Cardioprotective Potential of Flaxseeds in Diabetes

CHAPTER 24

Cardioprotective Potential of Flaxseeds in Diabetes Karen L. Sweazea, Carol S. Johnston College of Health Solutions, Arizona State University, Phoenix, AZ, United States

1. TYPE 2 DIABETES Type 2 diabetes is a complex disease associated with a host of comorbidities including obesity and cardiovascular disease. Cardiovascular disease, specifically, is currently the leading cause of death worldwide1 and the leading cause of death for people with type 2 diabetes.1,2 In fact, the Framingham Study conducted in the 1970s showed that people with diabetes are at three times greater risk for developing atherosclerosis.3 In addition, hypertension occurs twice as often in patients with type 2 diabetes as compared to individuals without diabetes.2 Risk factors for cardiovascular disease include obesity, dyslipidemia, hypertension, diabetes mellitus, smoking, and chronic kidney disease.4 Current theories speculate that chronic hyperglycemia, the predominant diagnostic characteristic of diabetes, results in the development of atherosclerosis as well as oxidative stress and inflammation, which promotes hypertension.5 However, research shows that risk for cardiovascular disease is present even before type 2 diabetes is clinically diagnosed.6 Some researchers have proposed a so-called “common soil hypothesis” stating that oxidative stress and inflammation may lead to the development of both diabetes and cardiovascular disease as opposed to diabetes being the direct cause of cardiovascular disease.7,8 Interestingly, researchers have repeatedly reported U-shaped curves describing the association between glucose regulation and mortality.9 While the famous ACCORD Trial showed that intensive glucose lowering increases incidences of mortality,10 a recent meta-analysis showed no effect of intensive glucose lowering on total mortality risk.11 Rather, Fang et al.11 reported that intensive glucose lowering reduces the risk of a major cardiovascular event as well as myocardial infarction when compared to conventional therapies used to regulate glucose levels. Moreover, an additional meta-analysis showed that intensive glucose lowering may have protective effects in the microvasculature by reducing the relative risk for developing kidney or eye events.12 According to a recent joint scientific statement published by the American Heart Association and the American Diabetes Association, less than 50% of adults with diabetes mellitus living in the United States are meeting the recommended diabetes care

Bioactive Food as Dietary Interventions for Diabetes https://doi.org/10.1016/B978-0-12-813822-9.00024-2

Copyright © 2019 Elsevier Inc. All rights reserved.

361

362

Bioactive Food as Dietary Interventions for Diabetes

guidelines.13 Managing lifestyle factors, including nutrition, exercise, and education to promote behavior change, were identified as key components of clinical care for these patients that should be implemented prior to pharmacological therapies.13 Of relevance to this chapter was the focus on nutrition as an important treatment for type 2 diabetes as well as preventive measure for cardiovascular disease.13 According to the American Diabetes Association, nutrition goals for adults with type 2 diabetes should be designed to improve weight management, glycemic, lipid, and blood pressure regulation to help prevent or delay the onset of complications association with diabetes.14 Nutritional strategies include eating a plant-based diet rich in fruits, legumes, vegetables, whole grains, nuts, and seeds.13,15,16 In addition, a recent systematic review and meta-analysis of 13 randomized controlled trials examined the effectiveness of replacing animal proteins with plant proteins at improving glucose regulation in subjects with diabetes. They found that replacing more than 35% of daily animal protein consumption with plant proteins resulted in significant reductions in glycated hemoglobin (HbA1c), fasting glucose, and fasting insulin compared to control diets in individuals with diabetes.17 Thus, plant-based diets and proteins are the favored, evidence-based dietary strategies to help improve glucose regulation and health of individuals living with diabetes.

2. FLAXSEED Wherever flaxseed becomes a regular food item among the people, there will be better health… Indian activist Mahatma Gandhi (1869–1948)

Although evidence is mounting for demonstrable health benefits associated with flaxseed ingestion, as indicated by over 260 research trials published since 1990, current expert consensus does not yet support a dietary flaxseed recommendation.18,19 This lack of consensus, however, should not diminish the excitement focused on the potential therapeutic properties of flaxseed. This chapter presents an overview of the unique constituents of flaxseed that are linked with its purported health benefits and addresses in detail the clinical research linking flaxseed ingestion to improvements in cardiovascular function. Flaxseed, or linseed, is the seed of flax (L. usitatissimum), a single stem, herbaceous annual plant native to central Asia and the Mediterranean Region. Flax is recognized as the oldest cultivated crop. It is termed flaxseed when used for human consumption and linseed when used for industrial products such as linoleum flooring, oil paints and varnishes, and many textiles. Today, Canada, Russia, China, Kazakhstan, the United States, India, Ethiopia, Ukraine, the United Kingdom, France, and Argentina are the largest producers of flaxseed, and the global flaxseed market reached USD 561.97 million in 2015.20 Selected nutrient information for flaxseed is presented in Table 1 along with comparative data for 10 common nuts and seeds. Two tablespoons of flaxseed (1 ounce or 28 g) is an excellent source of fiber and magnesium (
30% daily value) and a good source of protein (10% daily value).

