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Original Studies |
Divisions of Geriatric Medicine and Endocrinology and Metabolism, Department of Internal Medicine, and Institute of Gerontology, University of Michigan, and Michigan Diabetes Research and Training Center, and Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Medical Center, Ann Arbor, Michigan 48105
Address all correspondence and requests for reprints to: Robert V. Hogikyan, M.D., Geriatric Research, Education, and Clinical Center (11G), Department of Veterans Affairs Medical Center, Ann Arbor, Michigan 48105. E-mail: hogikyan{at}umich.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The current study characterizes a group of normotensive subjects with type 2 diabetes with regard to endothelial cell function and insulin sensitivity. We used the forearm blood flow (FABF) response to acetylcholine as an index of endothelium-mediated vasodilation and the FABF response to nitroprusside as an endothelium-independent measure of vasodilation. We controlled for obesity both by limiting the range of ideal body weight to less than 150% and by incorporating body mass index (BMI) and percent body fat into the statistical model used to analyze the FABF responses, as the diabetic subjects had an increased BMI relative to the control subjects. We also tested the hypothesis that those subjects with the lowest tissue sensitivity to the metabolic effects of insulin would have the greatest impairment in the FABF response to intraarterial acetylcholine.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty control subjects and 17 subjects with type 2 diabetes in otherwise good general health were recruited through newspaper advertisement and through the Human Subjects Core of the Geriatrics Center at the University of Michigan. Subjects were screened before study entry with a medical history, physical examination, and laboratory tests, including a complete blood count and routine chemistries. Subjects were classified as type 2 diabetes by their primary care providers. All had adult onset of their diabetes and no history of ketoacidosis. Glycosylated hemoglobin values of the subjects with diabetes ranged from 6.5–14.7% (normal, 4–8%). Body composition was estimated by bioelectric impedance using an RJL instrument (model BIA-103 B, RJL Systems, Mt. Clemens, MI).
Subjects were excluded from participation if they exceeded 150% of ideal body weight (Metropolitan Life Insurance Tables, 1983), had a history of hypertension or a resting seated blood pressure greater than 160 mm Hg systolic or greater than 90 mm Hg diastolic, or had evidence from history, physical exam, or laboratory results of other significant underlying illness. Subjects did not have clinical signs of peripheral vascular occlusive disease. Subjects were excluded if they were taking a calcium channel blocker, an angiotensin-converting enzyme inhibitor, or a ß-blocker. Three of the subjects with diabetes were receiving replacement therapy for hypothyroidism with a TSH level that was in the normal range. Diabetes treatment regimens included diet alone (n = 4), a sulfonylurea (n = 6), insulin (n = 5), a sulfonylurea and insulin (n = 1), and metformin (n = 1). With regard to known duration of diabetes, four subjects were newly diagnosed, five reported diabetes duration as 5 yr or less, three reported diabetes duration as 10 yr or less, and four reported diabetes duration as more than 10 yr. Twelve of the 20 control subjects had no personal or family history of diabetes. Eight control subjects underwent standard 75-g oral glucose tolerance tests because of a history of incidental hyperglycemia or a family history of diabetes mellitus. Subjects were excluded from the control group if their oral glucose tolerance test was positive for diabetes mellitus by National Diabetes Data Group criteria. Four of the control subjects met National Diabetes Data Group criteria for impaired glucose tolerance. All subjects gave written informed consent that was approved by the University of Michigan human use committee.
Study protocol
All subjects reported to the General Clinical Research Center of the University of Michigan Hospitals at 0730 h on each of the 2 days of study. They were instructed to fast from 2200 h the night before each of the 2 study days and to abstain from smoking for 12 h before the studies. Subjects were studied in the supine position in a quiet room maintained at a constant temperature of 23–25 C. In subjects with diabetes, oral hypoglycemics were discontinued 3 days before the study, and insulin was withheld beginning with the afternoon dose on the day before the study.
