Table of Contents Author Guidelines Submit a Manuscript
Experimental Diabetes Research
Volume 2008, Article ID 672021, 6 pages
http://dx.doi.org/10.1155/2008/672021
Research Article

Effects of Oral Glucose Load on Endothelial Function and on Insulin and Glucose Fluctuations in Healthy Individuals

1Cardiology Research Clinic Y, Bispebjerg University Hospital, Copenhagen, NV 2400, Denmark
2Cardiology Department P and Laboratory, Gentofte University Hospital, Hellerup 2900, Denmark
3Internal Medicine Clinic I, Bispebjerg University Hospital, Copenhagen, NV 2400, Denmark
4Cardiology department, Rigshospitalet Univeristy Hospital, Copenhagen 2100, Denmark

Received 22 July 2007; Accepted 31 December 2007

Academic Editor: George King

Copyright © 2008 A. Major-Pedersen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/aims. Postprandial hyperglycemia, an independent risk factor for cardiovascular disease, is accompanied by endothelial dysfunction. We studied the effect of oral glucose load on insulin and glucose fluctuations, and on postprandial endothelial function in healthy individuals in order to better understand and cope with the postprandial state in insulin resistant individuals. Methods. We assessed post-oral glucose load endothelial function (flow mediated dilation), plasma insulin, and blood glucose in 9 healthy subjects. Results. The largest increases in delta FMD values (fasting FMD value subtracted from postprandial FMD value) occurred at 3 hours after both glucose or placebo load, respectively: (P = .009) and (P = .15). Glucose and insulin concentrations achieved maximum peaks at one hour post-glucose load. Conclusion. Oral glucose load does not induce endothelial dysfunction in healthy individuals with mean insulin and glucose values of 5.6 mmol/L and 27.2 mmol/L, respectively, 2 hours after glucose load.

1. Introduction

Postprandial hyperglycemia is an independent risk factor for cardiovascular disease (CVD) in insulin-resistant individuals with type 2 diabetes or with the prediabetic state, impaired glucose tolerance (IGT) [110]. In line with these epidemiologic data, several studies have shown impairment of endothelial function, one of the earliest markers of atherosclerosis [11] after a meal or glucose challenge, in individuals with diabetes or IGT [1217].

Endothelial function following acute hyperglycemia has also been studied in healthy individuals. Some groups have shown attenuation of endothelial function [1826], whereas others have shown no change [2731]. A few studies have shown acute hyperglycemia induced vasodilation in healthy individuals [32, 33], and only 2 studies (in vitro/ex vivo studies) have specifically reported glucose induced enhancement of the endothelial function [34, 35].

These seemingly conflicting results could be attributed to differences in methodology and subject characteristics: diverging periods of post-glucose load observations, varying periods of exposition to different concentrations of glucose, diverging criteria in subject selection, enabling versus blocking insulin’s physiologic response, and finally administrating oral glucose load versus intra-arterial or intravenous glucose administration.

Endothelial dysfunction is a predictor of cardiovascular risk; consequently, postprandial endothelial dysfunction might be a very early marker of atherosclerosis and, thus, an early potential target for the prevention of cardiovascular complications in insulin resistance. In order to better understand and cope with postprandial endothelial dysfunction and accompanying postprandial hyperinsulinemia and hyperglycemia in insulin resistant individuals, we find it important to study postprandial glucose and insulin fluctuations and postprandial endothelial function in healthy, insulin-sensitive people.

2. Material and Methods

2.1. Study Population

Ten non-smoking subjects, with no history of cardiovascular or other chronic disease, with no signs of current acute disease, and no familiar disposition to glucose intolerance, were included after screening a total of 13 individuals. We assessed blood pressure, ECG, oral glucose tolerance test, calculations of body mass index (BMI) and homeostasis model assessment (HOMA), and biochemical parameters. Three subjects were excluded: two due to total cholesterol > 6 mmo/L and one due to history of anorexia nervosa. Participants' characteristics are shown on Table 1. All subjects gave written informed consent and the study was approved by the ethics committee for Copenhagen and Frederiksberg counties.