Table 1 Nutrient content for one serving (28 g) of common seeds and nutsa Energy Fat Protein Carbohydrate Fiber (kcal) (g) (g) (g) (g)

a

Iron (mg)

Potassium (g)

Magnesium (g)

138 146

8.7 11.8

4.7 9.2

12.0 3.8

9.8 1.1

179.2 12.0

2.2 4.2

115.6 226.0

95.1 150.0

152 155

12.0 14.1

5.2 5.5

8.2 4.3

7.8 2.6

72.4 19.9

1.6 1.1

230.9 241.4

111.3 36.6

157 160 162 163 164 167 186

13.8 13.6 13.0 13.2 14.2 14.1 18.5

9.0 4.8 6.0 4.3 6.0 6.9 4.3

2.5 7.3 8.0 9.3 6.1 6.0 3.9

1.1 4.0 2.9 0.9 3.6 2.4 1.9

19.9 280.9 30.4 12.8 76.4 16.5 27.8

2.3 4.2 1.1 1.7 1.1 0.4 0.8

340.8 134.9 286.0 160.5 208.2 180.1 125.2

198.8 101.1 31.0 73.8 76.7 50.6 44.9

Items are aligned by energy content.

Cardioprotective Potential of Flaxseeds

Chia seed Pumpkin seed Flaxseed Sunflower seed Hemp seed Sesame seed Pistachio Cashew Almond Peanut Walnut

Calcium (mg)

363

364

Bioactive Food as Dietary Interventions for Diabetes

Trials have demonstrated significant increases in protein and fiber intake when flaxseed is incorporated into habitual diets. In a small sample of adults diagnosed with irritable bowel syndrome (IBS) flaxseed consumption (24 g of either ground or whole flaxseed with 200 mL water) raised protein intakes 5%–16% after 4 weeks of treatment.21 However, the change in dietary protein intake was significant only for the adults ingesting whole flaxseed, a difference likely related to the higher compliance rates for the whole flaxseed treatment regimen. Fiber intakes increased significantly after the 4-week treatment period, +40% and +70% for the ground flaxseed and whole flaxseed groups, respectively.21 In a randomized cross-over trial conducted in healthy overweight and obese adults with prediabetes to examine the impact of flaxseed ingestion on biomarkers associated with the diabetic condition, 25 participants consumed 0, 13, and 26 g ground flaxseed daily over consecutive 12-week intervals separated by 2-week washout periods.22 Although not statistically significant, dietary protein increased 9% and 13% for the low and high flaxseed supplementation regimens, respectively. Soluble fiber intake increased significantly during the 26-g flaxseed supplementation period only (+26%). Although protein intakes are high among Americans on average, 82 g/day or 164% of the daily value,23 certain populations consume inadequate amounts of protein, including elderly women (
71 yr) and young vegetarians, and would benefit from supplemental protein.24,25 Moreover, many Americans may benefit from substituting plant-based protein for animalbased protein in terms of chronic disease reduction.17,26 As a plant protein, flaxseed production is sustainable at low environmental cost27 and can be easily incorporated into habitual diets as outlined in the intervention trials cited above. In addition to protein, the contribution of a daily serving of flaxseed to fiber intake (+8 g) is important since only 10% of Americans meet fiber intake recommendations. The average fiber intake for Americans is 16 g/day, which is 9 g short of the daily value of 25 g.28 Two-thirds of the fiber in flaxseed is insoluble and one-third is soluble. Lignan, classified as an insoluble fiber as well as a phytoestrogen, is a distinctive constituent of flaxseed fiber with unique health benefits. The lignan content of flaxseed (13 mg/g, a level that is 800-fold higher than most plant foods) is comparable to the level in wheat germ (15 mg/g) but below the level in wheat bran (56 mg/g).29,30 Although flaxseed is also an excellent source of magnesium (111 mg/serving), the impact of a daily serving of flaxseed on magnesium status or function is not known. Magnesium intake among Americans is 330 mg/day (daily value, 400 mg), and over 42% of Americans have below adequate intakes of magnesium.31 In addition, as indicated in Table 1, flaxseed is high fat, with about 70% kcal derived from fat, a characteristic shared by most seeds and nuts. Yet, the component fats vary widely among nuts and seeds (Table 2). This variance is most notable for the omega-3 fat content ranging from not detectible in almonds to nearly 6400 mg/serving for flaxseed. In fact, based on a 28 g serving, only several of the nuts and seeds provide the adequate intake for omega-3 fat (1100–1600 mg/day): flaxseed, chia seed, walnuts, and hemp seed. Furthermore, only flaxseed, chia seed, and hemp seed possess an omega-6/omega-3 ratio in the healthful range near 1.0.32

Cardioprotective Potential of Flaxseeds

Table 2 Fat profile for one serving (28 g) of common seeds and nutsa MonoPolyOmega-3 Total Saturated unsaturated unsaturated fatty acids fat (g) fat (g) fat (g) fat (g) (mg)

Chia seed Pumpkin seed Flaxseed Pistachio Cashew Sesame seed Hemp seed Sunflower seed Peanut Almond Walnut a

Omega-6 fatty acid (mg)

Omega 6/omega 3 ratio

8.7 11.8

0.9 1.0

0.7 3.7

6.7 5.4

5055 47

1654 5326

0.33 115

12.0 13.0 13.2 13.6

1.9 2.7 4.3 2.2

2.1 6.5 6.7 5.3

8.0 3.8 2.2 6.1

6388 71 17 105

1655 3696 2179 5984

0.26 52 125 57

13.8 14.1

1.2 2.4

1.8 5.2

10.8 6.5

2777 21

6896 6454

2 312

14.1 14.2 18.5

2.9 1.8 2.8

6.8 9.0 2.5

4.4 3.4 13.2

1 nd 2542

4355 3375 10,666

5444 4

Items are aligned by total fat content. USDA Food Composition Databases.

