|
 |
|
|||||||
|
|||||||||
Diabetes Care 30:2685-2689, 2007
DOI: 10.2337/dc07-0748
© 2007 by the American Diabetes Association
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Cardiovascular and Metabolic Risk |
Insulin Sensitivity, Vascular Function, and Iron Stores in Voluntary Blood Donors
1 Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
2 American Red Cross Blood Services, Farmington, Connecticut, and Dedham, Massachusetts
Address correspondence and reprint requests to Stuart D. Katz, MD, Yale School of Medicine, 135 College St., Suite 301, New Haven, CT 06510. E-mail: stuart.katz{at}yale.edu
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONRESEARCH DESIGN AND METHODS--RESULTS--CONCLUSIONS--References |
|---|
OBJECTIVE— Reduced iron stores after blood donation are associated with improved vascular function and decreased cardiovascular risk. We sought to determine whether iron-dependent changes in glucose metabolism may contribute to improved vascular function in blood donors.
RESEARCH DESIGN AND METHODS— We conducted a prospective cross-sectional study in 21 high-frequency blood donors (more than eight donations in the last 2 years) and 21 low-frequency blood donors (one to two donations in the last 2 years) aged 50–75 years. Serum markers of iron stores, whole-body insulin sensitivity index (WBISI) during oral glucose tolerance testing, and flow-mediated dilation in the brachial artery were determined in all subjects.
RESULTS— Serum ferritin was decreased (median values 23 vs. 36 ng/ml, P < 0.05) and flow-mediated dilation in the brachial artery was increased (median values 5.9 vs. 5.3%, P < 0.05) in high-frequency donors compared with low-frequency donors, respectively, but WBISI (median values 4.8 vs. 4.7) and related measures of glucose tolerance did not differ between groups. Flow-mediated dilation significantly decreased at 1 h after oral glucose loading in both groups, but the decrease in flow-mediated dilation at 1 h did not differ between high- and low-frequency donors.
CONCLUSIONS— High-frequency blood donation reduced serum ferritin and increased flow-mediated dilation compared with low-frequency donation but did not improve insulin sensitivity or protect the vascular endothelium from the adverse effects of acute hyperglycemia after oral glucose loading. These findings suggest that the mechanisms linking blood donation to improved vascular function are not likely related to changes in glucose metabolism.
Abbreviations: HOMA-IR, homeostasis model assessment of insulin resistance • WBISI, whole-body insulin sensitivity index
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODS--RESULTS--CONCLUSIONS--References |
|---|
Iron is a prooxidant cofactor that has been proposed to be associated with increased risk of cardiovascular events in humans (1,2). Chronic reduction in iron stores in response to frequent blood donation is associated with improved vascular function in the brachial artery and biochemical evidence of decreased oxidative stress (3). In a randomized trial of patients with peripheral vascular disease, reduction of iron stores with serial phlebotomy decreased mortality compared with conventional therapy in the subjects in the youngest age quartile (aged 43–61 years) (4).
A potential mechanistic link between iron stores, vascular function, and cardiovascular risk may be related to iron-dependent effects on glucose metabolism (5,6). Diabetes is a well-recognized modifiable cardiovascular risk factor associated with increased serum ferritin levels and evidence of vascular endothelial dysfunction (7,8). Iron overload is associated with decreased insulin production, increased insulin resistance, and increased risk of diabetes (5,6). We hypothesized that improved vascular function associated with reduction in iron stores after blood donation might be partly attributable to improved insulin sensitivity. To test this hypothesis, we assessed insulin sensitivity during an oral glucose tolerance test and measured flow-mediated dilation in the brachial artery in a prospective cross-sectional study of nondiabetic high- and low-frequency voluntary blood donors.
|
RESEARCH DESIGN AND METHODS— |
|---|
|
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODS--RESULTS--CONCLUSIONS--References |
|---|
High-frequency (more than eight donations in the last 2 years) and low-frequency (one to two donations in the last 2 years) blood donors aged 50–75 years were identified from American Red Cross records and randomly selected for written invitation to participate in the study. Subjects with a history of major bleeding events within the last 2 years, BMI >40 kg/m2, known diabetes, previous myocardial infarction, cancer or active chronic inflammatory disease, tobacco use within 6 months, or current use of medications known to influence glucose tolerance were excluded. The study protocol was approved by the human investigation committee of Yale University and the American Red Cross institutional review board. All subjects provided written informed consent before participation in the study.
