Effects of nuts on glucoregulation

Details of studies measuring the effect of nut consumption on glucoregulation are reported in Table 3. A total of eight observational and twenty-four intervention trials evaluated the effects of chronic consumption of nuts on glucoregulation. Nuts consumed included walnuts, pistachios, groundnuts, almonds, cashews and mixed nuts, with amounts consumed ranging from 10 to 108 g/d (⅓ ounce to 4 ounces) (approximately 2–20 % of energy intake). The duration of consumption ranged from 4 weeks to 16 years. Intervention studies made comparisons with a healthy diet (fourteen studies), habitual diet (three studies), high-fat diet (one study) or other food products (five studies): muffins, pretzels, cereal bar, cheese or another type of nut. One study used no control. Of the studies, four compared habitual or healthy diets with intervention diets including nuts (NORDIET⁽ Reference Adamsson, Reumark and Fredriksson ^{46 )} or a Mediterranean diet⁽ Reference Esposito, Giugliano and Giugliano ^{47 ,} Reference Thomazella, Góes and Andrade ^{48 )}).

Tree nuts were associated with a lower prevalence of fasting hyperglycaemia compared with non-nut consumers in the National Health and Nutrition Survey (NHANES) cohort study⁽ Reference O'Neil, Keast and Nicklas ^{49 )}. However, a healthy dietary pattern including nuts found no association with fasting glucose or insulin⁽ Reference Alvarez León, Henríquez and Serra-Majem ^{50 )}. It is possible that the amount of nuts consumed was insufficient to show benefits. Nut consumption has also been associated with a reduced risk of type 2 diabetes; evidence to support this comes from large epidemiological studies⁽ Reference Jiang, Liu and Manson ^{51 –} Reference Pan, Sun and Manson ^{54 )}. The Nurses' Health Study demonstrated that consumption of nuts ( ≥  5 times per week), peanut butter ( ≥  5 times per week) or walnuts ( ≥  twice per week) was associated with a 24, 21 and 15 % lower risk, respectively, of developing type 2 diabetes⁽ Reference Jiang, Liu and Manson ^{51 ,} Reference Pan, Sun and Manson ^{54 )} compared with those who never or rarely ate nuts; the effect was greatest in those of healthy body weight⁽ Reference Jiang, Liu and Manson ^{51 )}. In addition, the Shanghai Women's Health Study demonstrated that groundnut consumption was associated with a 22 % decreased risk of type 2 diabetes⁽ Reference Villegas, Gao and Yang ^{55 )}. The SUN Study demonstrated a 35 % reduced risk of type 2 diabetes with a Mediterranean diet including an unspecified quantity of nuts⁽ Reference Martínez-González, de la Fuente-Arrillaga and Nunez-Cordoba ^{53 )}. However, other components of the Mediterranean diet including olive oil and a high fibre intake may have also contributed to this outcome⁽ Reference Biesalski ^{56 )}. In contrast, the Iowa Women's Health Study did not find any association of consumption of foods high in vegetable fat (including nuts) and incidence of type 2 diabetes⁽ Reference Meyer, Kushi and Jacobs ^{57 )}, which may in part be due to the low mean intake of nuts in this cohort.