As an essential nutrient, omega-3 fat plays important roles in cell membrane structure, vision, the nervous system, and immune function. However, omega-3 fats are also considered bioactive agents, for example, food components responsible for changes in health status beyond their nutritional value.33 The omega-3 fat in nuts and seeds is alpha linolenic acid (ALA). Aside from these foods, only a few marine items provide the recommended level (1600 mg/day), most notable, Atlantic salmon (3 oz) and algae oil which provide eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), derivatives of ALA. Hence, a serving of flaxseed daily is a simple strategy for obtaining this essential fat. Flaxseed is the richest dietary source of lignans, which represent about 1% of the dry weight of flaxseed.34 Plant-derived lignans are phytoestrogens with antioxidant properties.35 The predominant lignan in flaxseed is secoisolariciresinol diglucoside (SDG), with lessor amounts as matairesinol, pinoresinol, and lariciresinol.36 SDG is resistant to digestion in the small intestine and passes into the colon where it is fermented to two enterolignans: enterodiol (ED) and enterolactone (EL).37 These bioactive phytoestrogens are believed to influence chronic disease outcomes and improve human health. Note that several bacterial groups are necessary for this biotransformation in the large intestine; hence, the bioactivation of dietary lignans is dependent on the bacterial diversity and community structure of the microbiome, and a great degree of variability between individuals would be expected.37,38 Moreover, shorter intestinal transit times and antibiotic use also appear to reduce the biotransformation of dietary lignans.39,40

365

366

Bioactive Food as Dietary Interventions for Diabetes

Ingesting ground flaxseed may improve the biotransformation process by increasing lignin accessibility by intestinal microflora.41 The enterolignans appear in plasma 8–10 h after ingestion with EL predominating; however, the correlation between serum EL and dietary lignans is low (r ¼ 0.11) demonstrating the high variability in biotransformation process.42,43 The nutrient value of flaxseed is evident, and the many purported health benefits of flaxseed are likely attributed to its unique combination of bioactive agents. No other natural food source provides an active dosage of lignans and omega-3 fat along with high concentrations of protein, fiber, and magnesium in one serving. There is strong mechanistic evidence linking these agents to diabetes and cardiovascular disease risk reduction as discussed further.

3. FLAXSEEDS AS A NUTRITIONAL THERAPY FOR DIABETES The bioactive ingredients in flaxseed align well with the key nutritional goals recommended for adults with type 2 diabetes and/or cardiovascular disease to promote weight management and improve blood glucose and lipid profiles as well as blood pressure.14,44,45 Furthermore, the clinical evidence supporting a therapeutic role of dietary flaxseed in diabetes is mounting.

3.1 Weight Management Some evidence suggests that flaxseeds may be useful for weight management. Administration of 30-g/day roasted flaxseed powder for 3 months significantly reduced body mass and BMI in subjects with dyslipidemia.46 Similarly, Ricklefs-Johnson et al.47 found that ground flaxseed (28 g/day) supplementation for 8 weeks significantly decreased waist circumference in adults with type 2 diabetes. Moreover, a study of adults aged 55 year with type 2 diabetes showed that flaxseed lignan complex (600 mg/day for 3 months) significantly reduced gains in waist circumference.48

3.2 Glucose Regulation Studies have shown that ground flaxseeds have beneficial effects on glucose regulation even prior to overt type 2 diabetes. A study of prediabetic overweight or obese men and postmenopausal women found that daily supplementation with 13 g of ground flaxseed for 12 weeks resulted in a 2.10  1.66 mg/L (P ¼ .036) decrease in fasting glucose and 2.12  1.00 mU/L drop in fasting insulin, resulting in a significant decrease in the homeostatic model assessment of insulin resistance (HOMA-IR). Although a higher dose of ground flaxseed (26 g/day) had no effect on these outcomes in adults with prediabetes,22 a separate study of obese subjects with insulin resistance showed a higher dose (40 g/day) of ground flaxseed significantly decreased HOMA-IR after 12 weeks.49

