A significant number of studies showed a link between regular nuts consumption and a reduction in risk of heart and metabolic disorders (73–76). Moreover, studies have shown that nuts consumption can improve glycemic responses in healthy and diabetic individuals (73). Nuts affect glycaemic response in a dose-dependent manner (77). According to the previous investigations, nuts help decrease glycaemic excursions; moreover, consuming nuts with carbohydrate-rich foods could reduce the postprandial impact on the insulin demand (77–80). The dose and duration of supplementation in studies that observed a significant effect of nuts consumption on glycaemic factors ranged from 30–60 g/day and 4–24 weeks, respectively (17, 18, 33, 35, 49, 52). The dose-dependent improvement in the glycaemic response to the meal has been revealed in previous investigations. In a study conducted on 10 healthy volunteers, it has been shown that the addition of 28 g of pistachios to white bread could improve glycaemic response, and this improvement was greater with the addition of 84 g of pistachios (79). In another study conducted on normo-glycaemic and individuals with T2D, adding 30, 60, and 90 g nuts to white bread reduced the glycaemic response of the meal by 11.2 ± 11.6% (P = 0.354), 29.7 ± 12.2% (P = 0.031), and 53.5 ± 8.5% (P < 0.001) (80).

It has been shown that people who eat more nuts in their diet have been shown to have a higher cardioprotective profile of glucose/insulin homeostasis (81). Findings from previous studies indicate a significant reduction in fasting insulin levels or an improvement in insulin resistance following the nuts consumption in both healthy and diabetic individuals (82, 83). Results from the Nurses' Health Study cohort indicated that eating more than 5 servings/week of nuts reduces the risk of diabetes compared to rare or no consumption (RR = 0.73, 95% CI = 0.60–0.89; P < .001) (84). Beneficial evidence is also supported by randomized controlled trials (RCTs). A meta-analysis of 12 RCTs with more than a 3-week follow-up period showed that consumption of a median dose of 56 g/day tree nuts could improve glycemic control in individuals with T2D compared to isocaloric diet without tree nuts (7). Additionally, the results of the study, conducted by Kendall et al. (80), showed that nuts eaten alone or with a high glycaemic index (GI) diet can lower postprandial blood sugar (PBG).

In addition to fat and protein, nuts have been reported to be rich sources of phenolics and phytates, both of which can decrease amylolytic digestion and postprandial blood sugar (85). In nuts, abundant fiber and polyphenols (flavonoids and non-flavonoids) may have a prebiotic effect and affect glucose metabolism (86). Several researchers have revealed that prebiotics' modulation of gut microbiota can improve glycemic control in healthy and diabetic subjects (87–89). Moreover, the blood sugar controlling effect of nuts can be attributed in part to the low carbohydrate content of nuts. Additionally, it has been shown that gastric emptying can be reduced by energy and fat load. Therefore, increasing the energy and fat load by increasing the dose of consumed nuts can partly explain the dose-dependent decrease in blood sugar in response to nuts consumption (80). In addition, it has also been shown that nuts can reduce the glycaemic response to a meal compared to a balanced meal in terms of energy and macronutrient contents (78). This can be due to nutsnuts' high unsaturated fat content, unsaturated fat content,and their unique physical structure. Unsaturated fatty acids in nuts in place of saturated fat and carbohydrate appear to, improve fasting, improve fasting and 2-h glucose levels significantly, but further studies should be performed with careful consideration of different types and amounts of nuts (90, 91).

In summary, overall nut intake has been revealed to be inversely associated with glycaemic factors. It may delay the development and progression of chronic metabolic diseases related to impaired glucose tolerance or glycaemic response.

The beneficial effects of nuts consumption on lipid profiles, especially total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), have been reported in clinical studies in both healthy and high-cholesterolemic individuals from various geographical areas (92). However, the effects varied based on the type and amount of nut, consumption duration, characteristics of the studied individuals, and study design (93–98). Most studies in this field that have shown a significant effect of nuts consumption on lipid factors have reported a dose of 20–64 g/day and a duration of 4–24 weeks (18, 20, 21, 53, 57, 70).

