Soy Isoflavones: History
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After consumption of soy isoflavones, a study revealed statistically insignificant reduction in fasting glucose, insulin, HbA1c, and HOMA-IR (changes in glucose metabolism). The observed ability of both extracted isoflavone and soy protein with isoflavones to modulate the lipid profile suggests benefits in preventing cardiovascular events in diabetic subjects.

  • T2DM
  • soy isoflavones
  • lipid profile
  • total cholesterol
  • HDL-C
  • LDL-C
  • triacylglycerol
  • glycemic control
  • HbA1c

1. Introduction

Improvements in glycemic control have been demonstrated in adults with T2DM through a combination of pharmaceuticals and lifestyle changes, and with lifestyle changes alone [1][2]. Lifestyle factors such as diet and physical activity can be individually modified. It is important to choose a diet in relation to the quality of nutrients, including carbohydrates, protein, fats, minerals and vitamins, and to establish its health benefits [3][4]. A number of studies on animal models [5][6][7] and intervention studies in humans [8][9][10][11][12] have shown that soy protein with isoflavones can improve the parameters of glycemic control and lipid homeostasis. Recently, several new studies on this topic have appeared [13][14][15].

2. Effects of Soy Isoflavones on Glycemic Control and Lipid Profile in Patients with Type 2 Diabetes

It demonstrated a significant reduction in the concentration of TC (‒0.21 mmol/L, p = 0.0008) and LDL-C (‒0.20 mmol/L, p < 0.0001) in the plasma, while the levels of HDL-C (‒0.02 mmol/L, p = 0.2008) and TAG (‒0.19 mmol/L, p = 0.1884) did not change significantly after ingesting soy isoflavone supplements. Zhang et al. [16] also showed significant reduction in TC (‒0.39, p < 0.01) and in LDL-C (‒0.30, p < 0.01) and non-significant decrease in HDL-C (‒0.05, p = 0.55) and TAG (‒0.094, p = 0.27), while Yang et al. [17] noted significant reduction in TC (‒0.42, p < 0.05), TAG (‒0.22, p < 0.05), significant reduction in LDL-C (‒0.30, p = 0.05) and significant increase in HDL-C (0.05, p < 0.05). Furthermore, Soltanipour et al. [18] observed significant reduction of TC (‒0.47, p < 0.01). In addition, soy products consumption was seen to be beneficial in decreasing LDL-C and TAG, but had no significant effects on HDL-C (results not shown). Beyond the aforementioned, Giordano et al. revealed in their study that soy isoflavones increased plasma TC concentrations and decreased triglyceride ones—adding further evidence to the notion that soy isoflavones have assorted effects on cardiometabolic risk factors [19].
Simultaneously the effects on glycemic control revealed that soy protein and/or isoflavones are not significantly effective in reducing circulating glucose levels. In addition, the outcome of our meta-analysis of randomized controlled trials has indicated that soy protein and/or isoflavones supplementation has no statistical significance effect on glycemic control in T2DM (FBG: ‒0.30 mmol/L, p = 0.28; FI: ‒3.40 pmol/L, p = 0.37; HbA1c: ‒0.80%, p = 0.13; and HOMA-IR: ‒0.07, p = 0.79). These results are similar to those of Yang et al. [17], who, in 2011, also did not show any significant effect of soy protein and/or isoflavones on the level of FBG, FI and HbA1c. In turn, the meta-analysis by Zhang et al. [16], published in 2016 and based on eight trials with 13 comparisons revealed significant changes in the FBG, FI and HOMA-IR values after administering soy preparations (‒0.207, p = 0.015; ‒0.29, p = 0.01; and ‒0.346, p < 0.01; respectively). Moreover, a recently published meta-analysis by Soltanipour et al. [18] reported that, according to the data from 14 RCTs, soy consumption had significant effects on HOMA-IR level (‒0.25, p < 0.01), in the absence of significant effects on FBG (‒0.14, p = 0.09; FI: ‒0.11, p = 0.11; and HbA1c: ‒0.22, p = 0.18).