Cardioprotective Potential of Flaxseeds

Some studies have reported potential antidiabetic effects of flaxseeds in subjects with hyperlipidemia or clinically diagnosed diabetes. One study showed a significant 23.7% reduction (P ¼ .03) in HOMA-IR in men and postmenopausal women with hyperlipidemia who consumed 40-g/day of ground flaxseeds added to baked goods for 10 weeks.50 Similarly, a study of patients with type 2 diabetes showed a significant reduction in fasting blood glucose by 18 mg/dL (P ¼ .03) after 3 months of consuming 5 g of flaxseed gum per day that was incorporated into wheat flour flatbreads.51 In addition, supplementation with 10-g/day flaxseed powder for only 1 month resulted in a 19.7% decrease in fasting blood glucose and a 15.6% decrease in HbA1c.52 However, in subjects with well-controlled type 2 diabetes, daily ingestion of 32-g/day milled flaxseed or 13-g/day flaxseed oil for 12 weeks had no effect on fasting plasma glucose, insulin, HbA1c, or HOMA-IR.53 Results from available studies suggest that the beneficial effects of flaxseeds on glucose regulation are present in the whole food but not isolated components. While flaxseed lignans (360 mg/day) were shown to significantly reduce HbA1c in subjects with mild hypercholesterolemia and type 2 diabetes, supplementation did not improve fasting glucose or insulin concentrations.54 Also, a recent meta-analysis of eight clinical trials concluded that diets enriched with ALA for a median of 3 months were not effective for reducing HbA1c, fasting blood glucose or insulin in subjects with type 2 diabetes.55 In fact, administration of 4-g/day purified EPA or DHA, the essential fatty acids derived from ALA and found in marine foods, for 6 weeks significantly increased fasting glucose concentrations (+1.4 and 0.98 mmol/L, respectively) in adults (61.2  1.2 yr) with type 2 diabetes who were receiving treatment for hypertension.56 However, HbA1c and fasting insulin were unaffected by EPA or DHA supplementation in these subjects.56

3.3 Lipid Regulation A variety of studies have reported the beneficial effects of flaxseeds on lipid regulation. In a study of 62 men and postmenopausal women, 40-g/day of ground flaxseeds incorporated into baked goods significantly reduced LDL cholesterol (P < .005) after 5 weeks, although the effects were no longer evident after 10 weeks of consumption.50 Flaxseeds may be a beneficial adjunct therapy for subjects with peripheral artery disease who have been prescribed cholesterol-lowering medications (statins). In fact, one study showed that supplementation with 30-g/day of milled flaxseed for 12 months significantly reduced LDL cholesterol more than medications alone in these patients.57 In addition, supplementation with 10-g/day flaxseed powder for only 1 month resulted in a 14.3% decrease in total cholesterol, 17.5% decrease in triglycerides, 21.8% reduction in LDL cholesterol as well as an increase in HDL cholesterol by 11.9%.52 Subjects with dyslipidemia treated for 3 months with 30-g/day roasted flaxseed powder also had significantly attenuated total cholesterol, triglyceride, LDL cholesterol, and vLDL cholesterol with

367

368

Bioactive Food as Dietary Interventions for Diabetes

concomitant increases in HDL cholesterol.46 Likewise, the addition of 5-g flaxseed gum per day to whole wheat flatbreads resulted in significantly reduced fasting LDL cholesterol from 110.8 mg/dL prior to the study to 92.9 mg/dL (P ¼ .02) after 3 months in subjects with type 2 diabetes.51 Similarly, Cassani et al.58 showed that adding 60-g/day flaxseed powder to a weight-loss program significantly attenuated plasma triglycerides in men (33  10 yr) who were overweight and had hypertension, hyperlipidemia, and hyperglycemia. These beneficial effects are not limited to patients diagnosed with a pathology. In fact, a recent study demonstrated that 10-g/day flaxseed oil lowered LDL cholesterol in healthy men after 12 weeks.59 A recent study attempted to measure the effects of lignans on cardiovascular outcomes in healthy adults (18–65 yr). Subjects were given nutrition bars containing similar amounts of fiber, 3 g ALA (or placebo) and either 0.15- or 0.41-g flaxseed-derived lignans daily for 6 weeks. Whereas low-dose lignans resulted in increased plasma triglycerides and oxidized lipoproteins, the high dose actually decreased total cholesterol and oxidized lipoproteins.60 Administration of flaxseed lignans (100 mg/day SDG in capsules for 12 weeks) also significantly reduced the ratio of LDL-to-HDL cholesterol in men with moderate hypercholesterolemia (180–240 mg/mL) in comparison to a placebo.61 These findings show that lignans alone have vasoprotective effects in healthy adults.60 In contrast, a study targeting older adults (60–80 yr) found no significant effect of 600 mg/day SDG on lipids after 6 months.62 Similarly, supplementation with capsules containing 360-mg/day-flaxseed lignans for 12 weeks had no significant effect on circulating lipids in patients with mild hypercholesterolemia and type 2 diabetes.54 Unlike flaxseed-derived lignans, neither 4-g/day-purified EPA nor DHA for 6 weeks is significantly altered serum total, HDL, or LDL cholesterol in hypertensive adults aged 61.2  1.2 yr with type 2 diabetes. Although serum triglycerides were decreased 19% in subjects treated with EPA and 15% in those treated with DHA.56 Likewise, administration of flaxseed oil-derived ALA (3 g/day) for 26 weeks had no effect on plasma HDL, LDL, or triglyceride concentrations.63 These findings suggest that flaxseeds should be consumed either ground or as a gum to exert beneficial effects on lipid regulation.

