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Department of Medicine (W.B., G.G., P.O., G.D.B.), University of Auckland, 1000 Auckland, New Zealand; and Department of Internal Medicine and Public Health, University of L’Aquila (C.F., G.D.), 67100 L’Aquila, Italy
Address all correspondence and requests for reprints to: Dr. W. Bagg, Department of Medicine, 4th Floor, Auckland Hospital, Park Road, Grafton, 1000 Auckland, New Zealand. E-mail: w.bagg{at}auckland.ac.nz
Abstract
The aims of this study were to elucidate the factors that contribute to endothelial activation and fibrinolytic abnormalities in patients with poorly controlled type 2 diabetes and to determine whether improved glycemic control reduces endothelial activation. Adhesion molecules [E-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1], von Willebrand factor, total nitric oxide (NO), endothelin-1, tissue plasminogen activator, and plasminogen activator inhibitor-1 were measured in 43 type 2 diabetic subjects with hemoglobin A1c of 9.0% or more at baseline (compared with 21 healthy controls) who after 20 wk had been randomized to either improved (IC) or usual (UC) glycemic control. At baseline, type 2 diabetic patients had significant endothelial activation and abnormal fibrinolysis compared with control subjects. Body mass index in the diabetic patients was the only independent predictor of E-selectin (P = 0.007), ICAM-1 (P = 0.01), and NO (P = 0.008) concentrations, but not vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, or tissue plasminogen activator (all P > 0.05). Type 2 diabetic patients with a body mass index of 28 kg/m2 or less had concentrations of E-selectin, ICAM-1, endothelin-1, and NO similar to those in healthy controls. After 20 wk, hemoglobin A1c was significantly lower in IC vs. UC (IC, 8.02 ± 0.25%; UC, 10.23 ± 0.23%; P < 0.0001), but there were no significant changes in markers of endothelial activation or indexes of fibrinolysis.
Obesity appears to be the most important predictor of endothelial activation in patients with type 2 diabetes. Short-term improvement in glycemic control does not appear to reduce endothelial activation.
ABNORMAL ENDOTHELIAL function and activation are known to occur in patients with type 2 diabetes (1, 2). Endothelial dysfunction, i.e. the impaired vascular response to endothelium-dependent vasodilators, is thought to play an important role in decreasing insulin sensitivity and increasing peripheral vascular resistance (3), thereby favoring the development of hyperinsulinemia and hypertension (4). Thus, endothelial dysfunction is thought to accelerate atherogenesis in patients with type 2 diabetes (4). Atherogenesis is also triggered and maintained by the up-regulation of endothelial adhesion molecules, i.e. endothelial activation (5). Endothelial activation allows for the movement of monocytes and leukocytes from the bloodstream into the subendothelial space, a process necessary for atheroma formation (6).
The mechanism(s) of endothelial dysfunction in patients with type 2 diabetes is likely to be multifactorial, but hyperglycemia per se may be important. In vitro animal studies have demonstrated that hyperglycemia increases the release of the potent endothelium-derived vasoconstrictor endothelin-1 (ET-1) (7). Hyperinsulinemia also increases ET-1 release in vitro as well as in vivo (8, 9). Moreover, hyperglycemia can reduce endothelial nitric oxide (NO) production and bioavailability (10, 11). In agreement with these findings clinical studies have shown that poor glycemic control increases the risk of the development of micro- and macrovascular disease in patients with type 2 diabetes mellitus, and the risk of microvascular complications is reduced when glycemic control is improved (12, 13). However, whether changes in the level of glycemia lead to alteration of either endothelium-dependent vasodilatation or the production of endothelium-derived vasoactive substances remains unsettled.
Vascular smooth muscle cells exposed to high glucose concentrations
demonstrate activation of the transcriptional factor nuclear
factor-
B, which, in turn, up-regulates adhesion molecule expression
(14). Furthermore, elevated concentrations of adhesion
molecules have been found in plasma from patients with type 2 diabetes
(15, 16, 17), and this correlated with indexes of glycemic
control (15). In addition, circulating vascular cell
adhesion molecule-1 (VCAM-1) levels were elevated in patients with type
2 diabetes and correlated with the presence of both symptomatic and
asymptomatic atherosclerosis (18). However, short-term
improvements in glycemic control in patients with poorly controlled
type 2 diabetes did not alter the concentrations of circulating
adhesion molecules (19).