Clinical trials examining nut consumption and diabetes risk, glycaemic control or insulin resistance have suggested some beneficial effects. Some short-term intervention studies have shown benefits of nut consumption on glucose homeostasis⁽ Reference Estruch, Martínez-González and Corella ^{58 ,} Reference Sari, Baltaci and Bagci ^{59 )} and insulin secretion⁽ Reference Adamsson, Reumark and Fredriksson ^{46 ,} Reference Estruch, Martínez-González and Corella ^{58 ,} Reference Casas-Agustench, López-Uriarte and Bulló ^{60 ,} Reference Wien, Bleich and Raghuwanshi ^{61 )}. The effects of nuts on insulin sensitivity are influenced strongly by changes in body weight, which may have accounted for the changes observed in one of these studies where participants reduced body weight with nut consumption. Longer intervention trials with Mediterranean diets supplemented daily with 20–50 g of walnuts or 30 g of mixed nuts (a mixture of walnuts, almonds and hazelnuts was used in the PREvencion con DIeta MEDiterranea (PREDIMED) trial as reported by Casas-Agustench et al. ⁽ Reference Casas-Agustench, López-Uriarte and Bulló ^{21 )}) resulted in a reduction in fasting glucose, insulin and improvement in insulin sensitivity (homeostatic model assessment of insulin resistance; HOMA)⁽ Reference Esposito, Giugliano and Giugliano ^{47 )} and the incidence of type 2 diabetes by 52 % over 4 years⁽ Reference Salas-Salvadó, Bulló and Babio ^{30 )}. Benefits shown in studies with nuts included as part of the intervention diet (NORDIET⁽ Reference Adamsson, Reumark and Fredriksson ^{46 )} or Mediterranean diet⁽ Reference Esposito, Giugliano and Giugliano ^{47 )}) may have been partly due to other components of these diets⁽ Reference Kalgaonkar, Almario and Gurusinghe ^{62 )}. Other studies have not shown benefits; consumption of pistachios, almonds, walnuts and a Mediterranean diet (supplemented with 10 g nuts/d) revealed no effect on fasting glucose or insulin⁽ Reference Thomazella, Góes and Andrade ^{48 ,} Reference Zaveri and Drummond ^{63 –} Reference Wien, Kandeel and Sabate ^{76 )}. One study that failed to achieve an improvement in insulin sensitivity supplemented participants' diets with 100 g almonds/d for 4 weeks. In this study there was a significant weight gain, which may have masked any benefit on insulin control⁽ Reference Lovejoy, Most and Lefevre ^{65 )}. Unexpected increases in plasma glucose (but not insulin) were observed with walnut and cashew consumption in women with polycystic ovary syndrome and adults with the metabolic syndrome, respectively⁽ Reference Mukuddem-Petersen, Stonehouse Oosthuizen and Jerling ^{71 ,} Reference Kasim-Karakas, Almario and Gregory ^{73 )}. Other studies investigated HbA1c in individuals with type 2 diabetes and found that 28 g walnuts/d and 36 g almonds/d reduced HbA1c by 4 %⁽ Reference Kalgaonkar, Almario and Gurusinghe ^{62 ,} Reference Cohen and Johnston ^{64 )}. However, in other individuals, HbA1c did not change with 37–75 g mixed nuts/d⁽ Reference Jenkins, Srichaikul and Banach ^{66 )}, 30–50 g walnuts/d⁽ Reference Tapsell, Gillen and Patch ^{69 ,} Reference Tapsell, Batterham and Teuss ^{70 ,} Reference Ma, Njike and Millet ^{72 )} or 57–112 g almonds/d (for 4 weeks)⁽ Reference Lovejoy, Most and Lefevre ^{65 )}. The lack of effect in the latter study may have been due to the short intervention time. Whilst epidemiological studies suggest an association of nut consumption with improvement in glucoregulation and diabetes risk, not all evidence from randomised controlled trials is supportive. Some inconsistencies in findings may be attributed to variations in the number or health status of the study participants, length of trial, or the dose of nuts used.

Weighted mean changes in glucoregulation indicate significant reductions in fasting insulin and HOMA scores of 14 (95 % CI − 24, − 4·5) % and 34 (95 % CI − 49, − 19) %, respectively, with small non-significant reductions of 2·8 (95 % CI − 6·9, 1·3) % and 1 (95 % CI − 3, 0·9) % for fasting glucose and HbA1c, respectively. This indicates positive effects of nut consumption on the most widely accepted markers of glucoregulation. Overall, there is considerable evidence of benefits of nut consumption for glycaemic control and insulin sensitivity observed after 4–6 weeks of consumption. However, inconsistencies make it difficult to reach precise conclusions on the role of nuts. The target population, dose and length of consumption (particularly to observe changes in HbA1c) need to be further considered so that targeted advice can be provided to consumers.

