European Journal of Clinical Nutrition (2012) 66, 722 - 726 & 2012 Macmillan Publishers Limited All rights reserved 0954-3007/12 www.nature.com/ejcn
ORIGINAL ARTICLE
Postprandial platelet aggregation: effects of different meals and glycemic index KDK Ahuja, GA Thomas, MJ Adams and MJ Ball BACKGROUND/OBJECTIVES: Hyperglycaemia is associated with increased platelet aggregation that increases the risk of thrombosis in people with type-2 diabetes and cardiovascular disease. Low glycemic index (GI) meals high in carbohydrate or moderately high in protein have been shown to acutely reduce postprandial excursions of plasma glucose and insulin compared with high carbohydrate high GI meals. However, it is not known whether these differences in glucose and insulin profile also impact on postprandial platelet aggregation. This study aimed to investigate the acute effects of three iso-energetic meals, on measures of postprandial platelet aggregation, in healthy individuals. SUBJECTS/METHODS: A randomised cross-over study compared the acute effects of a high GI high carbohydrate (HGI-HC), a low GI high carbohydrate (LGI-HC) and a low GI moderately high in protein and fat (LGI-MPF) meal on postprandial platelet aggregation, glucose, insulin and triglyceride concentrations. Comparisons were made at fasting, 60 and 120 min postprandially. RESULTS: A total of 32 volunteers (mean±s.d.; age 59.9±11.7 years, BMI 27.1±3.7 kg/m2) participated in the study. Results showed significant reductions in maximum platelet aggregation postprandially with nonsignificant differences (all P40.29) between the three meals. Glucose and insulin were significantly (both Po0.001) higher at 60 min postprandially on the HGI-HC meal compared with both LGI-HC and LGI-MPF meals. Triglycerides were not significantly different (all P40.25) between the three test meals. CONCLUSION: In healthy individuals platelet aggregation is reduced postprandially but this decrease is similar between meals of different GI that induce different glucose and insulin responses. European Journal of Clinical Nutrition (2012) 66, 722 -- 726; doi:10.1038/ejcn.2012.28; published online 21 March 2012 Keywords: platelet aggregation; cardiovascular disease; hyperglycaemia; insulin; glycaemic index
INTRODUCTION There is evidence that a strong relationship exists between type-2 diabetes, coronary heart disease and the glycemic index (GI) content of the overall diet.1 In contrast to high GI diets/meals, consuming low GI foods help to reduce extreme fluctuations in serum glucose concentrations.2,3 This in turn helps to reduce insulin resistance and increase insulin sensitivity.2,3 Although there is consensus that low GI foods are better for health, the debate continues whether the low GI diets rich in carbohydrates are better for health or if part of the carbohydrate in low GI diets can be replaced with protein and unsaturated fats. Impairment of platelet function and increased platelet aggregation are common in a range of vascular and metabolic disorders including diabetes and cardiovascular disease. It is thought that this increased platelet aggregation is due to abnormal glucose regulation leading to increased endothelial dysfunction, activation of the coagulation cascade and increased prothrombotic and proinflammatory markers.4 - 6 Chronic hyperglycaemia as observed in type-2 diabetes, or acute hyperglycaemia, as a result of ingestion of a meal causing postprandial glucose and insulin excursions, may increase platelet activation and reactivity.7,8 Foods such as garlic, cocoa, tomatoes, kiwi fruit, berries and so on have been shown to have anti-platelet properties that may help reduce the risk of thrombosis.9 - 12 We have previously reported13 a postprandial reduction in platelet aggregation, in healthy men and women, in response to a high carbohydrate, low fat meal (69% energy from carbohydrate, 16% from protein and
15% from fat). This may provide potential benefits. In the present study, we extend this research to investigate and compare the acute effects of three meals, known to induce different glycemic responses, on measures of postprandial platelet aggregation. We hypothesised that low GI meals (high carbohydrate and high protein) lead to a lower postprandial platelet aggregation than a high carbohydrate high GI meal due to their different effects on plasma glucose and serum insulin profiles. SUBJECTS AND METHODS The study was approved by the Human Research Ethics Committee (Tasmania) Network, Australia (EC00337). Each participant provided signed, informed consent.
Participants Participants included men and women aged between 18 and 80 years, with no self-known history of diabetes, liver or kidney disease. Those on regular antiplatelet therapy were excluded and all participants were instructed to abstain from aspirin, or similar anti-inflammatory medication, vitamin/mineral and omega-3 supplements, for at least 2 weeks (to allow for platelet turnover and normalisation) before their first test visit and until after their last testing session.
