*4.7. Glucagon-Like Peptide-1 (GLP-1)*

There was significant difference (*p* < 0.05) between the almond-based diet group and the control group with respect to the GLP-1 in the study by Ren et al. [14], although Cohen et al. [32] did not find any significant differences (*p* > 0.05) between the two groups.

Regarding the GLP-1 meta-analysis, two studies contributed data (almond gp, *n* = 28; control gp, *n* = 30) (Figure 7). GLP-1 was higher in the almond-based diet group compared with control, although the difference was not statistically significant (mean difference: 0.65; 95% CI: −0.16, 1.47; *p*-value = 0.12). The sensitivity analysis did not change the results between the almond group and the control group (*p* > 0.05) with to respect to GLP-1.

**Figure 7.** The effect of almond on GLP-1 (pmol/L).

#### *4.8. Fasting Insulin*

Bodnaruc et al. [30] found that an almond-based diet was associated with lower insulinemia, while Chen et al. [31] did not find any significant effect with respect to insulin levels in the almond-based and control diets. Five studies contributed data for this outcome (almond gp, *n* = 99; control gp, *n* = 100) (Figure 8). It was observed that there was no significant difference between the almond-based group compared to the control group in relation to insulin (standardised mean difference: −0.12; 95% CI: −0.40, 0.16; *p*-value = 0.39). There was also no significant difference (*p* > 0.05) between the almond group and the control group following the sensitivity analysis in regards to fasting insulin.


**Figure 8.** The effect of almond on fasting insulin (standardised mean difference).

#### **5. Discussion**

The results of the systematic review suggest that almond-based diets can promote the growth of short-chain fatty acid (SCFAs)-producing gut microbiota. Furthermore, the meta-analysis showed that almond-based diets were effective in significantly lowering (*p* < 0.05) glycated haemoglobin and body mass index (BMI) in patients with type 2 diabetes. However, it was also found that the effects of almond-based diets were not significant (*p* > 0.05) in relation to fasting blood glucose, 2 h postprandial blood glucose, inflammatory markers (C-reactive protein and TNF-α), GLP-1, HOMA–IR, and fasting insulin.

Our findings of the beneficial effects of almond-based diets on glycated haemoglobin are consistent with a previous study on almond supplementation in patients with type 2 diabetes [19] and an earlier review on the effect of tree nuts on glycaemic control in patients with diabetes [22]. Similarly, our results in relation to BMI are consistent with the findings of a previous study on the effect of almond consumption in the general population [18] and an earlier review of the effect of almonds on BMI [37].

The biological mechanisms responsible for the outcomes observed in this review in relation to reduction in glycated haemoglobin and BMI may be based on the nutrient composition of almond and its biological effects [37]. When compared to other nuts, it has been reported that almonds have the highest levels of fibre, monounsaturated and polyunsaturated fats, flavonoids, phytosterols, and phenolic acids [5,37]. Almonds also have a low glycaemic index [5] and almond-based diets have been shown to modulate gut microbiota dysbiosis and promote the production of GLP-1 in patients with type 2 diabetes [14].

The glycaemic index (GI) of food is an important measure of the quality of the food and it is a reflection of the digestibility of the available carbohydrates in the food compared with the reference food, often glucose [38]. It is a measure that ranks food based on the blood glucose response that they produce when ingested compared with the response to glucose or white wheat bread, which are reference foods [39]. Therefore, foods with low GI, such as almonds, usually breakdown slowly during digestion, and are slowly assimilated and, thus, have a slower impact on blood glucose levels and insulin response [40–42]. In a previous systematic review and meta-analysis, Ojo et al. [40], found that diets with low GI were more effective in improving glycated haemoglobin and fasting blood glucose compared with high-GI diets in patients with type 2 diabetes. In contrast, diets with high GI have been associated with type 2 diabetes and cardiovascular diseases due to their effect on blood glucose and insulin levels [38].