In addition to adhesion, the vascular endothelium also modulates fibrin polymerization and lysis. In keeping with this, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1), i.e. the major regulators of fibrinolysis and fibrinolytic activity, are both increased in patients with type 2 diabetes (20). Treatment with metformin favorably reduces PAI-1 concentrations in diabetic patients (21), but conflicting results have been found for the effects of insulin treatment on PAI-1 concentrations (22, 23).
In the current study we examined the characteristics that might predict increased endothelial adhesion molecule and ET-1 concentrations and decreased total NO concentration and fibrinolytic activity in patients with poorly controlled type 2 diabetes compared with normal controls. Furthermore, we conducted a randomized trial to evaluate the effects of improved vs. usual glycemic control on adhesion molecules, ET-1, total NO concentrations, and fibrinolytic activity in patients with poorly controlled type 2 diabetes.
Subjects and Methods
Patients
Patients in this study were primarily recruited to assess the effects of intensive glycemic control on endothelial function measured by ultrasound changes in flow-mediated and glyceryl trinitrate-mediated vasodilatation of the brachial artery (24). Patients (n = 43) were recruited through teaching hospital diabetes’ clinics and from general practitioners. Inclusion criteria included type 2 diabetes of less than 15-yr duration with hemoglobin A1c (HbA1c) greater than 8.9% (criteria for type 2 diabetes: age at diagnosis >35 yr, no episodes of ketoacidosis in the past, and insulin independence for >12 months after diagnosis or fasting plasma C peptide >0.21 pmol/liter if duration of disease <12 months). Exclusion criteria were age more than 75 or less than 40 yr, body mass index (BMI) more than 40kg/m2, current diastolic blood pressure more than 100 mm Hg, creatinine more than 0.16 mmol/liter, any severe concurrent illness, left ventricular failure, myocardial infarction or unstable angina in the 6 months before enrollment, and recent (<6 wk) commencement of vasoactive cardiac medications. The institutional ethic’s committee approved the study, and all patients provided written informed consent.
Controls
As previously reported (25), 21 healthy volunteers were recruited from physicians and nurses of our institution and served as control subjects. Volunteers had no family history of diabetes or hypertension. Furthermore, they had normal clinical examinations and did not take medication or dietary supplements including vitamins and antioxidants. Chest x-ray, resting and exercise electrocardiogram, and echocardiogram were also normal.
Baseline patient examination
At baseline, all patients underwent a physical and laboratory examination to establish the presence or absence of micro- and macrovascular disease. Electrocardiograms were examined for evidence of left ventricular hypertrophy or ischemic heart disease (Q waves). A modified neuropathy symptom and neuropathy disability score were used to assess the presence of peripheral or autonomic neuropathy (26). Retinopathy was assessed by retinal photography. Two casual urine specimens were collected before randomization to determine the albumin/creatinine ratio. The albumin excretion rate was calculated from this ratio (27), and a rate of less than 20 µg/min was classified as normal. Microalbuminuria was defined as 20–200 µg/min, and persistent proteinuria as more than 200 µg/min. Body weight in a single layer of clothing was measured to the nearest 0.1 kg, and height to the nearest 0.1 cm. Body mass index was calculated as weight (kilograms) divided by height (meters) squared. Waist circumference at the umbilical midline was measured to the nearest millimeter with flexible tape (28).
Patients were randomized on the basis of gender, age, and smoking status to either a usual control (UC; n = 22) or improved control (IC; n = 21) group for a 20-wk period. The aims for patients randomized to UC were to avoid symptomatic hyperglycemia and fortnightly fasting capillary glucose tests of more than 17 mmol/liter. Those assigned to IC used a PrecisionQID (Medisense, Bedford, MA) glucose meter and were asked to test capillary glucose before each meal and 2 h postdinner, aiming for a premeal capillary glucose level of 4–7 mmol/liter and a postmeal reading of less than 10 mmol/liter. A HbA1c target of less than 7% by 20 wk was set. The IC group received stepwise adjustments to therapy to achieve these targets initially with oral hypoglycemic agents before commencing insulin. In patients treated with diet only at baseline the initial primary therapy with an oral hypoglycemic drug was determined by the BMI; if sulfonylurea was less than 32 kg/m2 and BMI was 32 kg/m2 or greater, metformin was used first. Once the initial oral hypoglycemic drug had reached the maximum tolerated dose (10 mg glipizide daily or 1 g metformin three times daily), the secondary drug, was added and increased to the maximum tolerated dose. Bedtime intermediate-acting insulin (Protophane Novo Nordisk, Copenhagen, Denmark) was started at 0.2 U/kg and increased to daily if glycemic targets were not met using oral hypoglycemic drugs. Premixed (PenMix30, Novo Nordisk) or short-acting (Actrapid, Novo Nordisk) insulin could be instituted if deemed necessary to meet glycemic targets. Patients taking insulin were continued on one oral hypoglycemic agent, the choice of which was determined by the BMI as outlined above. Patients in IC had medication adjusted according to glycemic targets by one investigator (W.B.) who was in telephone contact with the patients at least once a week, and review in the clinic was undertaken every 4 wk. In addition, IC patients received dietary and nursing education on at least one occasion during the study period.