3.4 Blood Pressure Regulation The etiology of hypertension in the diabetic condition is attributed to a number of factors, most notably hyperglycemia-mediated endothelial dysfunction resulting in impaired vasodilation. Hyperglycemia results in the overproduction of free radicals such as superoxide, which can directly contribute to hypertension through attenuated activity of endothelial nitric oxide synthase (eNOS) and scavenging nitric oxide (NO).64–66 Nitric oxide is an important endothelium-derived vasodilator and helps prevent atherosclerosis.67 For these reasons, interventions that improve the bioavailability of NO may improve cardiovascular health.68–70 In a recent study, Ricklefs-Johnson et al.47 showed

Cardioprotective Potential of Flaxseeds

that 8-week supplementation with ground flaxseed (28 g/day) significantly increased circulating nitrates and nitrites in otherwise healthy adults (18–75 yr) with type 2 diabetes. Although this increase was not associated with changes in blood pressure,47 many studies have reported beneficial effects of flaxseeds in attenuating blood pressure. As mentioned, increases in circulating inflammatory factors are thought to contribute to the development of cardiovascular disease. Research from Cassani et al.58 showed that the addition of 60-g/day-flaxseed powder to a weight-loss program significantly attenuates plasma inflammatory factors C-reactive protein (CRP) and tumor necrosis factor alpha (TNFa) in overweight men (33  10 yr) with hypertension, hyperlipidemia, and hyperglycemia. In addition, administration of 40-g/day-ground flaxseed for 12 weeks significantly decreases TBARS in adults (55 yr of age) who were obese and insulin resistant.49 Likewise, Ricklefs-Johnson et al.47 showed a significant reduction in TBARS in subjects with type 2 diabetes who consumed 28 g/day for 8 weeks. Not all studies show beneficial outcomes with respect to regulation of inflammation, however. Administration of 13- or 26-g/day ground flaxseed for 12 weeks to prediabetic overweight or obese men and postmenopausal women had no significant effect on CRP or high sensitivity interleukin-6 (hsIL-6).22 Similarly, administration of flaxseed lignans alone (600 mg/day SDG) for 6 months in older adults (60–80 yr) had no effect on circulating CRP, TNFa, or the inflammatory cytokine interleukin-6 (IL-6).62 While research on the anti-inflammatory effects of flaxseeds is debated, the efficacy of flaxseeds at regulating blood pressure has been well documented. In 1997, Nestel et al.71 showed that flaxseed oil improved arterial compliance in obese subjects. In addition, flaxseed oil (8 g/day) for 12 weeks has been shown to significantly lower systolic and diastolic blood pressures in middle-aged patients with dyslipidemia.72 Similarly, consumption of 30 g of milled flaxseeds per day significantly reduced systolic (10 mmHg) and diastolic (7 mmHg) blood pressure in subjects with peripheral artery disease after 6 months. This decrease in blood pressure was correlated with an increase in plasma α-linolenic acid and enterolignans, major components of flaxseeds.73 The mechanism by which flaxseed-derived ALA lowers blood pressure is thought to involve inhibition of an enzyme responsible for breaking down oxylipins, which include endogenous PUFA-derived octadecanoids, eicosanoids, as well as docosanoids.74 Oxylipins such as epoxyeicosatrienoic acid (EETs) have vasodilatory properties although these effects may be mitigated by the metabolism of EETs to dihydroxyeicosatrienoic acid (DHETs) via the enzyme soluble epoxide hydrolase (sEH).74 Interestingly, studies have shown levels of sEH were decreased following 6 months of flaxseed consumption, which is thought to protect the bioavailability of vasodilatory EETs and thus contribute to the reduced blood pressure previously measured in these subjects.73,74 Flaxseed-derived lignans have likewise been shown to lower blood pressure. In a study of adults aged 60–80 yr, administration of 600 mg/day SDG reduced systolic blood pressure by 15 mmHg after 24 weeks.62 Flaxseed lignan complex may also reduce the

369

370

Bioactive Food as Dietary Interventions for Diabetes

risk for stroke and heart attacks as shown in a study of adults aged 55 yr with type 2 diabetes. After consuming 600 mg/day SDG for 3 months, increases in bleeding time were observed, which is a measure of thrombosis. These findings indicate that SDG may lower the risk for forming blood clots and thus reduce the risk for heart attacks and stroke.48

4. FLAXSEEDS: DIETARY RECOMMENDATION Flaxseed can be incorporated into diets as whole seeds, ground seeds sprinkled on foods, or milled whole flour used in baking.29 These whole seed products would conserve the unique combination of the bioactive ingredients of flaxseed. Although flaxseed oil is a concentrated source of ALA, it lacks other key nutrients such as protein, fiber, and magnesium; hence, robust effects may not be realized. The clinical trials cited above noted improvements in biomarkers with flaxseed ingestion ranging from 1 to 1.5 servings daily (28–40 g/day). Due to the uniquely high lignin content of flaxseed, and the potential for weak estrogenic or antiestrogenic effects, animal trials have been conducted to assess safety and monitor signs of toxicity for both flaxseed ingestion and high-dose lignin ingestion. Since several of these trials did note changes in the reproductive development of offspring,75,76 pregnant and lactating women are advised to minimize flaxseed ingestion.

5. SUMMARY Flaxseed, the oldest cultivated crop, has long provided key nutrients and bioactive agents to cuisines worldwide and has been recognized for centuries as a medicinal agent. Today, scientific investigations support the efficacy of flaxseed for improving biomarkers associated with type 2 diabetes. Research evidence has linked the bioactive ingredients in flaxseed to weight management and improvements in blood glucose and lipid profiles as well as blood pressure; and the clinical evidence supporting a therapeutic role of dietary flaxseed in cardiovascular disease is mounting. This research has important ramifications since the incidence of type 2 diabetes is growing at epidemic proportions globally. More long-term trials are needed to determine if disease risk and disease progression are influenced by regular flaxseed ingestion. There is an urgency to identify dietary strategies that can be easily adopted by many people, across cultures and irrespective of socioeconomic status, to ease the burden of chronic disease.

