce FFA levels or ROS formation could be beneficial for patients with increased plasma FFA levels.

Acknowledgments

We are grateful for the assistance and administrative work of Carola Fuchs, R.N.

Footnotes

This work was supported in part by a grant from the Austrian Science Foundation (FWF Grant 13213-MOB to M.R.).

Abbreviations: ACh, Acetylcholine; FBF, forearm blood flow; GTN, glyceryl trinitrate; NO, nitric oxide; ROS, reactive oxygen species.

Received December 28, 2001.

Accepted March 5, 2002.

References

1. Bonadonna RC, DeFronzo RA 1991 Glucose metabolism in obesity and type 2 diabetes. Diabetes Metab 17:112–135[Medline]
2. Colberg SR, Simoneau JA, Thaete FL, Kelley DE 1995 Skeletal muscle utilization of free fatty acids in women with visceral obesity. J Clin Invest 95:1846–1853
3. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD 1996 Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 97:2601–2610[Medline]
4. Palmer RM, Ferrige AG, Moncada S 1987 Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526[CrossRef][Medline]
5. Furchgott RF, Vanhoutte PM 1989 Endothelium-derived relaxing and contracting factors. FASEB J 3:2007–2018[Abstract]
6. Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H 2000 High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49:1939–1945[Abstract]
7. Niu XL, Liu LY, Hu ML, Chen X 1995 Some similarities in vascular effects of oleic acid and oxidized low-density lipoproteins on rabbit aorta. J Mol Cell Cardiol 27:531–539[Medline]
8. Ting HH, Timimi FK, Boles KS, Craeger SJ, Ganz P, Craeger MA 1996 Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 97:22–28[Medline]
9. Beckman JA, Goldfine AB, Gordon MB, Creager MA 2001 Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 103:1618–1623[Abstract/Free Full Text]
10. Krebs M, Stingl H, Nowotny P, Weghuber D, Bischof M, Waldhäusl W, Roden M 2000 Prevention of in vitro lipolysis by tetrahydrolipstatin. Clin Chem 46:950–954[Abstract/Free Full Text]
11. Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, Bayazeed B, Baron AD 1997 Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 100:1230–1239[Medline]
12. Pleiner J, Heere-Ress E, Langenberger H, Sieder AE, Bayerle-Eder M, Mittermayer F, Fuchsjäger-Mayrl G, Jansen B, Wolzt M 2002 Adrenoceptor hyporeactivity is responsible for LPS-induced acute vascular dysfunction in humans. Arterioscler Thromb Vasc Biol 22:95–100[Abstract/Free Full Text]
13. Petrie JR, Ueda S, Morris AD, Murray LS, Elliot HL, Connell JM 1998 How reproducible is bilateral forearm plethysmography? Br J Clin Pharmacol 45:131–139[CrossRef][Medline]
14. Roden M, Stingl H, Chandramouli V, Schumann WC, Hofer A, Landau BR, Nowotny P, Waldhausl W, Shulman GI 2000 Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. Diabetes 49:701–707[Abstract]
15. Polak K, Schmetterer L, Luksch A, Gruber S, Polska E, Peternell V, Bayerle-Eder M, Wolzt M, Krebs M, Roden M 2001 Free fatty acids/triglycerides increase ocular and subcutaneous blood flow. Am J Physiol Regul Integr Comp Physiol 280:R56–R61
16. Lind L, Fugmann A, Branth S, Vessby B, Millgard J, Berne C, Lithell H 2000 The impairment in endothelial function induced by non-esterified fatty acids can be reversed by insulin. Clin Sci (Lond) 99:169–174[Medline]
17. De Kreutzenberg SV, Crepaldi C, Marchetto S, Calo L, Tiengo A, Del Prato S, Avogaro A 2000 Plasma free fatty acids and endothelium-dependent vasodilation: effect of chain-length and cyclooxygenase inhibition. J Clin Endocrinol Metab 85:793–798[Abstract/Free Full Text]
18. De Fronzo RA, Tobin JD, Andres R 1979 Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol Endocrinol Metab Gastrointest Physiol 237:E214–E223
19. Stepniakowski KT, Goodfriend TL, Egan BM 1995 Fatty acids enhance vascular alpha-adrenergic sensitivity. Hypertension 25:774–778[Abstract/Free Full Text]
20. Ferrannini E, Barrett EJ, Bevilacqua S, Jacob R, Walesky M, Sherwin RS, DeFronzo RA 1986 Effect of free fatty acids on blood amino acid levels in human. Am J Physiol 250:E686–E694
21. Fontana L, McNeill KL, Ritter JM, Chowienczyk PJ 1999 Effects of vitamin C and of a cell permeable superoxide dismutase mimetic on acute lipoprotein induced endothelial dysfunction in rabbit aortic rings. Br J Pharmacol 126:730–734[CrossRef][Medline]
22. Davda RK, Stepniakowski KT, Lu G, Ullian ME, Goodfriend TL, Egan BM 1995 Oleic acid inhibits endothelial nitric oxide synthase by a protein kinase C-independent mechanism. Hypertension 26:764–770[Abstract/Free Full Text]
23. Laakso M, Edelman SV, Brechtel G, Baron AD 1992 Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 41:1076–1083[Abstract]
24. Paolisso G, Gambardella A, Tagliamonte MR, Saccomanno F, Salvatore T, Gualdiero P, D’Onofrio MV, Howard BV 1996 Does free fatty acid infusion impair insulin action also through an increase in oxidative stress? J Clin Endocrinol Metab 81:4244–4248[Abstract]
25. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG 1996 Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 97:1916–1923[Medline]
26. Frei B, England L, Ames BN 1989 Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci USA 86:6377–6381[Abstract/Free Full Text]
27. Evans RM, Currie L, Campbell A 1982 The distribution of ascorbic acid between various cellular components of blood, in normal individuals, and its relation to the plasma concentration. Br J Nutr 47:473–482[CrossRef][Medline]
28. Jackson TS, Xu A, Vita JA, Keaney Jr JF 1998 Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res 83:916–922[Abstract/Free Full Text]
29. Sherman DL, Keaney JF, Biegelsen ES, Duffy SJ, Coffman JD, Vita JA 2000 Pharmacological concentrations of ascorbic acid are required for the beneficial effect on endothelial vasomotor function in hypertension. Hypertension 35:936–941[Abstract/Free Full Text]