Patients in UC had one formal medical review during the 20-wk period and received nursing and dietary education on one occasion if this had not been provided in the 12 months before enrolment in the study. Patients in this group received similar stepped care if they had symptomatic hyperglycemia or a fasting blood glucose of more than 17 mmol/liter.
Hypoglycemic episodes were defined as any capillary glucose record less than 4 mmol/liter, or symptoms of hypoglycemia relieved by treatment expected to raise the level of blood glucose in the absence of a capillary glucose test. Severe hypoglycemia was defined as the presence of impaired consciousness requiring the help of another person, coma or seizure, and the presence of a low blood glucose.
Laboratory methods
Patients were examined using the same protocol at randomization and 20 wk later in the Cardiovascular Research Laboratory, Department of Medicine, University of Auckland (Auckland, New Zealand). The laboratory temperature was controlled between 21.5–23.5 C. Patients were studied supine in the morning after an overnight fast of 10 h. Blood pressure and pulse rate were electronically monitored (Omega 1400 NonInvasive Blood Pressure Monitor, Invivo Research Laboratories, Inc., Orlando, FL).
Under local anesthesia and sterile conditions an iv 20-gauge cannula was inserted in the right antecubital fossa and was kept patent by normal saline flush. At least 1 h later blood specimens were taken for ET-1, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, NO, von Willebrand factor (vWF), plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (t-PA), glucose (glucose oxidase; Roche Molecular Biochemicals, Indianapolis, IN), insulin (microparticle enzyme immunoassay, Abbott Laboratories, Abbott Park, IL), lipids, HbA1c (by a commercial ion exchange assay adapted in the Variant 2 HPLC analyzer Bio-Rad Laboratories, Inc., Hercules, CA), and creatinine. Specimens for ET-1 were collected in prechilled EDTA tubes with 200 µl aprotinin (Bayer Corp., Pymble, NSW, Australia) added and placed on ice for transport to the laboratory. Similarly, specimens for soluble adhesion molecules were collected in prechilled, no additive, silicone tubes and placed on ice. One hour later specimens were centrifuged at 4 C and then stored at -70 C.
Plasma ET-1 levels were assessed by RIA (Peninsula Laboratories, Inc., Belmont, CA) according to a previously described methodology (8, 9). Intra- and interassay variations were less than 10%. Circulating soluble ICAM-1, VCAM-1, and E-selectin concentrations were assessed by ELISA (R & D Systems, Minneapolis, MN). NO in plasma was evaluated as nitrite+nitrate concentration by the method based on the use of Griess reagent (29, 30), i.e. colorimetric detection of nitrite after conversion of all the sample nitrate into nitrite (Assay Design, Inc., Ann Arbor, MI). The assessment of plasma vWF was performed by immunoenzymatic method (Roche Molecular Biochemicals, Milan, Italy). t-PA and PAI-1 antigen levels were assessed by enzyme immunoassay tests (American Diagnostic, Inc., Greenwich, CT).