Table 1: Subject characteristics. Data are presented as mean value ± SEM.
2.2. Study Design

Cross over study, n = 10. Subjects met on 2 separate days at 8:00 am after a 12-hour fast and after at least 18 hours abstinence from exercise. On the “glucose day”, endothelial function was measured before a 75 g oral glucose load (200 mL) and again at 1, 2, 3, and 4 hours after glucose load. On the “placebo day”, the same procedure was followed, but the 75 g glucose was substituted with placebo (200 mL tap water) as shown in Figure 1. The first FMD measurement of the day commenced between 8:30 and 9:00 am, glucose/H20 was given between 9:00 and 9:30, and the last FMD measurement of the day ended between 13:30 and 14:00.

Figure 1: Flow chart showing the study sequence during a study day. FMD1, FMD2, FMD3, and FMD4, respectively. Flow mediated dilation study at 1, 2, 3, and 4 hours after glucose/placebo load. FMD0, flow mediated dilation study before glucose/placebo load.

We extrapolated our post-glucose load findings to postprandial effects, since plasma glucose concentrations measured 2 hours after the ingestion of 75 g glucose have been found to be closely related to those measured after a standardized mixed meal [36].

2.3. Measurements of Endothelial Function

We used the flow mediated dilation (FMD) method [37, 38]. 20 minutes after supine rest, a pneumatic cuff was placed distal to the antecubital fossa, a 7.5 MHz linear array transducer (Cypress/Siemens, Siemens Medical Solutions USA, Inc. Mountain View, CA) was placed proximal to the antecubital fossa, and the brachial artery was viewed in a 2-dimensional (B-mode) longitudinal plane. A baseline picture was saved to ensure that the same brachial picture was found in the successive studies. After acquiring a two-minute baseline image, the cuff was rapidly inflated to 300 mmHg (VBM tourniquets, Braun Scandinavia) for 5 minutes, followed by rapid cuff deflation. Images were registered during 4 minutes after cuff deflation. Brachial diameters (at baseline and after cuff-deflation) were measured simultaneously by automated software (VIA online flow mediated dilation software, MD Medic) [39]. This software enabled us to precisely localize the greatest EDV since dilation was depicted graphically (as well as numerically).

The following formula was used to calculate relative change in FMD (expressed in %): ((Peak post cuff-deflation diameter − basline diameter)/baseline diameter) [40].

An intravenous cannula was inserted into a large antecubital vein in the left arm for blood sampling.

2.4. Biochemical Measurements

Blood samples were drawn on both days before oral glucose load/placebo administration and at 15, 30, 60, 120, 180, and 240 minutes after plasma was separated after complete clot formation, subsequent to centrifugation, and thereafter frozen at −80°C for posterior analysis of insulin (Immulite 2000, DPC Scandinavia, Denmark).

Whole venous blood glucose was measured at the aforementioned times with HemoCue glucose (HemoCue AB, Angelholm, Sweden).

2.5. Data Analysis

Data are presented as mean ± SEM. Comparisons between time points on the same curve (pre-oral glucose load, 1hPG, 2hPG, 3hPG, and 4hPG) for FMD, insulin, and glucose were evaluated with paired student t test for each curve separately. The level of statistical significance used was P < .05. For comparison of FMD time response studies between the 2 curves (post-glucose curve versus post-placebo curve), we used MIXED MODEL analysis (SAS statistical software version 9.1, SAS Institute, Cary, NC, USA).

Model assumptions of homogeneity of variance and normal distribution of residuals were checked graphically. Subjects entered the model as random effect as did the interaction between subject and time. Time and experimental protocols (glucose versus placebo) were entered as fixed effects.