REFERENCES 1. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia. 2001;44(Suppl 2):S14–S21. 2. Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms. Can J Cardiol. 2018;34(5):575–584.

Cardioprotective Potential of Flaxseeds

3. Kannal WB, McGee DL. Diabetes and cardiovascular disease – the Framingham Study. JAMA. 1979;241:2035–2038. 4. Lennon RP, Claussen KA, Kuersteiner KA. State of the heart: an overview of the disease burden of cardiovascular disease from an epidemiologic perspective. Prim Care. 2018;45(1):1–15. 5. Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab. 2013;17:20–33. 6. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002;25:1129–1134. 7. Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol. 2004;24:816–823. 8. Stern MP. Diabetes and cardiovascular disease. The “common soil” hypothesis. Diabetes. 1995;44: 369–374. 9. Kontopantelis E, Springate DA, Reeves D, et al. Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective study. Diabetologia. 2015;58: 505–518. 10. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–2559. 11. Fang HJ, Zhou YH, Tian YJ, Du HY, Sun YX, Zhong LY. Effects of intensive glucose lowering in treatment of type 2 diabetes mellitus on cardiovascular outcomes: a meta-analysis of data from 58,160 patients in 13 randomized controlled trials. Int J Cardiol. 2016;218:50–58. 12. Zoungas S, Arima H, Gerstein HC, et al. Collaborators on trials of lowering glucose (CONTROL) group. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomized controlled trials. Lancet Diabetes Endocrinol. 2017;5(6):431–437. 13. Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2015;38:1777–1803. 14. Evert AB, Bouchre JL, Cypress M, et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care. 2014;37(suppl 1):S120–S143. 15. McMacken M, Shah S. A plant-based diet for the prevention and treatment of type 2 diabetes. J Geriatr Cardiol. 2017;14(5):342–354. 16. Sluik D, Boeing H, Li K, et al. Lifestyle factors and mortality risk in individuals with diabetes mellitus: are the associations different from those in individuals without diabetes? Diabetologia. 2014;57(1):63–72. 17. Viguiliouk E, Stewart SE, Jayalath VH, et al. Effect of replacing animal protein with plant protein on glycemic control in diabetes: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2015;7:9804–9824. 18. Basch E, Bent S, Collins J, et al. Flax and flaxseed oil (Linum usitatissimum): a review by the Natural Standard Research Collaboration. J Soc Integr Oncol. 2007;5(3):92–105. 19. Collins K. AICR In Depth: Flaxseed and Breast Cancer. American Institute for Cancer Research; 2010. 20. Mordor Intelligence. Flax Seeds Market—Growth, Trends, Industry Analysis and Forecast to 2022. Available from: https://www.mordorintelligence.com/industry-reports/flaxseeds-market; 2017. (Accessed March 2018). 21. Cockerell KM, Watkins AS, Reeves LB, Goddard L, Lomer MC. Effects of linseeds on the symptoms of irritable bowel syndrome: a pilot randomised controlled trial. J Hum Nutr Diet. 2012;25(5):435–443. 22. Hutchins AM, Brown BD, Cunnane SC, Domitrovich SG, Adams ER, Bobowiec CE. Daily flaxseed consumption improves glycemic control in obese men and women with pre-diabetes: a randomized study. Nutr Res. 2013;33(5):367–375. 23. Pasiakos SM, Agarwal S, Lieberman HR, Fulgoni 3rd VL. Sources and amounts of animal, dairy, and plant protein intake of US adults in 2007–2010. Nutrients. 2015;7(8):7058–7069. 24. Berner LA, Becker G, Wise M, Doi J. Characterization of dietary protein among older adults in the United States: amount, animal sources, and meal patterns. J Acad Nutr Diet. 2013;113(6):809–815. 25. Donovan UM, Gibson RS. Dietary intakes of adolescent females consuming vegetarian, semivegetarian, and omnivorous diets. J Adolesc Health. 1996;18(4):292–300. 26. Song M, Fung TT, Hu FB, et al. Association of animal and plant protein intake with all-cause and causespecific mortality. JAMA Intern Med. 2016;176(10):1453–1463.