Statistical methods
Except where otherwise stated, all results are presented as the mean and SEM. Continuous normally distributed variables were analyzed using the mixed procedure of SAS (Proc Mixed manual, 1997, SAS Institute, Inc., Cary, NC). This approach to repeated measures permits maximum likelihood imputation of missing random data while allowing adjustment for the randomization variables (gender, age, and smoking). Significant main and interaction effects were further explored using contrasts. In complementary analysis the effect of change in body weight on the efficacy of treatment was tested using covariate adjustment for weight change in the model. Results were then presented as least squares, marginal means, and the significance level test from type III sums of squares. The univariate correlates of adhesion molecules were examined using Spearman’s correlation. In multivariate analysis a variety of iterative procedures (stepwise, forward backward selection, and Max R) were used to determine the independent predictors of each adhesion molecule, ET-1, and NO in multiple linear regression. Colinearity diagnostics and data transformation were employed where appropriate. The procedure of Mantel and Haenzel was used to estimate the risk of hypoglycemic events in each of the treatment groups. A 5% significance level was maintained throughout these analyses. All tests were two-tailed.
Results
Suitable blood specimens for the assessment of adhesion molecules could not be obtained in one patient in IC and UC at baseline and wk 20; thus, data from 41 patients are presented. Twenty-one patients were assigned to UC, and all completed the study. Twenty patients were assigned to IC, but four patients were withdrawn after randomization; one suffered a brainstem cerebrovascular accident after 2 wk, one developed unstable angina after 6 wk, one developed diverticulitis after 12 wk, and one had a laparotomy for removal of a large benign ovarian mass after 16 wk in the study.
Section 1: patients with diabetes and normal controls (Tables 1
and 2 and Fig. 1)
Table 1 outlines the baseline characteristics and laboratory
results of the patients with diabetes and the normal controls. Compared
with controls, patients with diabetes manifested a marked degree of
endothelial activation, with significant (P < 0.05)
elevation of circulating E-selectin, ICAM-1, VCAM-1, vWF, t-PA, and
PAI-1 and a trend for increased ET-1 (P = 0.06)
concentrations and decreased NO (Table 1). However, after adjusting for
the potential confounding effects of differences in age, systolic and
diastolic blood pressures, total cholesterol, triglycerides, and BMI,
no differences between controls and diabetics remained (by analysis of
covariance type III sums of squares, all P >
0.05).
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), but not to age,
duration of diabetes, lipid parameters, HbA1c,
albumin excretion rate, fibrinogen, smoking, or insulin dose. No
univariate predictors of vWF, t-PA, or PAI-1 were identified. Multiple linear regression was employed to determine the independent predictors of each adhesion molecule, ET-1 and NO concentration from age, gender, mean arterial pressure, albumin excretion rate, insulin dose per kg BW, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, fibrinogen, HbA1c, and BMI. BMI accounted for most variance in models for E-selectin (partial r2 = 0.188; P = 0.006), ICAM-1 (partial r2 = 0.155; P = 0.01) and NO (partial r2 = 0.204; P = 0.002). BMI was not a significant independent predictor of VCAM-1 or ET-1. No other terms consistently remained significant in any of the models.
A reduced model was fitted, adjusting for HbA1c, BMI, and mean arterial pressure. Of these, only BMI at baseline independently predicted E-selectin (P = 0.007), ICAM-1 (P = 0.01), and NO (P = 0.008) concentrations, but not VCAM-1 (P = 0.84).
When an arbitrary cut-off BMI of 28 kg/m2 was
used to divide diabetic patients at baseline, this resulted in lean
(BMI, 24.8 ± 2.2 kg/m2; n = 14) and
obese (33.4 ± 3.7 kg/m2; n = 27)
groups. In the lean vs. obese groups (Fig. 1)
E-selectin (P = 0.015)
and ICAM-1 (P = 0.054) were lower, and NO
(P = 0.017) was higher. VCAM–1, vWF, t-PA, and PAI-1
were not different between the lean and obese groups (P
> 0.05). Furthermore, circulating adhesion molecules (with the
exception of VCAM-1), ET-1, and total NO did not differ between the
nonobese patients with type 2 diabetes and the normal controls (whose
BMI was 24.9 ± 1.0 kg/m2; P
= 0.18 vs. lean diabetic patients). The lean and obese
groups were similar with respect to sex, age, systolic and diastolic
blood pressures, lipid parameters, urinary albumin excretion rate, and
fibrinogen concentration.
Hypertensive (i.e. BP >140/90 mm Hg) and normotensive diabetic patients had similar levels of circulating adhesion molecules, ET-1, and NO (data not shown). Furthermore, no significant relationship of HbA1c or fasting blood glucose with adhesion molecules, ET-1, and NO could be demonstrated.