Height, weight, hip/waist circumference, resting supine blood pressure and heart rate, and brachial artery flow-mediated dilation were measured. After completion of the baseline measurements, oral glucose tolerance testing was performed as described below. Brachial artery flow-mediated dilation was measured at 1 and 3 h during the oral glucose tolerance test. Body composition measured with dual-energy X-ray absorptiometry was completed on a second study day within 1 week of the oral glucose tolerance testing.
Oral glucose tolerance testing
After an overnight fast, 75 g oral glucose was administered (Orangedex; Custom Laboratories, Baltimore, MD). Blood was drawn from an indwelling catheter in a forearm vein before and at 30, 60, 90, 120, 150, and 180 min after oral glucose administration. The composite whole-body insulin sensitivity index (WBISI) and the homeostatis model assessment of insulin resistance (HOMA-IR) were calculated as previously described (9,10). Insulin and glucose levels were evaluated by calculating the area under the curve of the incremental insulin and glucose levels by the trapezoidal method. The glucose levels at 2 h after oral glucose loading were also analyzed categorically to determine normal versus abnormal results according to American Diabetes Association criteria (11).
Body composition
Body composition in grams of fat, lean body mass, bone mineral content, and bone mineral density was measured with dual-energy X-ray absorptiometry (Hologic QDR 4500; Hologic, Bedford, MA). The whole-body composition of fat mass, lean body mass, and bone mineral content was measured and reported as subtotals (excluding the contribution from the head of the subject).
Analytical methods
Complete blood cell count (Abbott Celldyne 3500 cell counter), serum iron and total iron binding capacity (Roche Diagnostics Modular P system), percentage of iron saturation (calculated from the ratio of serum iron to total iron binding capacity), and serum ferritin (immunoassay, DPC IMMULITE Chemiluminescent Analyzer) were measured in the clinical laboratory at Yale–New Haven Hospital. Plasma glucose levels (YSI 2700 STAT Analyzer; Yellow Springs Instruments), insulin levels (radioimmunoassay, Linco Laboratories), and lipid levels (Autanalyzer, model no. 747-202; Roche-Hitachi) were measured in the Yale General Clinical Research Center Laboratory. Plasma C-reactive protein was measured with high-sensitivity C-reactive protein reagent (Alfa Wassermann ACE Clinical System). Serum interleukin-6 was measured with a commercially available enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN).
Ultrasound imaging.
Flow-mediated endothelium-dependent vasodilation in the brachial artery was determined with a duplex ultrasound imaging system connected to an 11-MHz transducer by a single blinded investigator, adapted from published guidelines as previously described (3,12). Brachial artery diameter and Doppler blood flow velocity were measured at rest and after transient arterial occlusion induced by 5-min inflation of a forearm pneumatic cuff to 200 mmHg. Flow-mediated dilation was calculated as the percentage of increase in brachial artery diameter 60 s after release of the occluding cuff.
Data analysis
All values are expressed as median (interquartile range). WBISI was the prespecified primary end point for the study. Nonparamateric tests were used to determine differences between low- and high-frequency donors for WBISI and other variables of interest (version 8.0; STATA, College Park, TX; command rank sum). Univariate and multivariate linear regression was used to detect association between predictor variables related to body composition and iron stores to WBISI. Variables with deviation from the normal distribution were log transformed before inclusion in regression models. Based on previous data in nondiabetic obese subjects, we anticipated that the mean ± SD of WBISI in low-frequency blood donors would be 1.8 ± 0.7 units (9). Twenty-one subjects in each group (high- vs. low-frequency donors) provided >80% power to detect a clinically relevant 25% difference (absolute 0.5 index units) between groups with two-tailed 
= 0.05.
|
RESULTS— |
|---|
|
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODS--RESULTS--CONCLUSIONS--References |
|---|
Clinical characteristics
Clinical characteristics (Table 1) of the high- and low-frequency blood donors did not differ. Only one subject in the study sample (a female high-frequency donor) met diagnostic criteria for the metabolic syndrome.