A Systematic Review conducted by Altamimi et al. (99) evaluated several dietary intervention studies that examined the effect of eating nuts on blood lipid levels. Analyses were performed on different types of nuts. Most of the studies showed improvement in lipid profile, including TC, LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) after nut consumption. Tapsell et al. (95) found that following a healthy diet enriched with 30 g of walnuts for 6 months caused a significant reduction in LDL-C and increased HDL-C in subjects with diabetes. A recent study also showed beneficial changes in lipid profile after a MeDiet enriched with 30 g of mixed nuts compared to the control diet in high-risk CVD patients, about half of whom with T2D (96). Compared to the low-fat diet, the average changes in the MeDiet enriched with the nuts group were −6.20 (P = 0.040) for TC level, −13.0 (p = 0.022) for TG level, and −0.26 (P = 0.002) for the TC/HDL-C ratio (96). Lee et al. (97) showed that supplementing 30 g/day of mixed nuts (walnuts, peanuts, and pine nuts) with a usual diet for 6 weeks had beneficial effects on lipid profile in women with MetS. Compared to those in the control group, TC and non-HDL-C levels significantly decreased in the nut group (P = 0.023 and P = 0.016, respectively). A cross-sectional study conducted to examine the relationship between nuts intake and lipid profile among Iranians showed that regular consumption of pistachios, almonds, hazelnuts, and walnuts is associated with a lower incidence of hyperlipidemia (98). Results of this study revealed that nuts consumption is significantly associated with decreased LDL-C, TG, and Apo B/Apo A in both men and women and decreased TC only in women. In a systematic review, Mukuddem-Petersen et al. (92) found a 2–16% reduction in TC and 2–19% in LDL-C among people who consumed nuts compared to those on controlled diets. In addition, a prospective cohort study with positive quality showed the same results of nuts consumption in reducing TC, non-HDL-C, LDL-C, and Apo B-100 concentrations in women with diabetes (100). Sabaté et al. (25) compared the effects of two different amounts of almonds with the effects of the National Cholesterol Education Program Step I on serum lipids and lipoproteins in healthy adults and those with mildly high cholesterol (Low and High almond diets for replaceing 10 and 20%, respectively, of energy of the Step I diet with almonds). They found that in addition to lowering LDL-C, the high-almond diet significantly reduced Apo B concentrations. Apo B is a component of serum LDL and VLDL and consequently reflects the concentration of atherogenic lipoprotein particles that confer risk of CVD (101). Sabaté et al. (25) observed a decreasing trend in Apo B concentration with increasing amounts of almonds in the diet, indicating a decrease in LDL-cholesterol concentration and the number of LDL particles.

Several claimed reasons explain the biological rationale of consuming nuts and improving the lipid profile. First, the bioavailability of fat content of nuts is low, which means that large amounts of this fat are excreted in the feces (102). Second, the crunchy texture of nuts promotes satiety because the mechanical action of chewing leads to the release of appetite suppressant hormones such as cholecystokinin, which ultimately leads to lower calorie and fat intake (103). Third, it is suggested that nut components other than fatty acids, such as vitamins (e.g., vitamin E, vitamin B6, niacin, and folic acid), minerals (e.g., magnesium, potassium, and copper), dietary fiber, plant protein (e.g., arginine), phytosterols, and phenolic antioxidants are also bioactive in lowering serum TC level (104). Recent evidence suggests that the phytosterols in nuts which are more hydrophobic than cholesterol, impair cholesterol absorption because their hydrocarbon molecule is larger and has a greater affinity for micelles than cholesterol (105). As a result, cholesterol is displaced from the micelles, and the amount available for absorption becomes more limited (106). Nuts are also a rich source of protein (nearly 25% of energy), especially high in L-arginine (107). L-arginine supplementation is usually recommended for people with dyslipidemia. It has been suggested that L-arginine ihelpmproves the lipid profile because of its potential in increasing nitric oxide (NO) production. Production of NO increases the activity of lipoprotein lipase and finally, improving the hydrolysis of TGs reduces its plasma concentration (108). A meta-analysis, conducted by Hadi et al. (109), concluded that L-arginine supplementation could significantly reduce blood TG levels; however, more studies are needed to prove its hypocholesterolemic effects.