Effects of nut consumption on blood pressure

Studies measuring the effect of nut consumption on blood pressure are found in Table 4. Nuts consumed included walnuts, pistachios, groundnuts, almonds, cashews, hazelnuts, macadamias and mixed nuts in different forms including oil, whole nuts and nut flour added to baked goods. As with many studies using whole-food products, participant blinding was not possible. Amounts consumed ranged from 10 to 108 g/d (⅓ ounce to 4 ounces/d) (approximately 2–20 % of energy intake). The length of consumption ranged from 3 weeks to 2 years. Whilst there were thirty-six intervention trials that reported on the effect of chronic consumption of nuts on blood pressure, most measured blood pressure as a secondary outcome. Comparisons were made with a healthy diet (sixteen studies), habitual diet (seven studies) or other food products including butter, muffins, processed meat, olive oil and cocoa. Of the studies, four compared habitual or healthy diets with intervention diets including nuts (NORDIET⁽ Reference Adamsson, Reumark and Fredriksson ^{46 )} or a Mediterranean diet⁽ Reference Esposito, Giugliano and Giugliano ^{47 ,} Reference Thomazella, Góes and Andrade ^{48 )}); only one of the studies reported controlling for salt intake⁽ Reference Adamsson, Reumark and Fredriksson ^{46 )}. The remaining studies used control diets with unsalted nuts added as the intervention but overall dietary salt intake was not specified. Four prospective cohort studies measured blood pressure or incidence of hypertension in participants consuming nuts. The Physicians' Study demonstrated a significant reduction in self-reported hypertension after 12 months in those consuming nuts ≥  twice per week (hazard ratio 0·87; 95 % CI 0·79, 0·96) and greatest reduction with consumption ≥  7 times per week (hazard ratio 0·77; 95 % CI 0·64, 0·93)⁽ Reference Djoussé, Gaziano and Kase ^{77 )}. However, salt intake and changes in weight were not accounted for, which could have affected outcomes observed. The Coronary Artery Risk Development in Young Adults (CARDIA) Study demonstrated an inverse relationship between nut consumption and prevalence of hypertension despite those classified as the highest consumers only consuming nuts ≥  2 times per week (hazard ratio 0·85; 95 % CI 0·64, 0·93)⁽ Reference Steffen, Kroenke and Yu ^{78 )}. In support of this, the Atherosclerosis Risk in Communities (ARIC) Study also reported that nut consumption was inversely related to a reduced risk of hypertension; those who consumed approximately two serves of nuts per week were at a lower risk of hypertension than those who rarely or never consumed nuts (hazard ratio 0·87; 95 % CI 0·77, 0·97)⁽ Reference Weng, Steffen and Szklo ^{79 )}. In contrast, the SUN Study demonstrated no association between hypertension and nut consumption after a 4-year follow-up⁽ Reference Martínez-Lapiscina, Pimenta and Beunza ^{80 )}. However, the young educated adult sample in this study is less likely to demonstrate improvements in blood pressure with a dietary intervention than older individuals who are more likely to have higher blood pressure.

In all, four cross-sectional studies were identified comparing blood pressure or prevalence of hypertension in nut consumers with low-/non-nut consumers. The National Health and Nutrition Survey (NHANES) observed a general population and found a 3 % lower risk of hypertension and 1 mmHg reduction in systolic and diastolic blood pressure in nut consumers⁽ Reference O'Neil, Keast and Nicklas ^{49 )}. The Canary Nutrition Survey demonstrated a trend for reduced prevalence of hypertension with higher nut consumption but this did not reach significance⁽ Reference Alvarez León, Henríquez and Serra-Majem ^{50 )}. The Multi-Ethnic Study of Atherosclerosis (MESA) in Spain did not find an association with a healthy dietary pattern (incorporating an undetermined quantity of nuts) and blood pressure⁽ Reference Nettleton, Schulze and Jiang ^{52 )}. The authors suggest that routinely assessed blood pressure may have increased risk factor awareness, thereby attenuating associations with dietary intake. No association was found with hypertension and nut consumption in participants with a high risk of CVD⁽ Reference Ibarrola-Jurado, Bulló and Guasch-Ferré ^{81 )}. However, 90 % of the participants were hypertensive which may have made it difficult to demonstrate a relationship in this population. It is more difficult to account for health benefits from an individual food with observational studies; hence intervention studies are important to isolate effects.