|
Laboratory markers of iron stores
Serum ferritin levels and white blood cell count were decreased in high-frequency donors compared with those in low-frequency donors (both P = 0.05) (Table 2). Other markers of iron status, hematocrit, hemoglobin, and other measures in the complete blood count did not differ between groups.
|
Oral glucose tolerance test results
WBISI and HOMA-IR did not differ between high- and low-frequency blood donors (P = 0.76 and P = 0.16, respectively) (Table 3). Other measures listed in Table 3 also did not differ between groups. In univariate regression analysis, the natural logarithm of WBISI was significantly associated with BMI (r2 = 0.21, P = 0.002), total fat mass (r2 = 0.14, P = 0.02), waist circumference (r2 = 0.13, P = 0.02), C-reactive protein levels (r2 = 0.18, P = 0.006), and serum interleukin-6 levels (r2 = 0.30, P < 0.001) but was not significantly associated with the natural logarithm of serum ferritin or the number of blood donations over 2 or 10 years. Comparable associations were observed between HOMA-IR and these predictor variables. Adjustment for these predictor variables in multivariate analysis did not alter the univariate finding of no significant association between blood donation frequency and either WBISI or HOMA-IR. In a post hoc analysis, the association between WBISI and blood donation frequency did not differ in subjects with abnormal versus normal glucose tolerance test results (WBISI in abnormal glucose tolerant low-frequency donors 3.9 ± 3.2 vs. high-frequency donors 4.6 ± 3.8; WBISI in normal glucose tolerant low-frequency donors 4.8 ± 2.6 vs. high-frequency donors 4.9 ± 1.9; P = 0.28 for glucose tolerance–by–donation frequency interaction).
|
Brachial artery flow-mediated dilation
Brachial artery flow-mediated dilation (Fig. 1) was greater in high-frequency donors compared with that in low-frequency donors before and during oral glucose tolerance testing (before testing 5.9 ± 4.4 vs. 5.3 ± 2.0%, 1-h post–glucose load 5.0 ± 4.6 vs. 3.9 ± 3.4%, and 3-h post–glucose load 6.1 ± 3.2 vs. 5.1%, respectively; repeated-measures ANOVA P = 0.045). The decrease in flow-mediated dilation at 1-h post–glucose loading was significant in both groups (within-group comparisons P < 0.02). However, the magnitude of decrease in flow-mediated dilation at 1 h did not differ between high- and low-frequency donors (repeated-measures frequency-by-time interaction term P = 0.98). Flow-mediated dilation in the brachial artery was not significantly associated with BMI, total fat mass, waist circumference, or C-reactive protein levels.
|
P < 0.02 for within-group comparisons versus pre–oral glucose tolerance testing value. |
CONCLUSIONS— |
|---|
|
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODS--RESULTS--CONCLUSIONS--References |
|---|
High-frequency blood donation was associated with reduced serum ferritin and increased brachial artery flow-mediated dilation compared with low-frequency blood donation. High-frequency blood donation did not improve insulin sensitivity after oral glucose loading and did not protect the vascular endothelium from the adverse effects of acute hyperglycemia after oral glucose loading compared with low-frequency blood donation. These findings indicate that increased flow-mediated dilation in high-frequency blood donors is not attributable to improved glucose tolerance.
Severe iron overload in the setting of hereditary hemochromatosis or thalassemia is associated with increased risk of diabetes related to impairment of insulin secretion and/or increased insulin resistance (5,6). In populations with severe iron overload, reduction of body iron stores with either phlebotomy or chelation therapy is associated with improved glucose tolerance (5,6). In subjects without overt iron overload, higher serum ferritin levels are significantly associated with biochemical evidence of decreased insulin sensitivity (5,6). However, epidemiological studies of the association between dietary iron intake or biomarkers of tissue iron stores and the risk of diabetes in populations without overt iron overload have yielded mixed findings (5,6,13–16). The inconsistencies in these reports may be partly attributable to the presence of inflammation or other unmeasured confounders that alter the relationship between dietary iron intake, biochemical markers of tissue iron stores, and metabolic effects of iron.