371

372

Bioactive Food as Dietary Interventions for Diabetes

27. Marambe HK, Wanasundara JPD. Protein from Flaxseed (Linum usitatissimum L.). In: Nadathur S, Wanasundara JPD, Scanlin L, eds. Sustainable Protein Sources. 1st ed. Cambridge: Academic Press; 2016:133–144. 28. Grooms KN, Ommerborn MJ, Pham DQ, Djousse L, Clark CR. Dietary fiber intake and cardiometabolic risks among US adults, NHANES 1999–2010. Am J Med. 2013;126(12):1059–1067. e1-4. 29. Goyal A, Sharma V, Upadhyay N, Gill S, Sihag M. Flax and flaxseed oil: an ancient medicine & modern functional food. J Food Sci Technol. 2014;51(9):1633–1653. 30. Fardet A. New hypotheses for the health-protective mechanisms of whole-grain cereals: what is beyond fibre? Nutr Res Rev. 2010 Jun;23(1):65–134. 31. Blumberg JB, Frei BB, Fulgoni VL, Weaver CM, Zeisel SH. Impact of frequency of multi-vitamin/ multi-mineral supplement intake on nutritional adequacy and nutrient deficiencies in U.S. adults. Nutrients. 2017;9(8):E849. 32. Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother. 2002;56(8):365–379. 33. Office of Dietary Supplements: National Institutes of Health. Summary of comments received in response to the Federal register notice (Federal Register, 69(179): Sept 16, 2004, 55821–55822): Defining bioactive food components [document on the Internet]. Maryland: USA Government; 2006. Available from: http://ods.od. nih.gov/Research/Bioactive_Food_Components_Initiatives.aspx. (Accessed 21 July 2008). 34. Johnsson P, Kamal-Eldin A, Lundgren LN, Aman P. HPLC method for analysis of secoisolariciresinol diglucoside in flaxseeds. J Agric Food Chem. 2000;48(11):5216–5219. 35. Adolphe JL, Whiting SJ, Juurlink BH, Thorpe LU, Alcorn J. Health effects with consumption of the flax lignin secoisolariciresinol diglucoside. Br J Nutr. 2010;103:929–938. 36. Sicilia T, Niemeyer HB, Honig DM, Metzler M. Identification and stereochemical characterization of lignans in flaxseed and pumpkin seeds. J Agric Food Chem. 2003;51(5):1181–1188. 37. Hullar MA, Lancaster SM, Li F, et al. Enterolignan-producing phenotypes are associated with increased gut microbial diversity and altered composition in premenopausal women in the United States. Cancer Epidemiol Biomark Prev. 2015;24(3):546–554. 38. Eeckhaut E, Struijs K, Possemiers S, Vincken JP, Keukeleire DD, Verstraete W. Metabolism of the lignan macromolecule into enterolignans in the gastrointestinal lumen as determined in the simulator of the human intestinal microbial ecosystem. J Agric Food Chem. 2008;56(12):4806–4812. 39. Kilkkinen A, Stumpf K, Pietinen P, Valsta LM, Tapanainen H, Adlercreutz H. Determinants of serum enterolactone concentration. Am J Clin Nutr. 2001;73(6):1094–1100. 40. Kilkkinen A, Pietinen P, Klaukka T, Virtamo J, Korhonen P, Adlercreutz H. Use of oral antimicrobials decreases serum enterolactone concentration. Am J Epidemiol. 2002;155(5):472–477. 41. Kuijsten A, Arts IC, van’t Veer P, Hollman PC. The relative bioavailability of enterolignans in humans is enhanced by milling and crushing of flaxseed. J Nutr. 2005;135(12):2812–2816. 42. Kuijsten A, Arts IC, Vree TB, Hollman PC. Pharmacokinetics of enterolignans in healthy men and women consuming a single dose of secoisolariciresinol diglucoside. J Nutr. 2005;135(4): 795–801. 43. Bhakta D, dos Santos SI, Higgins C, et al. A semiquantitative food frequency questionnaire is a valid indicator of the usual intake of phytoestrogens by south Asian women in the UK relative to multiple 24-h dietary recalls and multiple plasma samples. J Nutr. 2005;135(1):116–123. 44. Satija A, Hu FB. Cardiovascular benefits of dietary fiber. Curr Atheroscler Rep. 2012;14(6):505–514. 45. Wolk A, Manson JE, Stampfer MJ, et al. Long-term intake of dietary fiber and decreased risk of coronary heart disease among women. JAMA. 1999;281(21):1998–2004. 46. Saxena S, Katare C. Evaluation of flaxseed formulation as a potential therapeutic agent in mitigation of dyslipidemia. Biom J. 2014;37(6):386–390. 47. Ricklefs-Johnson K, Johnston CS, Sweazea KL. Ground flaxseed increased nitric oxide levels in adults with type 2 diabetes: a randomized comparative effectiveness study of supplemental flaxseed and psyllium fiber. Obes Med. 2017;5:16–24. 48. Barre DE, Mizier-Barre KA, Stelmach E, et al. Flaxseed lignan complex administration in older human type 2 diabetics manages central obesity and prothrombosis – an invitation to further investigation into polypharmacy reduction. J Nutr Netab. 2012;2012:585170.