Due to the gradual entrance of glucose into the blood leading to reduced and more sustained insulin release, low-GI diets are more effective in controlling glycaemia compared with high GI diets [41]. In addition, low GI diets may be effective in increasing insulin sensitivity by reducing fluctuations in blood glucose levels and minimising insulin secretion over the day [41]. Based on the effectiveness of low-GI diets in controlling glycemia in patients with diabetes, the FAO [42] has recommended the use of a glycaemic index of foods along with the information about food composition in clinical applications in patients with diabetes.

Apart from the potential to improve glycaemic control, it has been suggested that diets with low GI may be useful in reducing weight because they produce a low insulin response [43]. This view is based on the lipogenic effect of hyperinsulinaemia [43]. On the other hand, high-GI diets may elicit a higher postprandial insulin response and this may lead to quicker hunger response and overeating through the reduction in metabolic fuels in the body [43]. Increased satiety and reduced voluntary food intake has been proposed as another mechanism through which foods with low GI can reduce weight [43].

Nuts, including almonds, are rich in energy density and high in fat, therefore, the greater fat availability could lead to reduced gastric emptying and increased satiety [5,14].

Another area of interest is the high soluble fibre and unsaturated fatty acid content of almonds [6]. According to Huo et al. [6], unsaturated fatty acids have been reported to promote the movement of glucose receptors to the cell surface and this could enhance insulin sensitivity. The role of polyunsaturated fatty acids on insulin sensitivity may be based on the fatty acid composition of the cell membrane, which relies on the fatty acid composition of the diet and regulates insulin action [44]. Kien et al. [45] suggested that a possible mechanism of dietary fatty acids in reducing the risk of insulin resistance may be due to the presence of a high level of unsaturated fatty acids in the cell membrane that could influence the physical properties, including plasticity, which promotes the movement of glucose receptors to the cell surface. It has also been shown that skeletal muscle insulin resistance due to obesity or dietary fatty acids may result from defective mitochondrial oxidation of fatty acids, which could lead to the accumulation of ceramides that may inhibit insulin signalling [45]. In addition, a high saturated fatty acid level of the membrane phospholipids increases insulin resistance [44].

Haag and Dippenaar [46] noted that the high saturated fat content of the cell membrane may lead to rigid and unresponsive membranes, while membranes that are high in unsaturated fatty acids promote fluidity and responsiveness. Therefore, the polyun-

saturated content and omega-3/omega-6 ratio in the muscle and fat membranes are of significant importance in the aetiology of insulin resistance [46]. Furthermore, fatty acidderived entities such as long chain acyl-CoA (coenzymes) may impact negatively on insulin mediated glucose transport and disrupt the insulin signalling cascade [46]. These findings were confirmed in randomised controlled trials in overweight individuals conducted by Kahleova et al. [47], who found that fat quantity and quality were related to body weight and body composition, insulin secretion, and insulin resistance.

Unsaturated fatty acids can also promote the efficiency of β-cell function through their action in stimulating GLP-1 secretion [6]. The findings of this review did reveal that an almond-based diet was effective in promoting the secretion of GLP-1, although this was not significant compared to the control. GLP-1 is a 30-amino-acid agent, which regulates glucose by stimulating insulin after ingesting a meal [32].

High dietary fibre in almonds can also increase gastric distension, viscosity of gastrointestinal tract, and slower absorption of macronutrients, including slowing the absorption of carbohydrates and the level of postprandial blood glucose [6]. High dietary fibre has been reported to promote the growth of SCFAs producing bacteria, increasing the production of SCFAs and promoting GLP-1 secretion [14].

In the study by Zhao et al. [48], it was found that the presence of greater diversity and abundance of fibre-promoting SCFA producers improved glycated haemoglobin levels in patients with type 2 diabetes through the production of glucagon-like peptide-1. The dietary fibre undergoes fermentation by colonic microbiota to produce SCFAs, including propionic, acetic, and butyric acid, which have significant effects on host physiology [49]. The SCFAs are useful in regulating the metabolic and immune system of the host as well as in cell proliferation [50]. However, low dietary fibre intake can cause microbiota dysbiosis, reduction in SCFAs production, and lead to the utilisation of less favourable substrates, such as proteins and fat [50,51]. The lipopolysaccharides resulting from the use of a highfat diet can elicit an inflammatory response and contribute to the development of insulin resistance and type 2 diabetes [51].