Significant reductions in blood pressure were observed in nine intervention studies⁽ Reference Adamsson, Reumark and Fredriksson ^{46 ,} Reference Esposito, Giugliano and Giugliano ^{47 ,} Reference Estruch, Martínez-González and Corella ^{58 ,} Reference Llorente-Cortés, Estruch and Mena ^{67 ,} Reference Wien, Kandeel and Sabate ^{76 ,} Reference Jenkins, Vidgen and Trautwein ^{82 –} Reference Mena, Casas and Lamuela-Raventós ^{84 )}. Effect sizes could be calculated in seven of these and were small to large, ranging between 0·2 and 1·1. A substantial reduction in systolic blood pressure (14 mmHg) was reported in participants who were overweight or obese and mildly hypertensive consuming a diet containing 84 g almonds/d for 24 weeks, compared with an isoenergetic high-carbohydrate diet⁽ Reference Wien, Kandeel and Sabate ^{76 )}, with some participants reducing or eliminating the use of antihypertensive medications during the duration of the study. A weight reduction of 7 % (BMI reduction of 2·5 kg/mReference Drag and Bieliauskas ² ) was also observed in the participants consuming nuts compared with the control, despite the two groups being prescribed isoenergetic diets which would have accounted for at least some of the reduction in blood pressure observed⁽ Reference Wien, Kandeel and Sabate ^{76 )}. The PREDIMED Study tested the consumption of a Mediterranean diet which included 30 g mixed nuts/d compared with a Mediterranean diet devoid of nuts⁽ Reference Estruch, Martínez-González and Corella ^{58 )}. The study found a significant reduction in systolic and diastolic blood pressure of 7 and 3 mmHg, respectively. This study used a large cohort of 772 participants; subgroups of this study with 49–106 participants also reported similar reductions in blood pressure⁽ Reference Llorente-Cortés, Estruch and Mena ^{67 ,} Reference Mena, Casas and Lamuela-Raventós ^{84 ,} Reference Fito, Marrugat and Garcia-Arellano ^{85 )}. A larger cohort of the PREDIMED Trial found only a significant reduction in diastolic blood pressure⁽ Reference Toledo, Hu and Estruch ^{83 )}. The NORDIET included nuts as part of the intervention diet⁽ Reference Adamsson, Reumark and Fredriksson ^{46 )}, and reductions were demonstrated in systolic and diastolic blood pressure of 6 mmHg (effect size 0·6) and 2 mmHg (effect size 0·3), respectively. Almonds (23 g/d) consumed of as part of a portfolio diet with plant sterols and soya for 1 year demonstrated a reduction in systolic and diastolic blood pressure in a single-phase prospective study⁽ Reference Jenkins, Vidgen and Trautwein ^{82 )}. However, as no control group was used, it is possible that the regular clinic visits in this study increased participant awareness of hypertension as a CVD risk factor and other behaviour change may have contributed to the reduction in blood pressure in addition to the almond intervention⁽ Reference Jenkins, Vidgen and Trautwein ^{82 )}; without a control group this could not be determined. Consumption of a Mediterranean diet including 20–50 g walnuts/d compared with a prudent diet demonstrated reductions in systolic blood pressure of 3 mmHg (effect size 0·7) and in diastolic blood pressure of 2 mmHg (effect size 0·7)⁽ Reference Esposito, Giugliano and Giugliano ^{47 )}.

The majority of the remaining studies demonstrated either small blood pressure reductions which did not reach significance or no change. A reduction in systolic and diastolic blood pressure was observed with consumption of 40 g hazelnuts/d for 4 weeks from baseline; however, this was not significantly different from the reduction observed with cocoa used as the control⁽ Reference Solà, Valls and Godàs ^{86 )}. Inclusion of a control food that is not likely to change inflammation or endothelial function may have been a better choice to determine the effects attributable to hazelnuts⁽ Reference Davison, Berry and Misan ^{87 )}. An ad libitum diet with 56 g walnuts/d consumed by participants with type 2 diabetes for 8 weeks showed an increase in systolic (effect size − 0·8) and diastolic (effect size − 0·7) blood pressure. This unexpected result was from the only study that demonstrated a significant increase in blood pressure⁽ Reference Ma, Njike and Millet ^{72 )}. The authors were not able to determine a reason for this increase in blood pressure. However, other factors in the diet such as Na consumption may have contributed to the blood pressure elevation (despite being prescribed unsalted nuts); Na intake was not reported or controlled for in this study. Interventions using a portfolio diet⁽ Reference Jenkins, Josse and Leiter ^{88 ,} Reference Jenkins, Lapsley and Trautwein ^{89 )}, NORDIET⁽ Reference Adamsson, Reumark and Fredriksson ^{46 )} or Mediterranean diet⁽ Reference Esposito, Giugliano and Giugliano ^{47 ,} Reference Thomazella, Góes and Andrade ^{48 )} contained foods other than nuts which may also have been beneficial for improvements in blood pressure, making it difficult to tease out the effects of nuts alone. In contrast, Mediterranean diets in which mixed nuts⁽ Reference Estruch, Martínez-González and Corella ^{58 ,} Reference Llorente-Cortés, Estruch and Mena ^{67 )} replaced olive oil demonstrated improvements in blood pressure, indicating there may be some beneficial effect of nuts above that of other components of the Mediterranean diet. The largest effects of nuts on blood pressure were seen in participants with the metabolic syndrome or other risk factor for CVD, consuming 30–84 g of almonds, walnuts or mixed nuts/d for 4 weeks to 2 years. Significant reductions of 3–14 and 2–3 mmHg were observed in systolic and diastolic blood pressure, respectively⁽ Reference Adamsson, Reumark and Fredriksson ^{46 ,} Reference Esposito, Giugliano and Giugliano ^{47 ,} Reference Estruch, Martínez-González and Corella ^{58 ,} Reference Llorente-Cortés, Estruch and Mena ^{67 ,} Reference Wien, Kandeel and Sabate ^{76 ,} Reference Mena, Casas and Lamuela-Raventós ^{84 ,} Reference Fito, Marrugat and Garcia-Arellano ^{85 )}. Only two of thirty-six studies measured resting blood pressure as a primary outcome, so the remaining studies may not have been powered to detect small changes. In eight of the nine studies demonstrating blood pressure reductions, nuts were consumed for extended periods of between 12 weeks to 2 years. Most studies demonstrated no beneficial effect on blood pressure when nuts were consumed for shorter periods (3–12 weeks). This suggests a benefit of nut consumption only after an extended period of time as indicated with observational studies where habitual nut consumption was associated with reduced blood pressure or reduced prevalence of hypertension.