3. Results

3.1. Endothelial Function

Delta FMD values (fasting FMD value subtracted from postprandial FMD value) ± SEM for post-glucose load and post-placebo load showed increasing FMD delta values for both days (see Table 2). The largest post-glucose load increase occurred at 3hPG (P = .009); compared to baseline, the increase was already significant at 1hPG (P = 0.03). The largest post-placebo increase also occurred at 3 hours post-placebo (P = .15) but was not significant (see Table 2). When we compared the two curves employing mixed models (post-glucose load curve versus post-placebo load curve), we found the curves to be statistically different (P = .0007).

Table 2: Effects of glucose load and placebo load on FMD, blood glucose and plasma insulin. Data are presented as mean value ± SEM.
3.2. Metabolic Parameters
3.2.1. Glucose

Post-glucose load mean blood glucose concentration values showed a significant increase at both 1hPG (P = .03) and 2hPG (P = .002). Conversely, a significant fall in blood sugar was observed at 4hPG (P = .002, n = 6 since the study was interrupted before the fourth postprandial hour in 3 subjects due to symptomatic hypoglycemia). As expected, post-placebo load values showed no significant change in blood glucose concentrations in the fasting state (see Table 2).

3.2.2. Insulin

Mean insulin concentration post-glucose load values showed a marked increase at 1hPG (P = .0006) and fell rapidly thereafter, achieving pre-glucose-like values by 3hPG. Post-placebo load values fell across the 4 hour post-load period, which was already apparent at one hour post placebo load (P = .0006) (Table 2).

4. Discussion

Our principal finding was that oral glucose load did not impair endothelial function in conduit arteries in our group of healthy, insulin-sensitive individuals with mean 2hPG of 5.58 mmol/L. We found maximum glucose and insulin peak concentrations at 1hPG. Furthermore our findings imply that oral glucose load might enhance endothelial function in these individuals.

Many studies have examined the effect of acute hyperglycemia on the healthy endothelium [18, 20, 22, 23, 30, 41]. These studies, however, cannot be directly compared to ours since both the methodology and the purpose of the studies diverge from our study. The aforementioned studies demonstrated that hyperglycemia induced impaired endothelial function, in healthy individuals, by either applying a local glucose/dextrose clamp or by intra-arterial glucose infusion, hence obtaining elevated hyperglycemic values (7.0 to 16.7 mmol/L). Yet, postprandial hormonal mechanisms, such as those leading to the “incretin effect” [42], may not be triggered when examined through the hyperglycemic clamp technique or local hyperglycemia. Some of these studies [30, 41] had also administered systemic ocreotide to suppress insulin secretion response to hyperglycemia. We did not find it appropriate to inhibit insulin secretion in order to study the physiologic endothelial post-glucose load response in healthy individuals since we suspected that the post-oral-glucose load insulin response might be pivotal in contributing to endothelial dependent vasodilation. Aside from keeping all hormonal responses intact, we chose to investigate post-glucose load endothelial function up to 4 hours after glucose load, because we were aware of the possibility that the endothelial response might not necessarily occur simultaneously with the increasing glucose and insulin concentrations. Our study is further strengthened by the fact that “time to peak” (the time it takes to achieve maximal dilation after cuff-deflation) varies individually, and that, by using our automated edge-detecting software, we have been sure of appreciating the largest dilation at each FMD measurement. Earlier studies using the FMD method have been forced to find a spot more or less blindly, between 40 and 90 seconds post cuff-deflation, for their measurements [19, 25].

As mentioned, differences in subject selection, particularly regarding postprandial blood glucose concentrations, might too have contributed to the apparently diverse findings reported in our study and other studies. A continuous relationship between increasing fasting and postprandial glucose concentrations and the risk of cardiovascular mortality in healthy, normoglycemic subjects has been documented [9, 43, 44]. Furthermore, a strong inverse relationship has been demonstrated between glucose levels, and endothelial function and intima media thickness (IMT) across the normoglycemic continuum; this was marked already at the 5.2 mmol/cut-off, and was even more significant with fasting glucose above 5.7 mmol/L [45]. Interestingly, a directly proportional risk gradient between CVD and postprandial glucose has been evidenced at1hPG [9].