Study design This study was a randomised crossover design that assessed the effects of three different meals: a low GI high carbohydrate (LGI-HC) meal; a high GI
School of Human Life Sciences, University of Tasmania, Launceston, Tasmania, Australia. Correspondence: Dr KDK Ahuja, School of Human Life Sciences, University of Tasmania, Locked Bag 1320, Launceston, Tasmania 7250, Australia. E-mail:
[email protected] Received 14 September 2011; revised 29 November 2011; accepted 22 February 2012; published online 21 March 2012
Food and postprandial platelet aggregation KDK Ahuja et al high carbohydrate (HGI-HC) meal; and a low GI moderate protein/fat meal (LGI-MPF) on postprandial platelet aggregation. A washout period of 1 week was provided between consecutive test sessions. Meal order was randomised by a third party before any data collection. Although it was not possible to blind the study participants and the person preparing the meals, the person performing the platelet aggregation tests was blinded to the study meals.
Test day protocol Participants were advised to avoid the intake of alcohol and fried food in the 24 h before their testing sessions. For each test session participants fasted overnight for 10 - 12 h, and arrived at the School of Human Life Sciences clinical room on the following morning. After measurement of height and weight, a 20-gauge cannula was inserted in the participant’s antecubital vein for repeated blood sampling. Participants then rested in a semi-recumbent position for 20 min to reduce the stress response and platelet activation at the cannulation site. This was followed by blood sample collection without stasis for baseline measurements of fasting platelet aggregation, serum insulin, cholesterol, triglycerides and plasma glucose. After initial blood collection, participants consumed a LGI-HC, HGI-HC or LGI-MPF meal within 10 min. Subsequent blood samples for analyses of platelet aggregation, glucose, insulin and triglycerides were collected at 60 and 120 min postprandially. To control for the circadian effect14 on fasting samples individual participants were tested at the same time on all three test days. All participants started each test session between 0730 and 0900 hours.
Test meals The iso-energetic meal profiles (Table 1) were created using Foodworks 2.1 (Xyris, Brisbane, Queensland, Australia), incorporating AusFoods, AusNut and Nuttab 95 databases. The LGI-HC and HGI-HC meals provided similar amounts of carbohydrate, total fat and protein. The only difference between these two meals was the GI. The LGI-MPF meal provided lower amounts of carbohydrate, higher protein and more fat in the form of polyunsaturated and monounsaturated fats, in comparison with the other two meals. The GI of LGI-HC, HGI-HC and LGI-MPF meals was 45, 76 and 45, respectively.
Blood sampling and laboratory measurements Venous blood samples were collected in vacutainer tubes containing sodium citrate (3.8%) anticoagulant for platelet aggregation tests, sodium fluoride tubes for plasma glucose and plain tubes (anticoagulant free) for serum insulin, cholesterol and triglycerides. All samples for platelet aggregation were analysed within 2 h of collection as previously
Table 1.
described.13,15 Briefly, blood was centrifuged at 150 g for 10 min at room temperature to obtain platelet rich plasma (PRP). Platelet poor plasma was then obtained from the remaining blood by centrifugation at 2000 g for 20 min. Platelet poor plasma was used as the blank for each experiment and to adjust the platelet count of PRP to 250 109/l. Platelet aggregation (using 225 ml of PRP and 25 ml of agonist) was induced with agonist adenosine diphosphate (ADP; 2.5, 5 and 5 mM) (Sigma Chemical Company, St Louis, Mo, USA). To standardise the conditions, ADP was added after 40 s of lag time and transmission measured for 10 min using a four-channel AggRAM platelet aggregometer (Helena Laboratories, Beaumont, TX, USA) at 600 r.p.m. and 37 1C. Data on maximum aggregation, slope (rate of aggregation) and area under the curve (AUC) were collected for each test. Serum and plasma samples for glucose, insulin and triglyceride analysis were obtained by centrifugation of blood samples at 4 1C for 15 min at 3000 g. The separated samples were stored at 80 1C until required for laboratory analysis. Insulin was measured using a two-phase chemiluminescent method (Immulite, Siemens, Melbourne, Victoria, Australia). Glucose and triglycerides were measured using a spectrophotometric hexokinase method and an enzymatic/GPO method (Konelab 20XT, Thermo Fisher Scientific, Scoresby, Victoria, Australia), respectively, using commercially available kits (Thermo Fisher Scientific), according to the manufacturer’s instructions.