Weighted mean changes in blood pressure were calculated for twenty-four of the thirty-six intervention studies; systolic and diastolic pressure were significantly reduced by 0·73 (95 % CI − 1·3, − 0·2) % and 0·75 (95 % CI − 1·1, 0·4) %, respectively (see Table 9). Improvements in blood pressure control were observed particularly when nuts were consumed regularly for extended periods of time. Although the effect of nut consumption on blood pressure is small, this may still be clinically meaningful especially when used with other lifestyle measures.

Table 9 Weighted mean percentage changes in blood pressure, inflammatory markers, endothelial function and glucoregulation with nut consumption

BP, blood pressure; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; HOMA, homeostatic model assessment of insulin resistance.

* Statistically significant (P< 0·05).

† Endothelial vasodilator function assessed by either flow-mediated dilatation or Endo-PAT device.

Effects of nut consumption on inflammatory markers

Studies measuring the effect of nut consumption on inflammatory markers are found in Table 5. The most commonly measured inflammatory marker was CRP, reported in twenty-seven of the thirty-one studies. Other inflammatory markers measured included TNF-α, interleukins (IL-1, IL-1β, IL-6, IL-7 and IL-18) and cellular adhesion molecules (ICAM-1, VCAM-1 and E-selectin). We identified four cross-sectional studies and twenty-seven intervention trials measuring inflammatory markers with nut consumption. Of the intervention studies, eleven compared nuts with a healthy diet (low-fat or Mediterranean diet), five with a Western, American or habitual diet, six studies compared nut consumption with another food product (meat, cocoa, lactose or olive oil), one study compared two types of nut and one study was a single intervention using pre- and post-measures with no control or comparator food. The range of nuts used included almonds, walnuts, mixed nuts, Brazil nuts, cashews, pistachios and hazelnuts. The amounts ranged from 10 to 103 g (⅓ ounce to 4 ounces) of nuts per d (approximately 5–25 % of energy intake) for 4 weeks to 2 years. To date, only tree nuts have been tested for effects on inflammatory markers with chronic nut consumption.

In three of the four cross-sectional studies, nut consumption was associated with lower concentrations of the inflammatory markers CRP, IL-6 or ICAM. The Multi-Ethnic Study of Atherosclerosis (MESA) demonstrated an inverse association between frequency of consumption of nuts and seeds and serum CRP and IL-6 levels⁽ Reference Jiang, Jacobs and Mayer-Davis ^{90 )}. This association was moderately attenuated by additional adjustment for BMI. In two other studies, a Mediterranean diet pattern (PREDIMED study) or an American diet including nuts was inversely associated with anti-inflammatory markers⁽ Reference Salas-Salvadó, Casas-Agustench and Murphy ^{91 )}. Surprisingly, a large study (6309 women with diabetes), which categorised the largest nut consumption as ≥ 5 serves per week (1 serve = 28 g nuts or 18 g peanut butter) showed no association with inflammatory markers⁽ Reference Li, Brennan and Wedick ^{92 )}.