In accordance with our selection criteria, our subjects were metabolic healthier, with lower mean fasting and postprandial glucose values than those in studies which employed a methodology similar to ours and, yet, demonstrated impaired endothelial function [21, 25, 26]. To illustrate, Title’s study [19] reported impaired endothelial function after oral glucose loading in 10 study subjects with a mean 1hPG of 7.9 mmol/L (as opposed to 6.2 mmol/L in our subjects). Thereby, the apparently contradictory results between Title's study and ours are actually complementary.

A limitation to our study is that it does not shed light on the cellular mechanisms responsible for the postprandial endothelial response. Yet, several mechanistic studies support our findings. Taubert’s group [34], for example, demonstrated that insulin's NO vasodilatory effect was augmented in the presence of relative hyperglycemia [34]. Indeed, in our subjects, there was a short and modest postprandial plasma glucose spike, followed by a larger postprandial hyperinsulinemic spike, which, in conjunction, led to an enhancement of the endothelial function when compared to baseline endothelial function. Conversely, our group [46] has previously proposed that persistent hyperglycemia inhibits PI3K-dependent signaling. Taubert's group reported that glucose and insulin stimulated NO release was impaired in the presence of hyperglycemia lasting beyond 2 hours, and that acute hyperglycemia did not increase NO release after prolonged exposure to hyperglycemia, leading them to suggest that enhanced superoxide generation in chronic hyperglycemia could be responsible for accelerated NO degradation. These findings could explain why studies where hyperglycemic clamps were employed, and/or examined subjects with relatively high postprandial values, have not found enhanced endothelial function [1820, 23, 30, 47].

The greatest increment in endothelial function in our study occurred at 3 hours post-glucose load when glucose concentrations were back to baseline levels yet with insulin concentrations still 6 times higher than baseline insulin concentrations. Furthermore we observed a positive post-glucose load delta value at the cessation of the study (4hPG) for FMD and insulin concentrations. Interestingly, Cardillo et al. [48] found maximal insulin dilator effect after 2 hours of insulin infusion, leading them to postulate that insulin has a relatively slow-onset vasodilator effect. Accordingly, four hours of sustained hyperinsulinemia in the healthy has been shown to induce endothelial dependent vasodilation [49]. These observations could therefore explain our positive findings and why research groups that have limited their postprandial endothelial studies to 2 hours or less after a meal/glucose load [24] have not observed insulin induced endothelium dependent vasodilation following a hyperglycemic spike.

As aforementioned, post-glucose load glucose concentrations correlate closely to post-standardized meal glucose concentrations; yet we cannot directly compare our results with studies that have used standardized meals since these include lipids. Admitting that a standardized meal would have reflected a truer postprandial response, a standardized meal would have obscured the action of glucose alone on the endotheliuem, since it has been demonstrated that postprandial hyperlipidemia induces postprandial endothelial dysfunction in the healthy endothelium [5052].

5. Conclusion

In short, we find that endothelial dysfunction is not a normal, physiologic, post-glucose load response. Instead, this study finds preserved post-glucose load endothelial function, thus implying that sugar derived from meals does not promote endothelial dysfunction, providing that postprandial insulin and glucose responses are preserved. It seems that the interaction of glucose and insulin on the endothelial function is affected both by the magnitude of glucose and insulin concentrations, and by the duration of exposition to these.

The immediate question arising from this study is whether by targeting both postprandial glucose and insulin peaks in insulin resistant individuals, so that both postprandial peaks resemble those of insulin sensitive individuals, enhances postprandial endothelial function. There is a pressing need for a greater therapeutic focus on the postprandial state, accompanied by a redefinition of the “normal” postprandial state, marking the true threshold for the onset of cardiovascular risk.