Calculations and statistical analysis All data were analysed using random effects linear regression corrected for repeated measures, while adjusting for any order and period effects (STATA version 11; StataCorp. LP, College Station, TX, USA). Post estimation Holm test analysis was used to adjust P-values for multiple comparisons. Statistical analyses included comparison of baseline measures between the three meals for different concentrations of ADP and; comparisons between the meals for change from 0 to 60 and 120 min at different concentrations of ADP. Associations between measured metabolic parameters (z scores) and measures of platelet aggregation were checked. If significant, the above stated comparisons were also carried out while accounting/ adjusting for the effect of these metabolic parameters. Data/figures were generated using GraphPad Prism (version 5; GraphPad Prism, San Diego CA, USA).
RESULTS A total of 33 men and women participated in the study; however, one person was excluded from the study because of abnormal platelet function. Results were analysed for 32 participants (22 females; mean±s.d.; age 59.9±11.7 years, BMI 27.1±3.7 kg/m2). In all, 12 participants commenced the study with LGI-HC meal,
Ingredients and dietary composition of the test meals
Ingredients
Energy (kJ) Carbohydrate (g) BPercent of energy Total Fat (g) BPercent of energy (Sat: Poly: Mono in (g)) Protein (g) BPercent of energy Glycemic index
LGI-HC meal
HGI-HC meal
LGI-MPF meal
Skim/non-fat milk Apple juice Light cream cheese Toasted mixed grain bread Natural style muesli Fructose powder 1777 68 61 10 22 (5:1:2) 14 14 45
Skim/non-fat milk, Plain drinking tap water Light cream cheese Toasted white bread Corn flakes Glucose powder 1780 70 65 9 19 (5:1:2) 15 15 76
Reduced fat milk Plain drinking tap water Avocado dip Toasted mixed grain bread Poached egg Sustagen protein powder 1775 50 46 15 30 (6:4:5) 23 22 45
Abbreviations: HGI-HC, high glycemic index high carbohydrate; LGI-HC, low glycemic index high carbohydrate; LGI-MPF, low glycemic index moderate protein fat; Mono, Monounsaturated fat; Poly, Polyunsaturated fat; Sat, Saturated fat.
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European Journal of Clinical Nutrition (2012) 722 - 726
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Food and postprandial platelet aggregation KDK Ahuja et al
724 *
70
$
Insulin (µU/mL)
56
35 21
50
Glucose (mmol/L)
7 6.75
40
*
5.75
4.75 1.35
30
20 0
60
120
Triglyceride (mmol/L)
5 µM ADP
84
*
70
60
2.5 µM ADP
Maximum aggregation (%)
10 µM ADP
80
1 0.9
Time (minutes)
Figure 1. Maximum platelet aggregation at fasting, 60 and 120 min postprandially after the three test meals. Data presented as mean±s.e. of mean; n ¼ 28 -- 32. K Shows LGI-HC meal; D shows LGI-MPF meal; ’ shows HGI-HC meal. All data were analysed using random effects linear regression corrected for repeated measures, adjusted for order and period effects.