A total of twelve intervention studies demonstrated significant reductions (5–75 %) in inflammatory markers with nut consumption with a variety of nuts. Consumption of 21–100 g of walnuts, almonds, hazelnuts, pistachios or mixed nuts per d for 4 weeks to 2 years in healthy or hypercholesterolaemic participants or those at high risk of CVD resulted in significant reductions of CRP (5–75 %)⁽ Reference Esposito, Giugliano and Giugliano ^{47 ,} Reference Mena, Casas and Lamuela-Raventós ^{84 ,} Reference Solà, Valls and Godàs ^{86 ,} Reference Jenkins, Josse and Leiter ^{88 ,} Reference Jenkins, Lapsley and Trautwein ^{89 ,} Reference Zhao, Etherton and Martin ^{93 –} Reference Rajaram, Connell and Sabaté ^{95 )} or other inflammatory markers (ICAM, VCAM, E-selectin and interleukins) (7–28 %)⁽ Reference Esposito, Giugliano and Giugliano ^{47 ,} Reference Estruch, Martínez-González and Corella ^{58 ,} Reference Sari, Baltaci and Bagci ^{59 ,} Reference Mena, Casas and Lamuela-Raventós ^{84 ,} Reference Zhao, Etherton and Martin ^{93 ,} Reference Rajaram, Connell and Sabaté ^{95 –} Reference Ros, Núñez and Pérez-Heras ^{98 )}. A study incorporating walnuts (37 g/d) plus walnut oil (15 g/d) or walnuts and walnut oil plus flax seed as an additional source of ALA demonstrated anti-inflammatory effects compared with an American diet in hypercholesterolaemic individuals⁽ Reference Zhao, Etherton and Martin ^{93 )}. The vascular adhesion molecules ICAM-1, VCAM-1 as well as CRP were all reduced significantly, with a dose–response effect found for ALA in the diet with a 75 % reduction in CRP. Participants who consumed 20–50 g walnuts/d for 2 years as part of a Mediterranean diet demonstrated a reduction in CRP (36 %) and interleukins IL-6, IL-7 and IL-18 (9–28 %) when compared with a prudent diet⁽ Reference Esposito, Giugliano and Giugliano ^{47 )}. Mediterranean diets in which walnuts (about 65 g/d) or mixed nuts (30 g/d) replaced olive oil demonstrated improvements in one or more of the inflammatory markers CRP, ICAM-1, VCAM-1 and IL-6⁽ Reference Estruch, Martínez-González and Corella ^{58 ,} Reference Mena, Casas and Lamuela-Raventós ^{84 ,} Reference Ros, Núñez and Pérez-Heras ^{98 )}. A reduction in CRP was demonstrated in four studies with a portfolio diet containing either almonds⁽ Reference Jenkins, Lapsley and Trautwein ^{89 ,} Reference Jenkins, Li and Josse ^{94 ,} Reference Jenkins, Kendall and Marchie ^{99 )} (14–30 g/d) or hazelnuts (30 g/d)⁽ Reference Solà, Valls and Godàs ^{86 )} consumed for 4 weeks; one of these studies found an reduction equivalent to that observed with statin intake in the same individuals⁽ Reference Jenkins, Lapsley and Trautwein ^{89 )}. Beneficial improvements in inflammation observed in interventions which contained foods in addition to nuts (portfolio diet⁽ Reference Jenkins, Josse and Leiter ^{88 ,} Reference Jenkins, Lapsley and Trautwein ^{89 )} or Mediterranean diet⁽ Reference Esposito, Giugliano and Giugliano ^{47 ,} Reference Thomazella, Góes and Andrade ^{48 )}) may have been attributable to these other components. In contrast, Mediterranean diets in which walnuts⁽ Reference Canales, Sánchez-Muniz and Bastida ^{97 )}, mixed nuts⁽ Reference Estruch, Martínez-González and Corella ^{58 ,} Reference Llorente-Cortés, Estruch and Mena ^{67 )} or pistachios⁽ Reference Sari, Baltaci and Bagci ^{59 )} replaced olive oil demonstrated improvements in one or more of the inflammatory markers CRP, ICAM-1,VCAM-1 and IL-6, indicating that there may be some beneficial effect of nuts above that of other components of the Mediterranean diet. One study observed a reduction in CRP with a portfolio diet containing almonds only when participants with baseline CRP of ≤  3·5 mg/l were excluded from analysis⁽ Reference Jenkins, Li and Josse ^{94 )}. (CRP levels ≥  3·5 mg/l reflect acute inflammation associated with infection or acute illness that would mask any potential effects of nuts on chronic inflammation.)⁽ Reference Gotto ^{100 )} A 25 % reduction in IL-6 was observed with a relatively large dose (80–100 g/d) of pistachios consumed for 4 weeks⁽ Reference Sari, Baltaci and Bagci ^{59 )}. Consumption of a high-almond diet (68 g/d per 2000 kcal or 8368 kJ) and a low-almond diet (34 g/d per 2000 kcal or 8368 kJ) for 4 weeks significantly decreased CRP compared with an isoenergetic control diet in healthy men and women⁽ Reference Rajaram, Connell and Sabaté ^{95 )}; E-selectin (a marker of endothelial inflammation) was significantly lower in the higher-almond group than control. No dose–response relationship was observed with either inflammatory marker in this study. In participants at risk of CVD, statistically significant reductions of the cellular adhesion molecules ICAM-1 (effect size 0·3) and VCAM-1 (effect size 0·4) were demonstrated with relatively low doses (21 g/d) of walnuts added to a meat product compared with the meat product without walnuts. Despite little evidence for the magnitude of nut dose influencing inflammation, it is possible that there is a minimum dose required since no studies using <  30 g/d demonstrated benefits.