Abbreviations
1hPG, 2hPG: 1-hour and 2-hour glucose values after an oral 75 glucose load
3hPG, 4hPG: 3-hour and 4-hour glucose values after an oral 75 glucose load
CVD: Cardiovascular disease
FMD: Flow mediated dilation
HOMA: Homeostasis model assessment
IGT: Impaired glucose tolerance
NO: Nitric oxide
PI3K: Phsophatidylnositol -OH kinase

Acknowledgment

This work is supported by the Danish Diabetes Association.

References

  1. Q. Qiao, S. Larsen, K. Borch-Johnsen et al., “Glucose tolerance and cardiovascular mortality. Comparison of fasting and 2-hour diagnostic criteria,” Archives of Internal Medicine, vol. 161, no. 3, pp. 397–405, 2001. View at Publisher · View at Google Scholar
  2. E. Bonora and M. Muggeo, “Postprandial blood glucose as a risk factor for cardiovascular disease in Type II diabetes: the epidemiological evidence,” Diabetologia, vol. 44, no. 12, pp. 2107–2114, 2001. View at Publisher · View at Google Scholar
  3. B. L. Rodriguez, R. D. Abbott, W. Fujimoto et al., “The American diabetes association and world health organization classifications for diabetes: their impact on diabetes prevalence and total and cardiovascular disease mortality in elderly Japanese-American men,” Diabetes Care, vol. 25, no. 6, pp. 951–955, 2002. View at Publisher · View at Google Scholar
  4. M. Tominaga, H. Eguchi, H. Manaka, K. Igarashi, T. Kato, and A. Sekikawa, “Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the funagata diabetes study,” Diabetes Care, vol. 22, no. 6, pp. 920–924, 1999. View at Publisher · View at Google Scholar
  5. F. de Vegt, J. M. Dekker, H. G. Ruhé et al., “Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn study,” Diabetologia, vol. 42, no. 8, pp. 926–931, 1999. View at Publisher · View at Google Scholar
  6. J. E. Shaw, A. M. Hodge, M. De Courten, P. Chitson, and P. Z. Zimmet, “Isolated post-challenge hyperglycaemia confirmed as a risk factor for mortality,” Diabetologia, vol. 42, no. 9, pp. 1050–1054, 1999. View at Publisher · View at Google Scholar
  7. M. Coutinho, H. C. Gerstein, Y. Wang, and S. Yusuf, “The relationship between glucose and incident cardiovascular events: a metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years,” Diabetes Care, vol. 22, no. 2, pp. 233–240, 1999. View at Publisher · View at Google Scholar
  8. M. Hanefeld, C. Koehler, F. Schaper, K. Fuecker, E. Henkel, and T. Temelkova-Kurktschiev, “Postprandial plasma glucose is an independent risk factor for increased carotid intima-media thickness in non-diabetic individuals,” Atherosclerosis, vol. 144, no. 1, pp. 229–235, 1999. View at Publisher · View at Google Scholar
  9. B. L. Rodriguez, N. Lau, C. M. Burchfiel et al., “Glucose intolerance and 23-year risk of coronary heart disease and total mortality: the Honolulu heart program,” Diabetes Care, vol. 22, no. 8, pp. 1262–1265, 1999. View at Publisher · View at Google Scholar
  10. T. Temelkova-Kurktschiev, “Significance of postprandial glucose peaks for development of diabetic macroangiopathy,” Therapeutische Umschau, vol. 59, pp. 411–414, 2002. View at Publisher · View at Google Scholar
  11. H. Gaenzer, G. Neumayr, P. Marschang et al., “Effect of insulin therapy on endothelium-dependent dilation in type 2 diabetes mellitus,” The American Journal of Cardiology, vol. 89, no. 4, pp. 431–434, 2002. View at Publisher · View at Google Scholar
  12. A. Ceriello, “Acute hyperglycaemia: a ‘new’ risk factor during myocardial infarction,” European Heart Journal, vol. 26, no. 4, pp. 328–331, 2005. View at Publisher · View at Google Scholar