This article has been cited by other articles:

				F. Mittermayer, G. Schaller, J. Pleiner, K. Krzyzanowska, S. Kapiotis, M. Roden, and M. Wolzt Rosiglitazone Prevents Free Fatty Acid-Induced Vascular Endothelial Dysfunction J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2574 - 2580. [Abstract] [Full Text] [PDF]

				S. Watanabe, T. Tagawa, K. Yamakawa, M. Shimabukuro, and S. Ueda Inhibition of the Renin-Angiotensin System Prevents Free Fatty Acid-Induced Acute Endothelial Dysfunction in Humans Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2376 - 2380. [Abstract] [Full Text] [PDF]

				F. Mittermayer, J. Pleiner, G. Schaller, S. Zorn, K. Namiranian, S. Kapiotis, G. Bartel, M. Wolfrum, M. Brugel, J. Thiery, et al. Tetrahydrobiopterin corrects Escherichia coli endotoxin-induced endothelial dysfunction Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1752 - H1757. [Abstract] [Full Text] [PDF]

				S. Basi, L. B. Pupim, E. M. Simmons, M. T. Sezer, Y. Shyr, S. Freedman, G. M. Chertow, R. L. Mehta, E. Paganini, J. Himmelfarb, et al. Insulin resistance in critically ill patients with acute renal failure Am J Physiol Renal Physiol, August 1, 2005; 289(2): F259 - F264. [Abstract] [Full Text] [PDF]

				A. Ceriello, R. Assaloni, R. Da Ros, A. Maier, L. Piconi, L. Quagliaro, K. Esposito, and D. Giugliano Effect of Atorvastatin and Irbesartan, Alone and in Combination, on Postprandial Endothelial Dysfunction, Oxidative Stress, and Inflammation in Type 2 Diabetic Patients Circulation, May 17, 2005; 111(19): 2518 - 2524. [Abstract] [Full Text] [PDF]

				A. Ceriello and E. Motz Is Oxidative Stress the Pathogenic Mechanism Underlying Insulin Resistance, Diabetes, and Cardiovascular Disease? The Common Soil Hypothesis Revisited Arterioscler. Thromb. Vasc. Biol., May 1, 2004; 24(5): 816 - 823. [Abstract] [Full Text]

				S. K. Andersen, J. Gjedsted, C. Christiansen, and E. Tonnesen The roles of insulin and hyperglycemia in sepsis pathogenesis J. Leukoc. Biol., March 1, 2004; 75(3): 413 - 421. [Abstract] [Full Text] [PDF]

				J. R. Singleton, A. G. Smith, J. W. Russell, and E. L. Feldman Microvascular Complications of Impaired Glucose Tolerance Diabetes, December 1, 2003; 52(12): 2867 - 2873. [Abstract] [Full Text] [PDF]

				H. Urakawa, A. Katsuki, Y. Sumida, E. C. Gabazza, S. Murashima, K. Morioka, N. Maruyama, N. Kitagawa, T. Tanaka, Y. Hori, et al. Oxidative Stress Is Associated with Adiposity and Insulin Resistance in Men J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4673 - 4676. [Abstract] [Full Text] [PDF]

				M. A. Creager, T. F. Luscher, F. Cosentino, and J. A. Beckman Diabetes and Vascular Disease: Pathophysiology, Clinical Consequences, and Medical Therapy: Part I Circulation, September 23, 2003; 108(12): 1527 - 1532. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pleiner, J. Articles by Wolzt, M. Search for Related Content PubMed PubMed Citation Articles by Pleiner, J. Articles by Wolzt, M.