Due to their unique nutrient profile, enriching a healthy diet with nuts may positively affecting lipid profile. Lipid-lowering effects of nuts should be considered in future food-based dietary strategies for improving plasma lipid levels.

Inflammation plays a key role in the development of cardio-metabolic diseases, such as CVD and T2D and nuts may moderate inflammation and the development of endothelial dysfunction and cardio-metabolic disorders through their bioactive components such as L-arginine, alpha-linolenic acid (MUFA), polyphenols, and fiber (110). Cross-sectional studies in this field showed that people with regular nut consumption had lower serum concentrations of proinflammatory cytokines or endothelial cell adhesion molecules. Effective interventional periods ranged from 4 to 24 weeks, with doses ranging from 20 to 56 g/day (20, 21, 34, 52).

It has been shown that α-linolenic acid [18:3(n-3)], extracted from nut is inversely associated with interleukin-6 (IL-6), soluble tumor necrosis factor (TNF) receptors 1 and 2, fibrinogen, and C-reactive protein (CRP) levels in both healthy subjects and individuals with coronary artery disease (111, 112). Furthermore, subjects who ate more nuts showed lower levels of intercellular adhesion molecule 1 (ICAM-1)-1, vascular cell adhesion protein 1 (VCAM-1), CRP, and IL-6 (113). In a cross-sectional analysis of the Multi-Ethnic Study of Atherosclerosis, consumption of seed and nut was inversely associated with IL-6, CRP, and fibrinogen (114). Yu et al. examined the association of common consumption of nuts with inflammatory biomarkers in two large groups of American men and women (115). They showed that nuts consumption was inversely associated with the concentration of IL-6 and CRP. The health effects of nuts on inflammatory markers have also been investigated in clinical trials. In a randomized trial, patients with MetS were advised to follow a healthy diet with 30 g of daily supplementation of raw nuts for 12 weeks (7.5 g hazelnuts, 15 g walnuts, and 7.5 g almonds) (82). Among inflammatory markers, the diet of nuts significantly resulted in changes in plasma IL-6. In another clinical trial, almond diet (56 g/day) for 4 weeks reduced CRP by a median 10.3 % (95% CI: −24.1, 40.5), TNF-α by a median 15.7 % (95% CI: −0.3, 29.9), and IL-6 by a median 10.3 % (95% CI: 5.2, 12.6 %) in comparison with the control diet (28). Gulati et al. (35) showed that supplementation of pistachio (20% energy) for 24-wk significantly improved hs-CRP (P < 0.05) and TNF-α (P < 0.03) in individuals with MetS. A meta-analysis of 32 RCTs showed that consumption of nuts resulted in small and non-significant differences in CRP levels (10).

The beneficial effects of nuts on inflammatory markers are attributed to their composition, which is recognized by lesser saturated fatty acids, a greater level of mono-unsaturated fatty acids (MUFAs), no cholesterol, and a suitable amount of phytosterols, fiber, protein, antioxidants, and numerous vitamins and minerals (116, 117). An increasing number of studies have examined the effect of these nutrients on inflammation. As suggested in cross-sectional studies, the high content of phenolic compounds in nuts may anticipate the anti-inflammatory effect of regular consumption of nuts (100). Furthermore, nuts are rich sources of fiber and therefore have a low glycaemic index (GI). It has been reported that diets with low GI can reduce CRP levels (118). Nuts are an important source of antioxidants essential for human health (8). Modulation of oxidative stress (particularly reducing peroxide levels) can decrease inflammation. The fatty acid composition of nuts is beneficial because the content of saturated fatty acids (SFAs) is low (4–16%), and almost half of the total fat content is composed of unsaturated fats. In most nuts MUFA (oleic acid) and different amounts of PUFA (119). Earlier data indicate that MUFA and PUFAs can exhibit anti-inflammatory properties in various experimental models of inflammation (120). The mechanisms by which dietary fatty acids inhibit cytokine production are unknown but may be related to inhibition of the inflammatory cascade at the level of lipoxygenase (LOX) and cyclooxygenase (COX) (121). Regarding the protective effect of nuts, it has been reported that the MeDiet enriched with nuts can lower the incidence of major cardiovascular events among people at high risk of cardiovascular diseases (122).