  13. A. Ceriello, A. Cavarape, L. Martinelli et al., “The post-prandial state in type 2 diabetes and endothelial dysfunction: effects of insulin aspart,” Diabetic Medicine, vol. 21, no. 2, pp. 171–175, 2004. View at Publisher · View at Google Scholar
  14. M. Shimabukuro, N. Higa, I. Chinen, K. Yamakawa, and N. Takasu, “Effects of a single administration of acarbose on postprandial glucose excursion and endothelial dysfunction in type 2 diabetic patients: a randomized crossover study,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 3, pp. 837–842, 2006. View at Publisher · View at Google Scholar
  15. M. Shimabukuro, N. Higa, N. Takasu, T. Tagawa, and S. Ueda, “A single dose of nateglinide improves post-challenge glucose metabolism and endothelial dysfunction in type 2 diabetic patients,” Diabetic Medicine, vol. 21, no. 9, pp. 983–986, 2004. View at Publisher · View at Google Scholar
  16. S.-H. Kim, K.-W. Park, Y.-S. Kim et al., “Effects of acute hyperglycemia on endothelium-dependent vasodilation in patients with diabetes mellitus or impaired glucose metabolism,” Endothelium, vol. 10, no. 2, pp. 65–70, 2003. View at Publisher · View at Google Scholar
  17. T. C. Wascher, I. Schmoelzer, A. Wiegratz et al., “Reduction of postchallenge hyperglycaemia prevents acute endothelial dysfunction in subjects with impaired glucose tolerance,” European Journal of Clinical Investigation, vol. 35, no. 9, pp. 551–557, 2005. View at Publisher · View at Google Scholar
  18. D. Giugliano, R. Marfella, L. Coppola et al., “Vascular effects of acute hyperglycemia in humans are reversed by L-arginine: evidence for reduced availability of nitric oxide during hyperglycemia,” Circulation, vol. 95, no. 7, pp. 1783–1790, 1997. View at Google Scholar
  19. L. M. Title, P. M. Cummings, K. Giddens, and B. A. Nassar, “Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E,” Journal of the American College of Cardiology, vol. 36, no. 7, pp. 2185–2191, 2000. View at Publisher · View at Google Scholar
  20. S. B. Williams, A. B. Goldfine, F. K. Timimi et al., “Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo,” Circulation, vol. 97, no. 17, pp. 1695–1701, 1998. View at Google Scholar
  21. H. Kawano, T. Motoyama, O. Hirashima et al., “Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery,” Journal of the American College of Cardiology, vol. 34, no. 1, pp. 146–154, 1999. View at Publisher · View at Google Scholar
  22. J. A. Beckman, M. A. Creager, and P. Libby, “Diabetes and atherosclerosis epidemiology, pathophysiology, and management,” Journal of the American Medical Association, vol. 287, no. 19, pp. 2570–2581, 2002. View at Publisher · View at Google Scholar
  23. J. A. Beckman, A. B. Goldfine, M. B. Gordon, L. A. Garrett, and M. A. Creager, “Inhibition of protein kinase Cβ prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans,” Clinical Research, vol. 90, pp. 107–111, 2002. View at Publisher · View at Google Scholar
  24. C. M. Akbari, R. Saouaf, D. F. Barnhill, P. A. Newman, F. W. LoGerfo, and A. Veves, “Endothelium-dependent vasodilatation is impaired in both microcirculation and macrocirculation during acute hyperglycemia,” Journal of Vascular Surgery, vol. 28, no. 4, pp. 687–694, 1998. View at Publisher · View at Google Scholar
  25. A. Ceriello, C. Taboga, L. Tonutti et al., “Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment,” Circulation, vol. 106, no. 10, pp. 1211–1218, 2002. View at Publisher · View at Google Scholar