The observed differences in outcomes can be result of differences in the inclusion criteria. We relied only on studies assessing the effects of isoflavones contained in soy protein or on the isoflavones alone. Yang et al. [17] used a study by Anderson et al. [20] in which only soy protein was used. In turn, the meta-analysis by Zhang et al. [16] included research with soy protein alone [20] or black soybean peptides [21], but also a study involving nondiabetic people with metabolic syndrome [22]. Furthermore, Soltanipour et al. [18], in addition to including seven out of 16 studies using isolated soy protein and isoflavones [15][23][24][25][26][27][28][29], also analyzed studies using different types of soy products such as soy milk [30][31], bread fortified with soy flour [32], soy germ pasta enriched in isoflavones [12], multifilament soy protein-based diabetes-specific food [9], as well as other preparations containing native starch banana [33] or flavan-3-ols/isoflavones [34].
The molecular and physiological mechanisms underlying the metabolic action of phytoestrogens components containing in soybean have not yet been fully recognized. The studies conducted with soy dietary isoflavones and isoflavone alone in cell culture or in animal models and human studies have definitely demonstrated that isoflavones can improve some parameters associated with the course of diabetes. In addition, the structural similarity between soy isoflavones and endogenous 17-β-estradiol suggests that isoflavones, by binding to estrogen receptors (ERs), lead to gene activation and beneficial effects on glucose and lipid metabolism [35][36].
There is some evidence to intimate that estrogen receptor (ER) binding is only part of the isoflavone effect [37]. Genistein and daidzein (and its metabolite equol), improve glycemic control, and significantly alter glucose homeostasis through: (a) stimulating insulin secretion by inhibiting tyrosine kinase (TK) [38][39]; (b) activating adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)—which results in decrease blood glucose in the liver, while stimulating glucose uptake independently of insulin in skeletal muscles and modulating glucose transport in peripheral tissue [40]; (c) activating the peroxisome proliferator-activated receptor gamma (PPARγ); thus, enhancing the expression and translocation of GLUT-1 and GLUT-4—which results in increased glucose uptake in adipocytes and muscle cells and subsequent reduction in plasma glucose levels [41]; (d) inhibiting alpha-glucosidase (AG)—which leads to slowing down the absorption of glucose in the gut [42]; and (e) directly modulating pancreatic beta-cell function and conferring protection against apoptosis through mechanisms that involve cyclic AMP/Protein Kinase A (cAMP/PKA) signaling [43][44].
Moreover, isoflavones can also regulate lipid metabolism without the mediation of estrogen receptors; increase expression of PPARα and activate AMPK—which results in increased activity of genes involved in lipoprotein metabolism; reduce TG-rich particle production and increase their lipolysis; promote HDL metabolism and promote the uptake, utilization and catabolism of fatty acid [45][46][47]. Furthermore, isoflavones can inhibit the expression and activity of the sterol regulatory element binding protein-1c (SREBP-1c) and carbohydrate regulatory element binding protein-1 (ChREBP)—proteins that enhance the expression of lipogenic genes and key enzymes involved in de novo lipogenesis [48][49]. Other possible mechanisms of soy isoflavones that may modulate lipoprotein metabolism, include their effects on several enzymes important in lipid transformation, including lipoprotein lipase (LPL), hepatic lipase (HL) also called hepatic triglyceride lipase (HTGL), and 7alpha-hydroxylase [50][51].

3. Conclusions

We found that consumption of soy isoflavones brought about a statistically significant reduction in total and LDL cholesterol, while simultaneously demonstrating no significant effects on HDL and TAG. Influence of soy isoflavones on glucose levels has been shown to be statistically insignificant. Moreover, the ability of both extracted isoflavone and soy protein with isoflavones to modulate the lipid profile suggests benefits in preventing cardiovascular events in people with type 2 diabetes. However, further multicenter studies based on a larger pool of research material and a well accurately defined dose of isoflavones are necessary to determine their beneficial effects on glucose and lipid metabolism.

This entry is adapted from the peer-reviewed paper 10.3390/nu13061886


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