In fifteen studies no significant changes in inflammatory markers were demonstrated, although most of these demonstrated small reductions. A recent three-arm study compared fatty fish v. walnuts v. a fish-/nut-free diet (control). No significant changes were found between the walnut and the control diets but E-selectin was reduced with the walnut intervention compared with the fish intervention⁽ Reference Chiang, Haddad and Rajaram ^{96 )}. Consumption of 26 g almonds/d or 36 g walnuts/d for 6 weeks led to a 19 % reduction in IL-6 with the almonds and 20 % reduction in TNF-α with the walnuts compared with baseline, but this did not reach significance. In addition, two studies with obese individuals demonstrated small but non-significant improvements in CRP⁽ Reference Maranhão, Kraemer-Aguiar and de Oliveira ^{101 )} and IL-6⁽ Reference Casas-Agustench, López-Uriarte and Bulló ^{60 )} with Brazil nut and mixed nut consumption, respectively. Suggested reasons for small but non-significant reductions in inflammatory markers were recruitment of healthy individuals who may only demonstrate limited improvements and diurnal effects of IL-6 that are more difficult to detect than other markers. One study with obese individuals demonstrated small but non-significant improvements in CRP⁽ Reference Maranhão, Kraemer-Aguiar and de Oliveira ^{101 )}. Increased central adiposity and body weight are associated with increased CRP levels and adipose pro-inflammatory cytokines including IL-6⁽ Reference Mathieu, Lemieux and Després ^{102 )}. It is possible that these individuals may not demonstrate improvements in inflammatory markers with a dietary intervention without weight loss.

The calculated weighted mean changes for all studies where data revealed reductions in ICAM-1, VCAM-1 and CRP were 8·6 (95 % CI − 20·5, 3·3) %, 5·8 (95 % CI − 14·1, 2·5) % and 12 (95 % CI − 23·6, − 0·3) %, respectively (see Table 9). In summary, nut consumption has the potential to improve inflammatory markers, particularly with doses of 30 g or greater. This is in line with a health claim for nuts first established by the US Food and Drug Administration (FDA) in 2003; scientific evidence suggests that eating 42 g (1·5 ounces) of most nuts per d (as part of an overall healthy diet) may be able to reduce the risk of heart disease^{( 103 )}.

Effects of nut consumption on endothelial vasodilator function

Studies measuring the effect of nut consumption on endothelial vasodilator function are found in Table 6. In nine intervention studies the effect of nut consumption on endothelial vasodilator function (using either flow-mediated dilatation or Endo-PAT device) was measured, with the dose of nuts ranging from 10 to 100 g/d for periods ranging from 4 to 12 weeks. Of the nine studies, five demonstrated a significant effect.

Endothelial function was significantly improved (24–64 %) in healthy and hypercholesterolaemic participants who consumed 37–100 g of walnuts or pistachios per d for 4–8 weeks⁽ Reference Sari, Baltaci and Bagci ^{59 ,} Reference Ma, Njike and Millet ^{72 ,} Reference Ros, Núñez and Pérez-Heras ^{98 ,} Reference West, Holub and Kris-Etherton ^{104 )}. A Mediterranean diet supplemented with 65 g walnuts/d substituted for olive oil significantly improved vasodilation by 64 % in hypercholesterolaemic adults⁽ Reference Ros, Núñez and Pérez-Heras ^{98 )}. This study also demonstrated an inverse association between vasodilation and cholesterol:HDL ratio, suggesting that the effect of walnuts may have been mediated in part through an improved lipid profile⁽ Reference Ros, Núñez and Pérez-Heras ^{98 )}. It is well established that hypercholesterolaemia impairs endothelial function, which can be reversed by aggressive cholesterol lowering⁽ Reference Adams, Kinlay and Blake ^{105 )}. However, this study only demonstrated moderate cholesterol lowering, indicating that other mechanisms may also play a role. Investigators suggested that phenolic compounds in walnuts may have counteracted the pro-oxidant effects of PUFA on LDL. Mediterranean diets supplemented with 20–50 g walnuts/d⁽ Reference Esposito, Giugliano and Giugliano ^{47 )} and 80–100 g pistachios/d⁽ Reference Sari, Baltaci and Bagci ^{59 )} improved endothelial function by 21 and 24 %, respectively. Also observed with pistachio consumption was an improvement in glucose levels, lipid parameters, oxidative status and some indices of inflammation that may underlie the improved endothelial function⁽ Reference Sari, Baltaci and Bagci ^{59 )}. A diet with ad libitum consumption (56 g/d) of walnuts improved endothelial function by 45 % (effect size 0·6) in participants with type 2 diabetes⁽ Reference Ma, Njike and Millet ^{72 )}. Consumption of walnuts and walnut oil supplemented with flax seed (to boost the ALA content of the diet) increased endothelial function by 34 %, but no change was observed with the walnut diet alone⁽ Reference West, Holub and Kris-Etherton ^{104 )}. Of the five studies using higher doses (56–100 g/d) of nuts, four demonstrated benefits on endothelial function, indicating that higher doses may be required to elicit benefits⁽ Reference Sari, Baltaci and Bagci ^{59 ,} Reference Ma, Njike and Millet ^{72 ,} Reference Ros, Núñez and Pérez-Heras ^{98 ,} Reference West, Holub and Kris-Etherton ^{104 )}.