FABF protocol
Forearm volume (FAV) was measured using water displacement (7, 16). A 20-gauge 1.25-in. Angiocath catheter (Becton Dickinson Vascular Access, Sandy, UT) was placed into the brachial artery of the nondominant arm. The catheter was connected to a pressure transducer (model 1290A quartz transducer, Hewlett-Packard, Andover, MA). One of the basic electrocardiograph limb leads was monitored. FABF was measured using venous occlusion plethysmography during an intraarterial infusion protocol we have previously described (17). Studies were performed at least 110 min after arterial catheter placement. To establish a stable baseline, FABF was measured periodically until three consecutive readings over approximately 10 min were similar. To determine the effect of intraarterial infusions of acetylcholine on FABF, acetylcholine (acetylcholine HCl, Sigma Chemical Co., St. Louis, MO.) was diluted in 5% dextrose to achieve stepwise increasing infusion doses of 0.1, 0.4, 1.6, and 6.4 µg/dL FAV·min. Each acetylcholine dose was administered by an infusion pump (model 970T, Harvard Apparatus, South Natick, MA) for 4 min before recording FABF during the fifth minute of each infusion. After the FABF measurement at the 6.4-µg dose, the acetylcholine infusion was stopped.
After a washout period lasting a minimum of 10 min, repeat measurement to establish a stable baseline FABF was carried out as described above. To determine the effect of an endothelium-independent vasodilator on FABF, nitroprusside (Nitropress, Abbott Laboratories, North Chicago, IL) was diluted in 5% dextrose to achieve stepwise increasing infusion doses of 0.01, 0.04, 0.16, and 0.64 µg/dL FAV·min. The nitroprusside was protected from light at all times. After the FABF measurement at the 0.64-µg dose, the nitroprusside infusion was stopped.
Frequently sampled iv glucose tolerance test (FSIVGTT)
On the day after the FABF protocol, after another overnight fast, the FSIVGTT was carried out in all subjects. A FSIVGTT was performed on the second day of study as described by Bergman (18), with the addition of tolbutamide in control subjects and insulin in subjects with diabetes to enhance the precision of the estimates of insulin action (19, 20). Each medication was given as a bolus over approximately 25 s. This method has been found to yield estimates of insulin sensitivity that are reproducible (14% mean coefficient of intraindividual variation) (21) and are comparable to those obtained using the glucose clamp method (22). Subjects were studied in the supine position. An iv catheter was placed in the antecubital vein of one arm for the injection of glucose and tolbutamide or insulin. Another catheter was inserted in a retrograde manner into a dorsal hand vein of the contralateral arm, which was then placed into a warming box heated to 60 C to obtain arterialized venous blood samples for glucose and insulin determinations (19). Catheters were kept patent by a slow infusion of 0.45% saline (<50 mL/h). Beginning 20 min after the iv lines were inserted, three baseline blood samples were obtained, and blood pressure and heart rate were measured at 5-min intervals. Fifty percent glucose (300 mg/kg) was then given as an iv push over 30 s. Blood samples (3 mL) were collected 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, and 180 min after the glucose bolus. Tolbutamide (137 mg/m2 body surface area) was given to control subjects iv 20 min after the glucose injection to further stimulate insulin secretion. Insulin (0.05 U/kg) was given to the subjects with diabetes iv 20 min after the glucose injection.
Analytical methods
Mean arterial pressure (MAP) was determined from the electronically integrated area under the intraarterial blood pressure curve from the Marquette telemetry system (Marquette Electronics Series 7700, Marquette Electronics, Milwaukee, WI) just before each FABF measurement.
Baseline values reported from the FSIVGTT represent the mean of three measurements before glucose administration for each variable. Blood samples for plasma glucose and insulin were collected into chilled glass tubes containing sodium heparin, stored on ice, and separated immediately after each study. Plasma was stored at -70 C until assay. Plasma glucose was measured by the Autoanalyzer (Sigma, St. Louis, MO) glucose oxidase method, and plasma insulin was determined by RIA in the Core Laboratory of the Michigan Diabetes Research and Training Center. The percentage of glycosylated hemoglobin was determined at the Core Laboratory of the University of Michigan Diabetes Research and Training Center using the Isolab Glyc-Affin GHb test kit (Isolab, Akron, OH). Serum lipid levels were determined by the Clinical Laboratory of the University of Michigan Health System using the VITROS 950IRC analyzer (Johnson & Johnson Clinical Diagnostics, Rochester, NY).
The insulin sensitivity index (SI) and a measure of glucose effectiveness (SG) were calculated from a least squares fitting of the temporal pattern of glucose and insulin throughout the FSIVGTT using the MINMOD program (18). The acute insulin response to iv glucose (AIRG) was calculated as the mean rise in plasma insulin above baseline 3, 4, and 5 min after iv glucose administration. KG, a measure of glucose tolerance, is the rate of plasma glucose disappearance calculated as the least square slope of the natural logarithm of the absolute glucose concentration between 5–20 min after the glucose bolus (a normal value for KG is >1%/min).