In healthy men, a single 500-ml whole-blood donation results in a substantial loss of heme iron (
200–250 mg) and decreases serum ferritin levels by 44% (17). Previous studies on the relationship between blood donation and glucose metabolism have yielded mixed findings. In the Physician's Health Study sample of 33,541 men, blood donation frequency (determined by subject recall) was not associated with risk of incident type 2 diabetes over a 12-year follow-up period (18). Serum ferritin levels (determined in a subset of subjects) ranged from 187 ng/ml in those with no previous history of blood donation to 64 ng/ml in those with a history of 
30 blood donations. In a cross-sectional study of the effects of blood donation on insulin sensitivity, frequent blood donors (8 subjects with a median of four donations in the past 5 years and mean serum ferritin 87 ng/ml) demonstrated improved insulin sensitivity and decreased insulin secretion during an intravenous glucose tolerance test when compared with sporadic blood donors (13 subjects with one blood donation in the past 5 years and mean serum ferritin 110 ng/ml) and 66 nondonor control subjects (mean serum ferritin 162 ng/ml) (19). In an unblinded and uncontrolled study of 31 subjects with glucose intolerance, serial phlebotomy individually adjusted to induce near iron deficiency (mean serum ferritin decreased from 272 to 14 ng/ml) was associated with evidence of improved insulin sensitivity in response to oral glucose loading and reduced A1C levels (20). In another unblinded, randomized study in 28 patients with diabetes and baseline serum ferritin >200 ng/ml, three serial 500-ml phlebotomies reduced mean serum ferritin from 460 to 232 ng/ml and reduced A1C levels (21). The current study findings add to existing data, as our study subjects had a verified blood donation history (to eliminate recall bias), a greater number of blood donations, and lower serum ferritin levels compared with subjects in most previous reports. In our study sample with severe reductions in iron stores, insulin sensitivity was not associated with serum ferritin levels or the number of blood donations but was significantly associated with known clinical correlates of glucose intolerance related to increased adiposity and blood markers of inflammation. A large proportion of both groups was either overweight or obese, and approximately one-third of our subjects had abnormal glucose tolerance test findings despite very low serum ferritin levels. Taken together, the current findings in blood donors with very low serum ferritin levels and past studies in subjects with and without overt iron overload suggest a possible curvilinear or threshold relationship between serum ferritin and insulin sensitivity, with a relatively steeper slope at high serum ferritin levels and a less steep slope at low serum ferritin levels. Because flow-mediated dilation was significantly greater in high-frequency donors than in low-frequency donors, our findings also suggest differential effects of iron on insulin sensitivity and endothelial function at the lower range of iron storage.
Vascular endothelial dysfunction is associated with atherosclerosis progression and increased risk of morbidity and mortality in cardiovascular disease populations (22). The increased risk of cardiovascular events in diabetic patients is thought to be partly attributable to vascular endothelial dysfunction caused by altered glucose and insulin metabolism (8,23). Our finding of a transient decrease in flow-mediated dilation after oral glucose loading is in accord with previous studies in healthy subjects and in patients with impaired glucose tolerance or diabetes (24,25). Transient attenuation of endothelium-dependent vasodilation is thought to be mediated primarily by acute changes in glucose levels, as suppression of insulin secretion with octreotide does not alter the vascular response to acute hyperglycemia (26). Glucose-induced changes in endothelium-dependent vasodilation may be mediated by increased oxidative stress, as pretreatment with superoxide dismutase, antioxidant vitamins, and tetrahydrobiopterin have been reported to protect against hyperglycemia-induced vascular dysfunction in isolated blood vessels and the intact human circulation (25,27–29). Our observation that the decrease in flow-mediated dilation during oral glucose tolerance testing did not differ between high- and low-frequency blood donors raises the possibility that iron-dependent hydroxyl radical formation may not contribute to hyperglycemia-induced vascular dysfunction in nondiabetic subjects. Alternatively, our findings suggest that the effects of blood donation on insulin sensitivity may differ in subjects with normal versus abnormal glucose tolerance. This interpretation is consistent with the findings of Hirai et al. (30), who demonstrated differential effects of the antioxidant compound vitamin C in subjects with normal versus abnormal glucose tolerance. However, the findings of our post hoc analysis must be interpreted with caution, as the number of subjects in each subgroup is small. Additional studies with an iron chelation agent such as dexrazoxane are warranted to further characterize the relationship among iron-dependent generation of reactive oxygen species, glucose tolerance, and endothelial function (31).