  26. N. Ihlemann, C. Rask-Madsen, A. Perner et al., “Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 285, no. 2, pp. H875–H882, 2003. View at Publisher · View at Google Scholar
  27. A. J. H. M. Houben, N. C. Schaper, C. H. A. de Haan et al., “Local 24-h hyperglycemia does not affect endothelium-dependent or—independent vasoreactivity in humans,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 270, no. 6, pp. H2014–H2020, 1996. View at Google Scholar
  28. N. Charkoudian, A. Vella, A. S. Reed et al., “Cutaneous vascular function during acute hyperglycemia in healthy young adults,” Journal of Applied Physiology, vol. 93, no. 4, pp. 1243–1250, 2002. View at Publisher · View at Google Scholar
  29. W. Bagg, G. A. Whalley, A. Sathu, G. Gamble, N. Sharpe, and G. D. Braatvedt, “The effect of acute hyperglycaemia on brachial artery flow mediated dilatation in normal volunteers,” Australian and New Zealand Journal of Medicine, vol. 30, no. 3, pp. 344–350, 2000. View at Google Scholar
  30. A. S. Reed, N. Charkoudian, A. Vella, P. Shah, R. A. Rizza, and M. J. Joyner, “Forearm vascular control during acute hyperglycemia in healthy humans,” American Journal of Physiology—Endocrinology and Metabolism, vol. 286, no. 3, pp. E472–E480, 2004. View at Publisher · View at Google Scholar
  31. A. Siafarikas, K. Watts, P. Beye, T. W. Jones, E. A. Davis, and D. J. Green, “Lack of effect of oral glucose loading on conduit vessel endothelial function in healthy subjects,” Clinical Science, vol. 107, no. 2, pp. 191–196, 2004. View at Publisher · View at Google Scholar
  32. R. P. Hoffman, M. Hausberg, C. A. Sinkey, and E. A. Anderson, “Hyperglycemia without hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans,” Journal of Diabetes and Its Complications, vol. 13, no. 1, pp. 17–22, 1999. View at Publisher · View at Google Scholar
  33. S. van Veen, M. Frölich, and P. C. Chang, “Acute hyperglycaemia in the forearm induces vasodilation that is not modified by hyperinsulinaemia,” Journal of Human Hypertension, vol. 13, no. 4, pp. 263–268, 1999. View at Publisher · View at Google Scholar
  34. D. Taubert, A. Rosenkranz, R. Berkels, R. Roesen, and E. Schömig, “Acute effects of glucose and insulin on vascular endothelium,” Diabetologia, vol. 47, no. 12, pp. 2059–2071, 2004. View at Publisher · View at Google Scholar
  35. M. J. Cipolla, J. M. Porter, and G. Osol, “High glucose concentrations dilate cerebral arteries and diminish myogenic tone through an endothelial mechanism,” Stroke, vol. 28, no. 2, pp. 405–410, 1997, discussion 410-411. View at Google Scholar
  36. T. M. S. Wolever, J.-L. Chiasson, A. Csima et al., “Variation of postprandial plasma glucose, palatability, and symptoms associated with a standardized mixed test meal versus 75 g oral glucose,” Diabetes Care, vol. 21, no. 3, pp. 336–340, 1998. View at Publisher · View at Google Scholar
  37. D. S. Celermajer, K. E. Sorensen, V. M. Gooch et al., “Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis,” Lancet, vol. 340, no. 8828, pp. 1111–1115, 1992. View at Publisher · View at Google Scholar
  38. M. C. Corretti, T. J. Anderson, E. J. Benjamin et al., “Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the international brachial artery reactivity task force,” Journal of the American College of Cardiology, vol. 39, no. 2, pp. 257–265, 2002. View at Publisher · View at Google Scholar