Data and statistical analysis
Values are presented as the mean ± SE. P < 0.05 is considered statistically significant. Statistical analysis was performed using StatView 4.5 (Abacus Concepts, Berkeley, CA) and SAS/PROC MIXED (23).
Baseline characteristics and results of the FSIVGTT were compared
between study groups using Student’s t tests. The
homogeneity of the gender distribution in both groups was tested using
2 analysis. To describe the FABF responses to different
doses of acetylcholine and nitroprusside, two distinct analyses were
performed. The FABF data were analyzed as the percent change from
baseline FABF comparing groups, not adjusting for covariates, by
repeated measures ANOVA. To describe the absolute FABF response data to
different doses of acetylcholine and nitroprusside, separate linear
mixed effects (LME) models were developed. A LME model (24) is an
extension of the classical analysis of repeated measures methods.
Compared to standard repeated measures analysis, LME allows for data
missing at random, time-dependent covariates, and modeling of a
covariance structure.
To develop the best LME models for acetylcholine and nitroprusside
responses, several models were considered for each infusate. To
accommodate a skewed distribution of FABF responses and to stabilize
the variance, logarithmic transformation was applied to all FABF
measurements, including those at baseline and during responses to each
dose of acetylcholine and nitroprusside. Each of the models takes into
account that several measures were repeated on the same individual. To
describe between-subject random variation and correlation of individual
measurements, the optimal covariance structure was selected using
Akaike’s information criterion (25). Several independent variables,
listed in Tables 1
and 2, and their interactions with stimulus
dose and with study group were considered in each model selection
process. In choosing the optimal model, the likelihood ratio test was
used. To test the significance of specific terms (e.g. study
group effect) in the model, likelihood statistics were compared for two
nested models with and without the terms being tested (e.g.
with and without group effect). To obtain P values, the
likelihood ratio test statistic was referred to the 2
distribution. The number of degrees of freedom for the 2
distribution was determined by subtracting the number of parameters in
the models that were being compared. To check the goodness of fit of
the models developed, residuals were inspected by plotting them against
predicted values and against available covariates (not presented).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The characteristics of the control subjects and those with type 2
diabetes are compared in Table 1
. The groups were similar with respect
to age, gender mix, MAP, and cholesterol level. Although BMI was
significantly greater in the diabetic subjects than in the control
subjects, there was no significant difference in percent body fat
between groups. The subjects with type 2 diabetes differed from control
subjects in all parameters of glucose metabolism measured during the
FSIVGTT (Table 2). Fasting serum glucose (pre-FABF, Table 1; during the
FSIVGTT, Table 2) and insulin levels and glycosylated hemoglobin
percentages were higher among the subjects with diabetes. Plasma
insulin levels from one subject with diabetes could not be determined
due to the presence of insulin antibodies. SI,
SG, AIRG, and KG were all
significantly less in the subjects with diabetes compared to those in
the control subjects.
FABF during vasodilatory intraarterial infusions
Acetylcholine. Baseline FABF was significantly higher in the
diabetic subjects (Table 1). A plot representing the mean percent
increase in FABF from baseline (to correct for the baseline group
difference in FABF) at each of the four intraarterial infusion doses of
acetylcholine for control and diabetic subjects is presented in Fig. 1. By repeated measures ANOVA, the
diabetic subjects demonstrated less percent increase in FABF in
response to intraarterial acetylcholine than control subjects (by
ANOVA, P = 0.02). A linear mixed effects model was
developed using absolute FABF to estimate the influence of parameters
of interest and to test hypotheses regarding FABF responses. To adjust
for each subject’s baseline FABF, the baseline blood flow value was
entered into the model. The model revealed that the overall difference
in FABF response to acetylcholine between study groups remained
significant after adjusting for covariates (2 = 16.25;
df = 8; P = 0.04). FABF responses to individual
acetylcholine doses were significantly less in the type 2 diabetes
group at the 0.4 (P = 0.04) and 6.4 (P
= 0.02) µg/dL FAV·min acetylcholine doses.