Section 2: effects of improved glycemic control in the usual control and improved control patients with type 2 diabetes mellitus
Patient characteristics at randomization are listed in Table 3. Glycemic control improved in
the IC group as expected, and this resulted in a significant absolute
difference between the groups in HbA1c of 2.2%
(95% confidence interval, 1.5–2.9%; P < 0.0001).
Sixteen of the 17 patients in the IC group who completed the study were
receiving insulin treatment at wk 20 (0.84 ± 0.10 U/kg·d;
range, 0.12–1.65 U/kg·d). Twelve of these were in combination with
metformin, 2 in combination with glipizide, 1 in
combination with glipizide and metformin, and 1 taking
insulin alone. One subject in IC took metformin alone. In the UC group
8 patients received a combination of metformin and sulfonylurea (1 of
these patients also took acarbose), 4 took
sulfonylureas alone, 3 took metformin alone, and 1 was
treated with diet alone at wk 20. Six patients in UC received insulin
treatment (0.41 ± 0.09 U/kg·d; range, 0.19–0.135 U/kg·d); 5
of these in combination with metformin.
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At baseline, the IC group was, by chance, 9 kg heavier than the UC
group, but BMI values were not different (P = 0.02 and
P = 0.12, respectively; Table 4). Patients in the IC group
gained significantly more weight than patients in the UC group during
the 20-wk study period (P = 0.003; Table 4).
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) in the IC group. Adhesion molecule, ET-1, and NO results before and after improved or usual glycemic control
Improved glycemic control in IC patients resulted in a trend
toward decreased concentrations of E-selectin (P =
0.07), but this failed to achieve statistical significance (Table 5). In addition, no group by time
interaction effect was detected, and improved glycemic control did not
reduce the expression of vWF, t-PA, PAI-1, ICAM-1, or VCAM-1. ET-1
increased significantly in both IC and UC during the 20-wk study period
(P < 0.001). Similarly, NO increased in UC
(P = 0.04), but not in IC (P = 0.17). A
change in BMI during the study did not alter the expression of adhesion
molecules.
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The current study demonstrates a significant degree of endothelial activation, with increased circulating concentrations of vWF, E-selectin, ICAM-1, VCAM-1, and abnormal fibrinolysis with raised circulating concentrations of t-PA and PAI-1 in patients with poorly controlled type 2 diabetes. The production of endothelium-derived vasoactive substances was also abnormal, with increased plasma concentrations of the potent vasoconstrictor ET-1 and decreased production of the vasodilating agent NO. Interestingly, obesity with increased waist circumference, suggesting central body fat deposition, appeared to be the only significant predictor of endothelial activation in this group of patients. Multivariate analysis showed that blood pressure, glycemic control, and HbA1c did not correlate with circulating endothelial adhesion molecules, ET-1, and NO concentrations.
The presence of endothelial activation in the type 2 diabetic patients is in agreement with other studies demonstrating increased circulating levels of VCAM-1 (15, 16, 17), ICAM-1 (15, 16), E-selectin (17), and ET-1 (31). However, our data expand upon previous findings demonstrating that central obesity was the only significant independent predictor of raised E-selectin, ICAM-1, and decreased total NO. In particular, lean patients with type 2 diabetes had similar levels of circulating adhesion molecules, ET-1, and NO compared with nondiabetic, healthy controls. Other investigators have demonstrated an inverse relationship between obesity (in nondiabetic subjects) and endothelial function as assessed by flow-mediated dilatation (32) or change in blood flow in response to methacholine (33). Moreover, in obese nondiabetic subjects a strong inverse correlation exists between endothelium-dependent vasodilatation and abdominal fat distribution (32). Finally, the blunted change in blood flow in response to methacholine (a test of endothelial function) is similar in obese nondiabetic subjects and diabetic subjects (33). Taken together, the above data strongly suggest that obesity, in particular central obesity, plays a pivotal role in inducing endothelial activation in patients with type 2 diabetes. It is possible that larger numbers of patients in the lean diabetic group and control group may have yielded differences between the groups. However, we wish to emphasize that the control subjects were carefully selected for their lack of risk factors for cardiovascular and metabolic disease. Thus, we are of the opinion that the data are robust.