  39. V. R. Newey and D. K. Nassiri, “Online artery diameter measurement in ultrasound images using artificial neural networks,” Ultrasound in Medicine and Biology, vol. 28, no. 2, pp. 209–216, 2002. View at Publisher · View at Google Scholar
  40. L. Lind, J. Hall, A. Larsson, M. Annuk, B. Fellström, and H. Lithell, “Evaluation of endothelium-dependent vasodilation in the human peripheral circulation,” Clinical Physiology, vol. 20, no. 6, pp. 440–448, 2000. View at Publisher · View at Google Scholar
  41. K. Esposito, F. Nappo, R. Marfella et al., “Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress,” Circulation, vol. 106, no. 16, pp. 2067–2072, 2002. View at Publisher · View at Google Scholar
  42. H. Elrick, L. Stimmler, C. J. Hlad Jr., and Y. Arai, “Plasma insulin response to oral and intravenous glucose administration,” Journal of Clinical Endocrinology & Metabolism, vol. 24, pp. 1076–1082, 1964. View at Google Scholar
  43. J. H. Fuller, M. J. Shipley, G. Rose, R. J. Jarrett, and H. Keen, “Coronary-heart-disease risk and impaired glucose tolerance. The Whitehall study,” Lancet, vol. 1, no. 8183, pp. 1373–1376, 1980. View at Google Scholar
  44. M. Pyörälä, H. Miettinen, P. Halonen, M. Laakso, and K. Pyörälä, “Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: the 22-year follow-up results of the Helsinki policemen study,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 20, no. 2, pp. 538–544, 2000. View at Google Scholar
  45. G. N. Thomas, P. Chook, M. Qiao et al., “Deleterious impact of “high normal” glucose levels and other metabolic syndrome components on arterial endothelial function and intima-media thickness in apparently healthy Chinese subjects: the CATHAY study,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 4, pp. 739–743, 2004. View at Publisher · View at Google Scholar
  46. C. Rask-Madsen, N. Ihlemann, T. Krarup et al., “Insulin therapy improves insulin-stimulated endothelial function in patients with type 2 diabetes and ischemic heart disease,” Diabetes, vol. 50, pp. 2611–2618, 2001. View at Google Scholar
  47. J. A. Beckman, A. B. Goldfine, M. B. Gordon, and M. A. Creager, “Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans,” Circulation, vol. 103, no. 12, pp. 1618–1623, 2001. View at Google Scholar
  48. C. Cardillo, C. M. Kilcoyne, S. S. Nambi, R. O. Cannon III, M. J. Quon, and J. A. Panza, “Vasodilator response to systemic but not to local hyperinsulinemia in the human forearm,” Hypertension, vol. 32, no. 4, pp. 740–745, 1998. View at Google Scholar
  49. A. Ceriello, C. Taboga, L. Tonutti et al., “Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment,” Circulation, vol. 106, no. 10, pp. 1211–1218, 2002. View at Publisher · View at Google Scholar
  50. J.-H. Bae, E. Bassenge, K.-B. Kim et al., “Postprandial hypertriglyceridemia impairs endothelial function by enhanced oxidant stress,” Atherosclerosis, vol. 155, no. 2, pp. 517–523, 2001. View at Publisher · View at Google Scholar
  51. M. Hanefeld and T. Temelkova-Kurktschiev, “The postprandial state and the risk of atherosclerosis,” Diabetic Medicine, vol. 14, 3, pp. S6–S11, 1997. View at Publisher · View at Google Scholar
  52. R. A. Anderson, M. L. Evans, G. R. Ellis et al., “The relationships between post-prandial lipaemia, endothelial function and oxidative stress in healthy individuals and patients with type 2 diabetes,” Atherosclerosis, vol. 154, no. 2, pp. 475–483, 2001. View at Publisher · View at Google Scholar