10 with HGI-HC meal and the remaining 10 with LGI-MPF meal. Owing to difficulties in blood collection or haemolysed samples not all concentrations of ADP were tested for each individual. Platelet aggregation results for a minimum of 28 participants were available for all tests and each ADP concentration. There was no significant difference (all P40.42) for maximum platelet aggregation (Figure 1), slope and AUC aggregation curve (all P40.45) at baseline for the three meals at all concentrations of ADP. All meals led to statistically significant (all Po0.02) reductions in maximum platelet aggregation for 2.5- and 5-mM ADP over 2-h testing period (Figure 1). Although LGI-HC and LGI-MPF meals also showed significant (Po0.04) reductions with 10-mM ADP, the HGI-HC meal lead to a nonsignificant (P ¼ 0.13) reduction. Comparison of the three meals did not show any significant differences at any time points (all P40.29) for any concentration of ADP. Results for AUC aggregation curve were similar to those for maximum aggregation (data not shown). Although the rate of aggregation (slope) was reduced in the postprandial state, this was not significantly different between the three time points or the three test meals. There were no statistically significant differences in fasting plasma glucose, serum insulin and serum triglycerides (all P40.1) concentrations between the three test days (Figure 2). Among the three meals, HGI-HC meal led to the largest increases in plasma glucose and insulin concentrations in the postprandial state with LGI-MPF meal showing the least increase. Serum insulin concentrations for HGI-HC meal were significantly higher, at 60 and 120 min postprandially, than LGI-HC and the LGI-MPF meals (all Po0.001). The differences between LGI-MPF and LGI-HC were not significant at any of the time points (all P40.11). For glucose, HGI-HC meal showed significantly higher results than both LGI-HC and LGI-MPF meals at 60 min postprandially (both European Journal of Clinical Nutrition (2012) 722 -- 726
0
60
120
Time (minutes)
Figure 2. Serum insulin, plasma glucose and serum triglycerides at fasting and up to 120 min postprandially in response to the three test meals. Data presented as mean±s.e. of mean; n ¼ 32. K Shows LGI-HC; D LGI-MPF meal; & shows HGI-HC meal. All data were analysed using random effects linear regression corrected for repeated measures, adjusted for order and period effects. *HGI-HC significantly different from LGI-HC and LGI-MPF meals; $LGI-HC significantly different from LGI-MPF.
Po0.001), but not at 120 min postprandially (both P40.41). The differences between LGI-MPF and LGI-HC were not significant at any of the time points (all P40.08). There were no significant differences in triglyceride levels at any of the postprandial time points between the three meals (all P40.25). Maximum aggregation and AUC aggregation were positively associated with glucose and negatively associated with insulin and triglycerides, hence comparisons between meals for their effect on platelet aggregation were repeated accounting for any effects of the measured metabolic covariates. Table 2 presents the strength of association between metabolic parameters and measures of platelet aggregation in response to 5-mM ADP. Similar to the nonadjusted analyses, adjusted analysis showed a significant reduction (all Po0.02) in maximum platelet aggregation for all three meals over the 2-h test period with 2.5-mM ADP. Although there was a reduction in platelet aggregation with 5 and 10-mM ADP these changes were not statistically significant. The adjusted analysis also showed no significant differences between the three meals at any postprandial time points. Results for AUC and slope were similar for adjusted and nonadjusted analyses. DISCUSSION This study was designed to determine and compare the effects of meals/foods known to induce different postprandial glycemic responses on measures of platelet aggregation in healthy individuals. We expected that the low GI meals that is, LGI-HC & 2012 Macmillan Publishers Limited
Food and postprandial platelet aggregation KDK Ahuja et al
725 Table 2.
Strength of effect of metabolic parameters on measures of platelet aggregation in response to 5-mM ADP Maximum aggregation (%)
Insulin Glucose Triglycerides
AUC aggregation curve (%)
Slope (95% CI)
P-value
Slope (95% CI)
P-value
2.54 (3.59 to 1.50) 2.49 (0.92 to 4.06) 2.71 (5.38 to 0.4)
o0.001 0.006 0.074
2.58 (3.62 to 1.54) 2.34 (0.67 to 4.01) 2.66 (5.51 to 0.18)
o0.001 0.002 0.053
Abbreviations: ADP, adenosine diphosphate; AUC, area under the curve; CI, confidence interval. Data presented as the slope (95% CI; P-value vs zero effect) of the relationship between metabolic parameters and maximum aggregation and AUC, estimated by mixed methods linear regression. This table presents the effect of each one-unit increase in s.d. of the metabolic parameters, calculated as z score (mean/s.d.), on maximum aggregation and AUC in response to 5 mM concentration of ADP.