Cardioprotective Potential of Flaxseeds

49. Rhee Y, Brunt A. Flaxseed supplementation improved insulin resistance in obese glucose intolerant people: a randomized crossover design. Nutr J. 2011;10:44. 50. Bloedon LT, Balikai S, Chittams J, et al. Flaxseed and cardiovascular risk factors: results from a double blind, randomized, controlled clinical trial. J Am Coll Nutr. 2008;27(1):65–74. 51. Thakur G, Mitra A, Pal K, Rousseau D. Effect of flaxseed gum on reduction of blood glucose and cholesterol in type 2 diabetic patients. Int J Food Sci Nutr. 2009;60(S6):126–136. 52. Mani UV, Mani I, Biswas M, Kumar SN. An open-label study on the effect of Flax Seed Powder (Linum usitatissimum) supplementation in the management of diabetes mellitus. J Diet Suppl. 2011;8 (3):257–265. 53. Taylor CG, Noto AD, Stringer DM, Froese S, Malcolmson L. Dietary milled flaxseed and flaxseed oil improve N-3 fatty acid status and do not affect glycemic control in individuals with well-controlled type 2 diabetes. J Am Coll Nutr. 2010;29(1):72–80. 54. Pan A, Sun J, Chen Y, et al. Effects of a flaxseed-derived lignin supplement in type 2 diabetic patient: a randomized, double-blind, cross-over trial. PLoS One. 2007;2(11):e1148. 55. Jovanovski E, Li D, Ho HVT, et al. The effect of alpha-linolenic acid on glycemic control in individuals with type 2 diabetes. A systematic review and meta-analysis of randomized controlled clinical trials. Medicine. 2017;96(21):e6531. 56. Woodman RJ, Mori TA, Burke V, Puddey IB, Watts GF, Beilin LJ. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Am J Clin Nutr. 2002;76(5):1007–1015. 57. Edel AL, Rodriguez-Leyva D, Maddaford TG, et al. Dietary flaxseed independently lowers circulating cholesterol and lowers it beyond the effects of cholesterol-lowering medications alone in patients with peripheral artery disease. J Nutr. 2015;145:749–757. 58. Cassani RSL, Fassini PG, Silvah JH, Lima CMM, Marchini JS. Impact of weight loss diet associated with flaxseed on inflammatory markers in men with cardiovascular risk factors: a clinical study. Nutr J. 2015;14:5. 59. Kawakami Y, Yamanaka-Okumura H, Naniwa-Kuroki Y, Sakuma M, Taketani Y, Takeda E. Flaxseed oil intake reduces serum small dense low-density lipoprotein concentrations in Japanese men: a randomized, double blind, crossover study. Nutr J. 2015;14:39. 60. Almario RU, Karakas SE. Lignan content of the flaxseed influences its biological effects in healthy men and women. J Am Coll Nutr. 2013;32(3):194–199. 61. Fukumitsu S, Aida K, Shimizu H, Toyoda K. Flaxseed lignin lowers blood cholesterol and decreases liver disease risk factors in moderately hypercholesterolemic men. Nutr Res. 2010;30:441–446. 62. Di Y, Jones J, Mansell K, et al. Influence of flaxseed lignan supplementation to older adults on biochemical and functional outcome measures of inflammation. J Am Coll Nutr. 2017;36(8):646–653. 63. Harper CR, Edwards MC, Jacobson TA. Flaxseed oil supplementation does not affect plasma lipoprotein concentration or particle size in human subjects. J Nutr. 2006;136(11):2844–2848. 64. Bajaj S, Khan A. Antioxidants and diabetes. Ind J Endocrinol Metab. 2012;16(Suppl 2):S267. 65. Dobrian AD, Davies MJ, Schriver SD, Lauterio TJ, Prewitt RL. Oxidative stress in a rat model of obesity-induced hypertension. Hypertension. 2001;37(2):554–560. 66. Taniyama Y, Griendling KK. Reactive oxygen species in the vasculature molecular and cellular mechanisms. Hypertension. 2003;42(6):1075–1081. 67. Taddei S, Ghiadoni L, Virdis A, Versari D, Salvetti A. Clinical significance of the assessment of endothelial function. Ital Heart J Suppl. 2004;5(5):357–365. 68. Bryan NS. Pharmacological therapies, lifestyle choices and nitric oxide deficiency: a perfect storm. Pharmacol Res. 2012;66(6):448–456. 69. Fiorentino TV, Prioletta A, Zuo P, Folli F. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr Pharm Des. 2013;19(32):5695–5703. 70. Machha A, Schechter AN. Dietary nitrite and nitrate: a review of potential mechanisms of cardiovascular benefits. Eur J Nutr. 2011;50(5):293–303. 71. Nestel PJ, Pomeroy SE, Sasahara T, et al. Arterial compliance in obese subjects is improved with dietary plant n-3 fatty acid from flaxseed oil despite increased LDL oxidizability. Arterioscler Thromb Vasc Biol. 1997;17(16):1163–1170.

373

374

Bioactive Food as Dietary Interventions for Diabetes

72. Paschos GK, Magkos F, Panagiotakos DB, Votteas V, Zampelas A. Dietary supplementation with flaxseed oil lowers blood pressure in dyslipidaemic patients. Eur J Clin Nutr. 2007;61:1201–1206. 73. Rodriguez-Leyva D, Weighell W, Edel AL, et al. Potent antihypertensive action of dietary flaxseed in hypertensive patients. Hypertension. 2013;62:1081–1089. 74. Caligiuri SPB, Aukema HM, Ravandi A, Guzman R, Dibrov E, Pierce GN. Flaxseed consumption reduces blood pressure in patients with hypertension by altering circulating oxylipids via an α-linolenic acid-induced inhibition of soluble epoxide hydrolase. Hypertension. 2014;64:53–59. 75. Tou JC, Chen J, Thompson LU. Flaxseed and its lignan precursor, secoisolariciresinol diglycoside, affect pregnancy outcome and reproductive development in rats. J Nutr. 1998;128(11):1861–1868. 76. Collins TF, Sprando RL, Black TN, et al. Effects of flaxseed and defatted flaxseed meal on reproduction and development in rats. Food Chem Toxicol. 2003;41(6):819–834.