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Nitroprusside. FABF before nitroprusside infusion was similar
in the subjects with type 2 diabetes and the control subjects (control,
5.19 ± 0.33; type 2, 5.33 ± 0.35 mL/dL FAV·min;
P = 0.8). A plot representing the mean percent increase
in FABF from baseline (to control for any baseline variation in FABF)
at each of the four intraarterial infusion doses of nitroprusside for
control and diabetic subjects is presented in Fig. 2. By repeated measures ANOVA, the
diabetic subjects demonstrated similar percent increases in FABF in
response to intraarterial nitroprusside as control subjects (by ANOVA,
P = 0.30). A second linear mixed effects model was
developed using absolute FABF to estimate the influence of parameters
of interest and to test hypotheses pertinent to FABF responses to
different nitroprusside doses. To adjust for each subject’s baseline
FABF, the baseline blood flow value was entered into the model as a
covariate. The model revealed that there was no overall significant
difference between study groups (2 = 9.01; df = 8;
P = 0.34).
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Subset analysis
A secondary analysis was also performed to assess whether endothelial dysfunction was present in type 2 diabetes when subject groups were more closely matched for BMI. Subjects were eliminated from analysis who had BMI values either greater than 30.0 kg/m2 or 21.0 kg/m2 or less. This eliminated three control subjects and five diabetic subjects. In this subset, there was no significant difference in BMI between subject groups (control, 25.5 ± 0.6; type 2, 26.6 ± 0.8 kg/m2; P = 0.24). The findings in this subgroup analysis of percent change in FABF responses to acetylcholine and nitroprusside were not altered from those of the larger group (acetylcholine, P = 0.03; nitroprusside, P = 0.90).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In this study, we used intraarterial infusions of acetylcholine and nitroprusside to investigate differences between control subjects and subjects with type 2 diabetes in their FABF responses. Because intraarterial acetylcholine and nitroprusside caused dose-dependent increases in FABF, we were able to quantitate sensitivity to these vasodilators. One advantage of the brachial arterial infusion methodology is that FABF is varied over a 4- to 5-fold range without producing major systemic effects in heart rate or blood pressure that could confound interpretation of the results, as has been demonstrated in other studies (10).
Our finding of vasomotor dysfunction in subjects with diabetes is in general agreement with previous studies of vascular endothelial function in diabetic animals (26, 27) and in humans with insulin-dependent diabetes mellitus (4, 5, 6, 7, 8, 9) and type 2 diabetes (10, 11, 12, 14, 15). Although the results from these studies overall suggest that there is endothelial dysfunction in animals and humans with diabetes, the findings have not been unanimous. In animal models of diabetes, there is good evidence for specific endothelial dysfunction (26, 27). In humans with insulin-dependent diabetes mellitus, there is evidence for specific endothelial dysfunction (8), but also evidence of intact endothelium-dependent vasodilation in response to metacholine and endothelium-independent vasodilation in response to nitroprusside (4). Investigations in humans have also tried to identify factors such as glycemic control, cholesterol level, body composition, and age that may account for some of the variability found in responses to both endothelium-dependent and -independent vasodilators.
In humans with type 2 diabetes, three previous studies have used venous occlusion plethysmography to define endothelium-dependent vasodilation during brachial arterial infusions of acetylcholine (10, 13) and metacholine (11) in middle-aged (10) and younger (11, 13) subjects with diabetes. Two of these studies identified impaired responses in the diabetic subjects to both the endothelium-dependent and -independent vasodilators (10, 11), and one identified intact endothelial function (13). When the responses to NG-monomethyl-L-arginine (10) and verapamil (11) were taken into account, the studies that reported impaired endothelium-dependent responses concluded that multiple mechanisms are involved in the vascular impairment characterized, inclusive of endothelial dysfunction. In the study by Avogaro et al. (13), in which no differences in either endothelium-dependent or -independent responses were identified, a narrower dose range of acetylcholine was used, achieving lower peak vasodilatory responses, which may have contributed to their negative finding.
In the three studies discussed above, there was a range of obesity among the subjects with diabetes. Subjects in the study by Avogaro et al. were matched for BMI and were only moderately obese, with mean BMIs of 27 and 29 kg/m2 in the control and diabetic groups, respectively. In the study by McVeigh et al. (10), the diabetic subjects had a higher mean BMI than the control subjects, but as this difference was not statistically significant, the FABF analyses did not take into account BMI. In the study by Williams et al. (11) to address the possible role of obesity, a subgroup analysis of a nonobese subset of the diabetic subjects was performed that demonstrated an impairment in endothelium-dependent and -independent vasodilation.