The fact that weight gain in the improved control group of diabetic patients was not associated with a further increase in endothelial activation is not in contrast with this evidence, as the increase in body weight due to improved glycemic control was modest, and patients were obese at baseline. Thus, it is likely that more pronounced changes in body weight, such as those occurring when patients switch from an obese to a nonobese state, are necessary to down-regulate endothelial adhesion molecules. We have previously shown that marked weight loss in obese men resulted in significant reductions of increased plasma soluble E-selectin, ICAM-1, and VCAM-1 levels (5). On the other hand, obesity with central adiposity is known to increase cardiovascular risk in humans (5). Furthermore, recent studies have confirmed visceral obesity as an important predictor of cardiovascular morbidity (34, 35). Thus, obesity-related endothelial activation might be an important contributor to the increased cardiovascular risk in type 2 diabetic patients.
In the current study obesity did not predict the concentrations of vWF, VCAM, PAI-1, and tPA in patients with diabetes. Other investigators have demonstrated a relationship between markers of obesity and PAI-1, tPA and vWF in both diabetic (20) and nondiabetic patients (36). However, age, smoking habits, microalbuminuria, and the presence of diabetes may each have an effect on these variables (20). Thus, it is possible that the presence of diabetes and especially the diabetic complications of our patients played a more important role than obesity in predicting the concentrations of vWF, PAI-1, tPA, and VCAM.
In the current study we failed to demonstrate significant blood pressure influences on endothelial variables. These data are in agreement with previous findings demonstrating the lack of correlation between hypertension and endothelial activation, at least in hypertensives without either diabetes or obesity (5, 15, 17). Furthermore, in agreement with Yudkin et al. (19), we demonstrated that intensive glycemic control was not associated with a significant reduction in the concentrations of circulating adhesion molecules. The baseline differences between the two groups in this study should not be forgotten. Indeed, those assigned to improved control were more obese, had higher fibrinogen concentrations and more microvascular complications. Although baseline adhesion molecules were not different between the groups, improvements resulting from improved glycemic control may have been offset by these adverse factors.
Finally, we noted significant increments in circulating ET-1 concentrations at the end of the 20 wk of study in both the IC and UC groups. The release of ET-1 from the endothelium is tightly controlled by insulin, and circulating insulin and ET-1 concentrations are correlated in type 2 diabetic patients (31). Furthermore, insulin significantly stimulates the gene expression and secretion of ET-1 in cultured bovine cells (37). In humans both with and without diabetes, insulin administration is followed by a rise in circulating ET-1 levels (8, 38). Moreover, physiological increments in circulating insulin concentrations due to oral glucose administration are combined to simultaneously increase plasma ET-1 levels (9). Thus, changes in circulating ET-1 concentrations in both the improved and usual care groups could have reflected the administration of human recombinant insulin. Similarly, the increased concentrations of plasma NO concentrations at the end of the 20 wk of treatment may be due to increased production and decreased degradation of NO because of reduced oxidative stress (10, 11).
In conclusion, the present study demonstrates the pivotal role of obesity with an increased waist circumference in determining a significant degree of proatherogenic endothelial activation in type 2 diabetic patients with poor metabolic control. In particular, neither blood pressure nor glycemic control influenced endothelial variables. In contrast, obesity with visceral adiposity was the only independent predictor of endothelial activation, thus supporting recent evidence suggesting that obesity is one of the most important determinants of increased cardiovascular risk in type 2 diabetics as well as in the general population (34, 35). This randomized controlled study does not demonstrate that improved metabolic control protects the vascular endothelium against accelerated atherogenesis, at least in patients with type 2 diabetes whose endothelium is already activated in a proatherogenic manner. This may be due to the increased burden of vascular disease in the improved control group, the short duration of the study, and the only modest glycemic control in the improved control group. Furthermore, no attempt was made to improve lipid parameters in this study.
Footnotes
This work was supported by the AMP Society of New Zealand (Grant 3480115), the Health Research Council of New Zealand (Grant 3338748), the Auckland Medical Research Foundation (Grant 3331420), and the Auckland Rotary Club (Grant 3480143).
Abbreviations: BMI, Body mass index; ET-1, endothelin-1; Hb A1c, hemoglobin A1c; IC, improved glycemic control; ICAM-1, intracellular adhesion molecule-1; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; t-PA, tissue plasminogen activator; UC, usual glycemic control; VCAM, vascular cell adhesion molecule; vWF, von Willebrand factor.
Received January 3, 2001.
Accepted July 19, 2001.
References
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,
P < 0.05, control subjects vs. both
groups of diabetic patients. The line in the scatter
plot indicates the mean.