Of the studies, four did not show significant effects on flow-mediated dilatation. A hazelnut-enriched diet consumed by healthy men improved lipid parameters. In spite of this, endothelial functional improvement did not reach statistical significance⁽ Reference Mercanligil, Arslan and Alasalvar ^{74 )}. A quantity of 10–30 g nuts per d consumed by participants with either CVD risk or the metabolic syndrome also demonstrated no benefits on endothelial function⁽ Reference Thomazella, Góes and Andrade ^{48 ,} Reference López-Uriarte, Nogués and Saez ^{106 )}. Consumption of two doses (10 and 20 % of energy) of pistachios did not lead to a reduction in endothelial function⁽ Reference West, Gebauer and Kay ^{107 )} despite relatively high doses of up to 126 g/d consumed for 4 weeks. The authors suggested that pistachios used were roasted which may have reduced polyphenol activity unlike walnuts used in other studies, which were not roasted before consumption.

Calculations of the weighted mean changes from nine of the ten studies indicated a 19·7 (95 % CI 4·3, 35·0) % relative increase in vasodilatation with nut consumption (Table 9). The effects of nuts on endothelial function demonstrate potential benefits, particularly walnuts. However, limited studies have been conducted with other types of nuts that may also demonstrate benefits. Endothelial dysfunction is often detected before increased blood pressure is observed and may be a more sensitive indicator than arterial compliance of early decline in vascular health; hence it may be a better target than blood pressure control or arterial compliance⁽ Reference Ghiadoni, Taddei and Virdis ^{108 )}.

Effects of nut consumption on arterial compliance

Studies measuring the effect of nut consumption on arterial compliance are found in Table 7. These include one cross-sectional study and one intervention study. A dose of 15 g walnuts/d consumed for 4 weeks demonstrated no effect on arterial stiffness⁽ Reference Din, Aftab and Jubb ^{109 )}. Whilst this dose is small, investigators chose a realistic amount likely to be consumed in free-living individuals for an extended period of time rather than higher doses used in other nut intervention studies. The cross-sectional study measured arterial compliance and compared quintiles of a healthy dietary pattern including nuts⁽ Reference Nettleton, Schulze and Jiang ^{52 )}. No association was found between a healthier diet pattern with an undetermined quantity of nuts and measures of arterial compliance. Few studies have investigated the effects of nuts on arterial compliance; therefore more studies in this area are warranted.

Effects of nut consumption on cognitive performance

There is little known of the impact of nut consumption on cognitive function. Studies measuring the effect of nut consumption on cognitive performance are found in Table 8. A 5-year prospective cohort study demonstrated a positive association between nut consumption and cognitive performance, equivalent to a substantial age reduction effect of 5–8 years in the highest-nut consumers (amount of nuts not specified)⁽ Reference Nooyens, Bueno-de-Mesquita and van Boxtel ^{110 )}. In addition, cognitive performance did not decline over the 5-year period in the highest-nut consumers. In a cross-sectional study (PREDIMED) an association was found between walnut consumption (but not other nuts) and improvements in performance on tests of working memory (see Table 8). In older adults nut consumption was associated with improved but non-significant scores for executive function in a cross-sectional study⁽ Reference Nurk, Refsum and Drevon ^{111 )}, with a low mean intake of nuts of 5 g/d. Only one intervention study in human subjects has been performed; this was conducted with students consuming 60 g ground walnuts/d for 8 weeks⁽ Reference Pribis, Bailey and Russell ^{112 )}. The study demonstrated a medium effect size (0·4) for improvement in inferential reasoning; however, other cognitive tests demonstrated no change. Despite the lack of intervention trials, observational studies indicate that long-term consumption of even small amounts of nuts may elicit benefits for cognitive function and reduction in cognitive decline. More evidence is needed from controlled intervention studies before a conclusive benefit can be determined.