Steinberg et al. studied two very obese (mean BMI, 36 kg/m2) young subject groups, one with and one without type 2 diabetes, using thermal dilution blood flow measurement in the lower extremity (12). Among these obese subjects with and without diabetes, there was an attenuated increase in leg blood flow in response to metacholine and no difference in the blood flow response to intrafemoral artery nitroprusside compared to the response in nonobese control subjects. However, no significant difference was observed in the vasodilator response to metacholine between the obese subjects with and without diabetes. Results from the current study are in agreement with the findings of Steinberg et al. of specific endothelial dysfunction in subjects with type 2 diabetes. However, they identified obesity as an important predictor of endothelial dysfunction in type 2 diabetic subjects. The current study was designed to test endothelial function in normotensive type 2 diabetic subjects with mild to moderate obesity. Our primary model analysis demonstrated that body composition, as measured in this study, did not significantly influence the finding of specific endothelial dysfunction among the diabetic subjects. We also carried out a secondary analysis, similar to that used in the study by Williams et al. (11), which demonstrated specific endothelial dysfunction when the subject groups were matched for BMI. Possible explanations for the difference in the effect of obesity between our study and that of Steinberg et al. include there being a threshold of obesity that needs to be surpassed before it becomes an independent predictor of endothelial dysfunction and possible differences due to the choice of extremity where endothelial function was tested. Additionally, measures of the distribution of body fat, particularly central adiposity rather than total body fat, may have shown a relationship with the response to acetylcholine.
To better understand modulators of endothelial function in addition to obesity, given the heterogeneity of the population of patients with type 2 diabetes as a whole, a number of characteristics of the subjects in this study that were not controlled for in the study design were also examined as covariates. As described in Results, although most of the potential covariates tested did not predict responses to the intraarterial vasodilators infused, subject age did, both within each group and when evaluating the combined groups. Other studies have identified impaired endothelium-dependent vasodilation with increasing age in healthy subjects (3, 28), whereas in obese subjects with type 2 diabetes, no change was demonstrated in endothelium-independent vasodilation with subject age (12). In the present study, after identifying the best-fit model, age correlated positively with acetylcholine response and negatively with nitroprusside response. Steinberg et al. suggested that the negative correlation between acetylcholine response and aging identified in earlier studies may be the result of the increase in body fat with age (12). Controlling for covariates, including obesity, in identifying a best-fit model for the current study may account for the difference in relationship between age and the FABF response to acetylcholine identified compared to the relationship observed in other studies.
The other covariate that entered into the model of FABF responses to both vasodilators is the baseline FABF. In a study of 30 healthy young subjects, Chowienczyk et al. found that FABF responses to acetylcholine, but not to nitroprusside, were positively correlated with baseline blood flow (29). They suggest that baseline FABF is an important factor that needs to be taken into account when interpreting the FABF response to infusions of acetylcholine and nitroprusside. In the present study, we found that FABF responses to both acetylcholine and nitroprusside were directly related to baseline blood flow in each subject group except at the highest dose of acetylcholine, at which this relationship only held for the subjects with diabetes. As discussed earlier, the group difference in FABF response to acetylcholine was most apparent in subjects with the lowest baseline FABF.
It has been suggested by Steinberg et al. that the endothelial cell may be a target organ of insulin action with respect to the nitric oxide system (12), as there is now evidence to suggest that insulin exerts its vasodilating effect at least in part through the release of nitric oxide (28, 30). As subjects with type 2 diabetes are an insulin-resistant group, the current study also sought to test whether subjects with the lowest SI had the poorest responses to acetylcholine. Steinberg et al. found that the extent of insulin resistance was correlated with increasing impairment of endothelium-dependent vasodilation. In the current study, a similar comparison between the maximum FABF response to acetylcholine and SI across both groups, using univariate linear regression, shows a borderline significant positive relationship. However, the narrow range of SI values among our diabetic subjects limits the usefulness of such an analysis within the diabetes group alone. It is also possible that we did not identify a relationship between the FABF response and the sensitivity to insulin due to the methods we used to characterize the sensitivity to insulin. As has been shown previously, SI may differ depending on whether tolbutamide or insulin is used, the dose of insulin, and whether the insulin is given as an infusion or a bolus (31, 32, 33, 34). To the extent that insulin has been shown to at least in part exert its vasodilating effect through nitric oxide release, it is also possible that had we measured vasomotor insulin sensitivity (blood flow response to insulin infusion) we might have identified a relationship between blood flow response to insulin and SI (35, 36, 37, 38). The best-fit linear mixed effects models for the acetylcholine and the nitroprusside dose-response data failed to identify a significant correlation between any of the parameters of glucose metabolism and the FABF response to either acetylcholine or nitroprusside. These results held both within each group and when evaluating the combined groups. A similar analysis of the FABF response to nitroprusside did identify a negative correlation with the baseline insulin level. However, the significance of this finding is unclear.