The cross-sectional study design does not provide insight into potential mechanisms that may have contributed to our findings. Although we attempted to carefully characterize our study sample with regard to clinical factors that could influence insulin sensitivity, it is possible that unmeasured confounders may have contributed to the lack of association between blood donation frequency and glucose tolerance. Our findings are also limited to observations during oral glucose loading. Although the WBISI has previously been shown to be significantly associated with measures of insulin sensitivity obtained with euglycemic insulin clamp techniques (9,10), it is possible that subtle differences in insulin sensitivity between groups were not detectable with our chosen methodology. Finally, the relationship between iron stores and insulin sensitivity observed in our nondiabetic subjects may differ from that in patients with diabetes.
In conclusion, we found no evidence of a significant association among blood donation frequency, serum ferritin levels, and insulin sensitivity during oral glucose tolerance testing in voluntary blood donors. These findings indicate that the mechanisms linking blood donation to improved vascular function are not likely related to changes in glucose metabolism.
|
Acknowledgments |
|---|
This work was supported in part by the Division of Research Resources, General Clinical Research Center at Yale University; by National Insututes of Health Grant 5 MO1 RR00645; and by National Heart, Lung, and Blood Institute grants HL K24-04024 and HL R01-51433 (to S.D.K).
We gratefully acknowledge Dr. Sonia Caprio of the Yale School of Medicine Section of Pediatric Endocrinology for her assistance in study planning and manuscript review.
|
Footnotes |
|---|
Published ahead of print at http://care.diabetesjournals.org on 13 July 2007. DOI: 10.2337/dc07-0748.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.
Received for publication April 17, 2007. Accepted for publication July 10, 2007.
|
References |
|---|
|
TOPABSTRACTINTRODUCTIONRESEARCH DESIGN AND METHODS--RESULTS--CONCLUSIONS--References |
|---|
- Sullivan JL: Iron and the sex difference in heart disease risk. Lancet 1:1293–1294, 1981[Medline]
- Sullivan JL: Is stored iron safe? J Lab Clin Med 144:280–284, 2004[Medline]
- Zheng H, Cable R, Spencer B, Votto N, Katz SD: Iron stores and vascular function in voluntary blood donors. Arterioscler Thromb Vasc Biol 25:1577–1583, 2005
[Abstract/Free Full Text] - Zacharski LR, Chow BK, Howes PS, Shamayeva G, Baron JA, Dalman RL, Malenka DJ, Ozaki CK, Lavori PW: Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease: a randomized controlled trial. JAMA 297:603–610, 2007
[Abstract/Free Full Text] - Swaminathan S, Fonseca VA, Alam MG, Shah SV: The role of iron in diabetes and its complications. Diabetes Care 30:1926–1933, 2007
[Free Full Text] - Fernandez-Real JM, Lopez-Bermejo A, Ricart W: Cross-talk between iron metabolism and diabetes. Diabetes 51:2348–2354, 2002
[Abstract/Free Full Text] - Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, Taillefer R, Wittlin SD, Heller GV, Filipchuk N, Engel S, Ratner RE, Iskandrian AE, the Detection of Ischemia in Asymptomatic Diabetics Investigators: Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care 27:1954–1961, 2004
[Abstract/Free Full Text] - Beckman JA, Creager MA, Libby P: Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287:2570–2581, 2002
[Abstract/Free Full Text] - Yeckel CW, Weiss R, Dziura J, Taksali SE, Dufour S, Burgert TS, Tamborlane WV, Caprio S: Validation of insulin sensitivity indices from oral glucose tolerance test parameters in obese children and adolescents. J Clin Endocrinol Metab 89:1096–1101, 2004
[Abstract/Free Full Text] - Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462–1470, 1999