Considering existing evidence regular consumption of nuts can be associated with a nutritional profile of inflammatory biomarkers. However, further studies are needed to definitively address the important question of the anti-inflammatory effects of nuts.

Consumption of nuts as food sources of antioxidants can prevent pro-oxidation and excessive oxidation of LDL (123). Consumption of antioxidant foods as components of the diet playss an important role in managing cardio-metabolic disorders (124). Vitamin E and phenolic compounds are among the nutrients with antioxidant activities that nuts are a rich source of both. (125). In vitro studies (126, 127), animal models (128, 129), observational studies (130), and randomized trials (35, 72) suggest the potential benefits of including various nuts in the diet with regards to oxidative stress biomarkers. Most of the studies that have reported the potential beneficial effects of eating nuts on oxidative stress have focused on pistachios, almonds, peanuts, or walnuts, all of which are rich sources of MUFA. For instance, a sub-analysis of the PREDIMED (Prevención con Dieta Mediterránea) study, which assessed biomarkers associated with oxidative stress, identified higher superoxide dismutase (SOD) and catalase activity and lower plasma xanthine oxidase activity in the intervention group (the MeDiet + extra-virgin olive oil and the MeDiet + nuts) (131). The effective dose and duration observed in clinical studies were 20–84 g/day and 4–16 weeks, respectively (28, 30, 50, 53, 65, 72).

The nutritional intervention of 1 unit/d (20 g/day) of Brazil nuts for 3 months in hemodialysis patients resulted in improved plasma glutathione peroxidase (GPx) levels and a reduction in 8-isoprostane and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels (p < 0.001) (55). A clinical trial on 46 overweight and obese women found that after 8 weeks of intervention, the Baru nuts group (20 g/day) showed a significant increase in GPx activity compared to the placebo group (72). Jenkins et al. (132) showed that a full dose of almond supplement (73 ± 3 g/day, 22% of energy) or half a dose over 4 weeks reduced oxidized LDL in subjects with dyslipidemia. Liu et al. (28) found similar results after 4 weeks of supplementation with almond (~ 6 g/day) in individuals with dyslipidemia and T2D. Pistachio supplementation (10 or 20% of energy) for 4 weeks was also effective in reducing oxidized LDL in people with hyperlipidemia (133).

It has been revealed that bioactive compounds (phytosterols, polyphenols), MUFA, Se, and tocopherols are the main factors in the beneficial effects of nuts in modulating oxidative stress. These agents can also reduce the pro-oxidant effects of PUFA on LDL oxidation and DNA damages (134). The main fat compounds in hazelnuts and almonds are MUFA and are associated with decreased LDL sensitivity to oxidation (119). Therefore, differences in the fat content of different nuts may partly explain why pistachios, walnuts, almonds, and other MUFA-rich nuts can reduce oxidative stress, whereas walnuts (PUFA-rich) Do not have. Se, phytosterols, and polyphenols can activate the Nrf2 (nuclear factor erythroid 2-related factor 2) pathway (134). Nrf2 stimulates the antioxidant response element (ARE) genes transcription and encodes the antioxidant (e.g., GPx) and detoxifying enzymes (55). The Nfr2 pathway also activates NQO1, stabilizing proteins and protecting them against oxidative degradation (135).

Consumption of antioxidant food sources and/or antioxidant supplements seems to contribute to the prevention and/or treatment of metabolic disorders through widely known mechanisms; nuts are a good example of such food sources because of their good taste and dose-effect that allows them to be included in diets.

Based on the findings of evaluated studies, depending on the dose and duration of consumption (Table 2), mixed nuts can have health effects on metabolic markers, including glycaemic response, lipid factors, oxidative stress, and inflammation. In contrast, no adverse effects of nuts intake on metabolic biomarkers have been found in clinical trials (136).