We acknowledge that our study design presents some limitations in the interpretation of the results. In the analysis of FABF responses to vasoactive infusates, four subjects with impaired glucose tolerance were included in the control group. This is a conservative approach that might tend to diminish differences between control and diabetic subject groups. When these subjects with impaired glucose tolerance are excluded from the analysis, the same differences between groups are present. With two control and one diabetic subject receiving estrogen supplementation, and the study groups statistically not different with regard to gender, we believe that the subject groups are adequately matched for the potential of an estrogen effect (39), although this could not be incorporated into the LME model. Two of the control and none of the diabetic subjects were cigarette smokers at the time of study, which again would tend to make it more difficult to detect a decrement in the FABF response to acetylcholine among the diabetic subjects (40). Eight of the diabetic subjects were taking an oral hypoglycemic agent, and it is possible that there may have been a residual effect even after it had been withheld for 3 days. More specifically, the one subject taking metformin may have experienced increased blood flow, as has been characterized previously (41). Peripheral vascular occlusive disease was not clinically present in these subjects. However, the presence of subclinical peripheral vascular occlusive disease in the diabetic subject group may have contributed to the difference in FABF responses to acetylcholine between groups. Finally, the baseline FABF before nitroprusside infusion was higher than the preacetylcholine FABF. Although this could indicate incomplete return to baseline, which might limit our ability to interpret the FABF response to nitroprusside, chance alone is another possible explanation.
In summary, we have identified evidence for a specific impairment of endothelium-dependent vasodilation in a population of normotensive subjects with type 2 diabetes. Obesity did not have a statistically significant influence on this result. Baseline FABF was identified as an important predictor of FABF responses to acetylcholine- and nitroprusside-mediated vasodilation and so was controlled for in the data analysis. Finally, in this population, after controlling for other variables, a LME model failed to identify a correlation between parameters of glucose metabolism including SI and the FABF response to acetylcholine. In conclusion, this is the first study to identify specific endothelial cell dysfunction that remains significant after adjustment for obesity in a population of normotensive subjects with type 2 diabetes.
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Acknowledgments |
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Footnotes |
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Received December 17, 1997.
Revised March 16, 1998.
Accepted March 19, 1998.
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References |
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-adrenergic responsiveness compensates
for decreased sympathetic nervous system tone. J Clin Invest. 91:1429–1435.
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 K. J. Mather, S. Verma, and T. J. Anderson Improved endothelial function with metformin in type 2 diabetes mellitus J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1344 - 1350. [Abstract] [Full Text] [PDF]
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 B. Hennig, M. Toborek, and C. J. McClain High-Energy Diets, Fatty Acids and Endothelial Cell Function: Implications for Atherosclerosis J. Am. Coll. Nutr., April 1, 2001; 20(2): 97 - 105. [Abstract] [Full Text] [PDF]
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 J. Calles-Escandon and M. Cipolla Diabetes and Endothelial Dysfunction: A Clinical Perspective Endocr. Rev., February 1, 2001; 22(1): 36 - 52. [Abstract] [Full Text]
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 D. FLISER, R. DIKOW, S. DEMUKAJ, and E. RITZ Opposing Effects of Angiotensin II on Muscle and Renal Blood Flow under Euglycemic Conditions J. Am. Soc. Nephrol., November 1, 2000; 11(11): 2001 - 2006. [Abstract] [Full Text]
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 D. Perregaux, A. Chaudhuri, S. Rao, A. Airen, M. Wilson, B.-H. Sung, and P. Dandona Brachial Vascular Reactivity in Blacks Hypertension, November 1, 2000; 36(5): 866 - 871. [Abstract] [Full Text] [PDF]
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D.W. Laight, M.J. Carrier, and E.E. Anggard Antioxidants, diabetes and endothelial dysfunction Cardiovasc Res, August 18, 2000; 47(3): 457 - 464. [Abstract] [Full Text] [PDF]
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F. Brunner, G. Wolkart, S. Pfeiffer, J. C Russell, and T. C Wascher Vascular dysfunction and myocardial contractility in the JCR:LA-corpulent rat Cardiovasc Res, July 1, 2000; 47(1): 150 - 158. [Abstract] [Full Text] [PDF]
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J. M. Lash, G. P. Nase, and H. G. Bohlen Acute hyperglycemia depresses arteriolar NO formation in skeletal muscle Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1513 - H1520. [Abstract] [Full Text] [PDF]
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