and LGI-MPF would potentially lead to lower platelet aggregation compared with HGI-HC meal because of the lower postprandial glucose and insulin responses with low GI meals. The results demonstrate that in healthy individuals, (1) the intake of iso-energetic meals of different GI or protein/fat content all induce significant reductions in postprandial platelet aggregation and (2) these reductions are not significantly different between meals even though there is a significant difference in glucose and insulin response. Postprandial glucose and insulin responses were similar to those expected and often reported in the literature, with the high GI meal inducing the largest glucose and insulin response while LGI-HC and LGI-MPF showed lower responses. These results are similar to and extend our previous study,13 where we reported significant reduction in platelet aggregation from fasting to postprandial state (up to 120 min) after a high carbohydrate low fat meal. In the current study, the maximum reduction in platelet aggregation after the three meals was observed at 60-min post meal with little further decrease from 60 to 120 min. The mean reduction after the three meals ranged from 3 to 7% with 10-mM ADP, 7 -- 9% with 5-mM ADP and 19 -- 23% with 2.5-mM ADP, with the HGI-HC meal (1775 kJ, 65% carbohydrate, 19% fat, 15% protein and 76 GI) showing a mean decrease of maximum aggregation by B3, 7 and 19% with 10, 5 and 2.5-mM ADP, respectively. These results are slightly lower compared with earlier study (1900 kJ, 69% carbohydrate, 15% fat, 16% protein and 84 GI) which showed B9, 14 and 25% lower platelet aggregation (for 10, 5 and 2.5-mM ADP, respectively) at 120 min after a high carbohydrate low fat meal intake in 16 healthy individuals.13 We are unable to comment if these differences are due to variations in meal composition, energy and macronutrient content or the difference in GI content of the meals, between the two studies. Owing to interactions between plasma lipoproteins and components of haemostasis, including platelet aggregation and fibrinolysis, it is thought that there may be increased thrombotic activity in postprandial state of hyperglycaemia,7 however, results from experimental in vitro studies investigating the effect of hyperglycaemia, ranging from 5 to 45 mmol/l glucose, are not conclusive.16 - 19 Interestingly, in vitro studies conducted in presence of aspirin consistently demonstrate a significantly reduced ability of aspirin to inhibit platelet aggregation with increasing concentrations of glucose (5, 8.3 and 16.6 mM used by De La Cruz et al.;20 5.6, 11.2, 16.2 and 22.4 mM used by Kobzar et al.19), even though platelet aggregation does not seem to be affected by increasing concentrations of glucose alone.19 In our study, despite a positive association between maximum aggregation and plasma glucose concentrations (Table 2), and statistically significant differences in glucose responses between the three meals, we did not observe significant differences in platelet aggregation between the three meals. Even though the range for glucose results with HGI-HC meal was larger (3.1 -- 12.0 mmol/l) than both LGI-HC (3.0 -- 10.2 mmol/l) and LGI-MPF (3.0 -- 8.5 mmol/l) meals, and the mean postprandial results were also significantly & 2012 Macmillan Publishers Limited
higher (Figure 2) with HGI-HC meal, it is plausible that the differences between the meals were not large enough to induce different effects on platelet aggregation. Considering the observed opposing effects of insulin and triglycerides compared with glucose in the present investigation (Table 2), it is also possible that the combined effect of insulin and triglycerides led to a reduction in postprandial aggregation. In contrast to glucose, insulin is known as an antiplatelet agent, which inhibits platelet aggregation in healthy and insulin resistant individuals.21,22 Insulin functions via a nitric oxide-dependent release mechanism and inhibits both platelets and platelet agonists by upregulating PGE1 and PGI2 receptors mainly resulting in both a decreased intracellular Ca2 þ concentration and platelet aggregation.23 - 25 Although triglyceride concentrations did not change significantly over the postprandial time, we observed a negative association between triglycerides and measures of platelet aggregation (Table 2). Hypertriglyceridemia that leads to increased platelet aggregation is thought to contribute significantly toward thrombosis and atherosclerosis. However, studies investigating the specific effects of postprandial hypertriglyceridemia (or representing situations for testing under in vitro conditions) on platelet aggregation have usually reported reduced platelet aggregation when testing with PRP.26 - 28 Aggregation was enhanced using washed platelets27 but standardised PRP (as used in the present investigation) would seem to provide a closer representation to in vivo situation than washed platelets. It would also be interesting to measure whole blood platelet aggregation. Interestingly, statistically adjusting for effects of glucose, insulin and triglycerides did not change the comparative results for platelet aggregation, between the three meals. This suggests that other unknown or unmeasured variables (for example, other hormones, nutrients, change in blood flow) associated with food or food intake may reduce platelet aggregation, while masking any effects of the different concentrations of glucose, insulin or triglycerides. It would be interesting to extend this work to people with impaired glucose tolerance or diabetes to test whether the responses to these meals differ in populations with abnormal glucose and lipid metabolism compared with the healthy individuals. In conclusion, the present study shows that, in healthy individuals, meals with substantially different glycemic content led to similar reductions in postprandial platelet aggregation.
CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS This study was funded by the Clifford Craig Medical Research Trust, Launceston, Australia. We are grateful to Ms Susan Shaw and Mr Nicholas Green for their help in day to day running of the study.
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