[Abstract/Free Full Text] - Diagnosis and classification of diabetes mellitus (Position Statement). Diabetes Care 29(Suppl. 1):S43–S48, 2006
- Zheng H, Huang X, Zhang Q, Katz SD: Iron sucrose augments homocysteine-induced endothelial dysfunction in normal subjects. Kidney Int 69:679–684, 2006[Medline]
- Rajpathak S, Ma J, Manson J, Willett WC, Hu FB: Iron intake and the risk of type 2 diabetes in women: a prospective cohort study. Diabetes Care 29:1370–1376, 2006
[Abstract/Free Full Text] - Jiang R, Manson JE, Meigs JB, Ma J, Rifai N, Hu FB: Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA 291:711–717, 2004
[Abstract/Free Full Text] - Jehn ML, Guallar E, Clark JM, Couper D, Duncan BB, Ballantyne CM, Hoogeveen RC, Harris ZL, Pankow JS: A prospective study of plasma ferritin level and incident diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Epidemiol 165:1047–1054, 2007
[Abstract/Free Full Text] - Ford ES, Cogswell ME: Diabetes and serum ferritin concentration among U.S. adults. Diabetes Care 22:1978–1983, 1999
[Abstract/Free Full Text] - Finch CA, Cook JD, Labbe RF, Culala M: Effect of blood donation on iron stores as evaluated by serum ferritin. Blood 50:441–447, 1977
[Abstract/Free Full Text] - Jiang R, Ma J, Ascherio A, Stampfer MJ, Willett WC, Hu FB: Dietary iron intake and blood donations in relation to risk of type 2 diabetes in men: a prospective cohort study. Am J Clin Nutr 79:70–75, 2004
[Abstract/Free Full Text] - Fernandez-Real JM, Lopez-Bermejo A, Ricart W: Iron stores, blood donation, and insulin sensitivity and secretion. Clin Chem 51:1201–1205, 2005
[Abstract/Free Full Text] - Facchini FS, Saylor KL: Effect of iron depletion on cardiovascular risk factors: studies in carbohydrate-intolerant patients. Ann N Y Acad Sci 967:342–351, 2002
[Abstract/Free Full Text] - Fernandez-Real JM, Penarroja G, Castro A, Garcia-Bragado F, Lopez-Bermejo A, Ricart W: Blood letting in high-ferritin type 2 diabetes: effects on vascular reactivity. Diabetes Care 25:2249–2255, 2002
[Abstract/Free Full Text] - Katz SD, Hryniewicz K, Hriljac I, Balidemaj K, Dimayuga C, Hudaihed A, Yasskiy A: Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation 111:310–314, 2005
[Abstract/Free Full Text] - Rask-Madsen C, King GL: Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab 3:46–56, 2007[Medline]
- Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H: Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol 34:146–154, 1999
[Abstract/Free Full Text] - Title LM, Cummings PM, Giddens K, Nassar BA: Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E. J Am Coll Cardiol 36:2185–2191, 2000
[Abstract/Free Full Text] - Williams SB, Goldfine AB, Timimi FK, Ting HH, Roddy MA, Simonson DC, Creager MA: Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 97:1695–1701, 1998
[Abstract/Free Full Text] - Tesfamariam B, Cohen RA: Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol 263:H321–H326, 1992[Medline]
- Beckman JA, Goldfine AB, Gordon MB, Creager MA: Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 103:1618–1623, 2001
[Abstract/Free Full Text] - Ihlemann N, Rask-Madsen C, Perner A, Dominguez H, Hermann T, Kober L, Torp-Pedersen C: Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects. Am J Physiol Heart Circ Physiol 285:H875–H882, 2003
[Abstract/Free Full Text] - Hirai N, Kawano H, Hirashima O, Motoyama T, Moriyama Y, Sakamoto T, Kugiyama K, Ogawa H, Nakao K, Yasue H: Insulin resistance and endothelial dysfunction in smokers: effects of vitamin C. Am J Physiol Heart Circ Physiol 279:H1172–H1178, 2000
[Abstract/Free Full Text] - Zheng H, Dimayuga C, Hudaihed A, Katz SD: Effect of dexrazoxane on homocysteine-induced endothelial dysfunction in normal subjects. Arterioscler Thromb Vasc Biol 22:E15–E18, 2002
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |