Functional foods for health: Focus on diabetes

1. Diabetes 

Diabetes mellitus is one of the most common endocrine disorders affecting almost 6% of the world's population. The number of diabetic patients will reach 300 million in 2025 [1]. More than 97% of these patients will have type 2 diabetes. Research shows that the prevalence of type 2 diabetes is more common in females than in males [2]. In addition, the risk for cardiovascular disease (CVD), the most common complication attributable to diabetes, is more serious among women then men. Notably, women with diabetes lose their premenopausal protection from CVD and have risk for this condition as great as, or greater than that of diabetic or non-diabetic men. Therefore, a unique challenge exists between menopause – and the years leading up to it – and diabetes because of the additional need for glycemic control.

Studies have shown that modest weight-loss of 5–10% body weight is associated with improvements in cholesterol, blood pressure and insulin sensitivity, known risk factors for CVD and type 2 diabetes [3], [4], [5], [6]. In addition, current guidelines for the prevention of type 2 diabetes include the increase in total dietary fiber intake [3], since prospective studies have observed reduced diabetes risk with high cereal fiber and whole grain consumption [7]. It has been suggested that the benefits of increased fiber intake result principally from the greater consumption of soluble forms due to effects on gastric emptying, macronutrient absorption, and reduced postprandial glucose response. Overall, current nutritional recommendations for diabetes frequently include modest weight loss and increase in fiber intake.

Clearly, weight control is an effective diabetes management technique and functional foods promoting weight loss could be aimed towards those with type 2 diabetes. However, it may also be possible to incorporate functional foods in the diet that impact insulin action independently of weight loss. In general, a functional food is similar in appearance to, or may be, a conventional food that is consumed as part of a usual diet, and is demonstrated to have physiological benefits and/or reduce the risk of chronic disease beyond basic nutritional function. Therefore, the goal of this review is to examine the current evidence from recently published trials that supports the recommendation of intake of novel functional foods such as nuts including peanuts, omega-3 fatty acids (FAs) and cinnamon as they relate to the markers of glucose tolerance, such as fasting blood glucose (FBG), hemoglobin A1C (HgbA1C), and fasting insulin levels, in people with diabetes and insulin resistance.

2. Nuts 

Nuts, including peanuts, are documented as having the potential to improve the blood lipid profile in humans [8]. Several epidemiological studies have revealed that people who consume nuts regularly are less likely to suffer from CVD [9], [10]. More recently, interest has developed in the potential value of including nuts in the diets of individuals with diabetes. Data from the Nurses Health Study indicate that there are benefits to consuming higher nut and peanut butter consumption to lower risk of type 2 diabetes in women [11]. In this study, the relative risk of developing diabetes was reduced by 27% in women who ate nuts five or more times per week compared with those who rarely or never ate nuts.

In general, nuts contain 70–80% fat, and most FAs in nuts are unsaturated—being either polyunsaturated and monounsaturated, which may be beneficial for glucose and insulin homeostasis. Several studies have shown that a high amount of monounsaturated and polyunsaturated fat vs. saturated fat improves glucose homeostasis [12], [13]. The mechanisms by which specific types of dietary fat affect insulin sensitivity are not well understood. It has been shown that the fatty acid composition of phospholipids in skeletal muscle cell membranes is directly related to insulin sensitivity in humans [14]. Therefore, changes in dietary FAs might result in compositional changes of membrane phospholipids, perhaps in turn modulating insulin action and sensitivity in skeletal muscle. In addition, other components of nuts such as fiber and magnesium may decrease insulin demand and resistance [10]. Nuts are a rich source of vitamins, minerals, antioxidants and plant protein, which could be also beneficial [10]. In this respect, nuts contain many bioactive components, which may have potential advantages for glycemic control.

Only a few long-term [15], [16] and short-term [17], [18], [19] clinical studies have investigated the effects of nuts and peanut consumption on glycemic control in type 2 diabetic patients (Table 1). Two long-term, randomized controlled trial [15], [16] confirmed the beneficial effects of nuts on blood lipids in non-diabetic and type 2 diabetic patients, but did not report improvement in glycemia. This particular study by Lovejoy et al., demonstrated that an almond-enriched diet for 1 month did not alter insulin sensitivity in healthy adults, or glycemia in patients with diabetes [15]. Similarly, Tapsell et al. determined that a moderate-fat diet with 30g of walnuts/d did not affect long-term glycemic control, as indicted by HgbA1C levels, in healthy subjects [16]. In sum, obvious long-term effects of nuts and peanuts have yet to be recognized.

Table 1. Recent intervention studies on nuts and peanuts on glycemic control in healthy and type 2 diabetes populations.

	Study design	Study diet	Results
	Lovejoy et al. [15]	Received 100g almonds/d for 4 weeks	↑ Body weight
	Study 1		↔ FBG and fasting insulin
	20 free-living healthy volunteers with normoglycemia		↔ Insulin sensitivity
			↓ TC and LDL-C
	Lovejoy et al. [15]	Randomized to one of four diets: (1) high-fat, high-almond (37% total fat, 10% from almonds), (2) low-fat, high-almond (25% total fat, 10% from almonds), (3) high-fat control (37% total fat, 10% from olive or canola oil), and (4) low-fat control (25% total fat, 10% from olive or canola oil) for 4 weeks each	↔ FBG, fasting insulin or HbA1c levels
	Study 2		↔ 2-h glucose and 2-h insulin
	30 subjects with type 2 diabetes in a randomized crossover study		↓ TC with the high-fat, high-almond diet
			↓ HDL-C with the almond diets
	Tapsell et al. [16]	Randomized to one of three diets with 30% energy as fat: (1) low fat, (2) modified low fat, and (3) modified low fat inclusive of 30 g of walnuts per day for 6 months	↔ Body weight, percent body fat or total antioxidant capacity
	58 men and women in a parallel randomized controlled study		↔ HbA1c levels
			↑ HDL-C to TC ratio and HDL-C in walnut diet vs. control
			↓ LDL-C in walnut diet vs. control
	Jenkins et al. [19]	Consumed two bread control meals and three test meals: (1) almonds and bread, (2) parboiled rice, and (3) instant mashed potatoes, balanced in carbohydrate, fat, and protein	↓ Blood glucose and insulin for the rice and almond meals vs. for the potato meal
	15 healthy subjects in 5 sessions with minimum 1 week washout		↔ Total antioxidant capacity
			↑ Serum protein thiol concentration following the almond meal indicating ↓ oxidative protein damage
	Josse et al. [18]	Randomly consumed two white bread control meals and three test meals containing each 50g of available carbohydrate from white bread eaten alone or with 30, 60, or 90g of almonds	↓ Glycemic index of the composite meal in a dose-dependent manner for the 30-g, 60-g, and 90-g doses of almonds to white bread
	9 healthy volunteers in 5 sessions with minimum 1 week washout		↓ Glycemix index and glucose peak height in 90-g almond meal vs. white bread control meal
	Jenkins et al. [17]	Randomized to consume one of three isoenergetic supplements (1) full-dose almonds (73±3g/d), (2) half-dose almonds plus half-dose muffins and (3) full-dose muffins for 1 month each	↔ FBG, insulin, or insulin resistance
	27 hyperlipidemic men and postmenopausal women in a randomized crossover study		↓ 24-h urinary C-peptide output (marker of 24-h insulin secretion) on the half-and full-dose almonds by compared to control

However, acute postprandial studies suggest that nuts should be combined with the carbohydrate portion of the meal to reduce postprandial glycemia. A lower glycemic response is often thought to equate to a lower insulin demand, better long-term blood glucose control and a reduction in blood lipids. Josse et al. demonstrated that almonds may reduce the glycemic impact of carbohydrate foods with which they are eaten [18]. Additionally, another study concluded that reductions in 24-h insulin secretion appear to be a further metabolic advantage of nuts, which the investigators suggest may in the longer term help to explain the association of nut consumption with reduced CVD risk [17]. Further, Jenkins et al. suggested that almonds are likely to lower this risk by decreasing the glycemic response and by providing antioxidants [19], since inflammation and oxidation may be causative in the initial pathogenesis of insulin resistance, loss of beta-cell response to glucose, and development of both micro- and macro-vascular complications in type 2 diabetes. Overall, acute feeding studies have established the ability of nuts, when eaten with carbohydrate, to depress postprandial glycemia, but long-term benefits of consuming nuts have not yet been established.

In conclusion, more long-term clinical trials should evaluate the effect of nuts on glycemic control. However, nuts may have favourable effects on the postprandial response in both people with normal blood glucose and those with type 2 diabetes. Thus, nuts can be incorporated into a healthy diet to lower the glycemic index of a meal or snack for individuals with diabetes or those at risk for diabetes, on condition that overall caloric intake is regulated to maintain a healthy body weight.

3. Omega-3 fatty acids 

Dietary or supplemental omega-3 polyunsaturated FAs, mainly eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3), have well documented potent triglyceride (TG) lowering effects in healthy and diabetic subjects. An epidemiological study estimated that replacing 2% of energy from trans-isomer FAs isoenergetically with polyunsaturated fat would lead to a 40% lower risk for type 2 diabetes [20]. Another prospective cohort study of 35,988 older women supported this inverse relationship between incident type 2 diabetes and vegetable fat, and the benefit of substituting polyunsaturated FAs for saturated FAs and cholesterol [21]. Overall, the usefulness of omega-3 FAs in diabetes management includes reducing levels of TG, increasing high-density lipoprotein cholesterol (HDL-C), increasing glucose-induced insulin secretion, and possibly lowering insulin resistance. The effects of omega-3 FAs on insulin sensitivity are through to be mediated by different possible mechanisms: competition for the same enzymes and/or transcription factors, production of eicosanoids with different anti-inflammatory potency and change in membrane fluidity.

In the 1980s and the early 1990s, several clinical studies reported that omega-3 FAs may worsen glucose tolerance and insulin resistance in patients with type 2 diabetes who consumed large amounts of fish oil [22], [23], [24], [25]. For example, Borkman et al. [25] demonstrated that fasting blood glucose increased by 14% during fish oil, and by 11% during safflower oil supplementation compared with baseline. Yet, it is now believed that these negative effects were due to the high doses of omega-3 FAs used, such as 10g fish oil per day or more. Subsequently, Friedberg et al. [26] conducted a meta-analysis of 26 trials and concluded that the use of fish oil had no adverse effect on HgbA1C in both patients with type 1 and type 2 diabetes. Montori et al. [27] also performed a meta-analysis of 18 randomized, placebo-controlled trials which used a range of 3–18g/d fish oil and concluded that fish oil supplementation had no effect on glycemic control.

Recent studies in normolglycemic individuals have demonstrated unclear effects of omega-3 FAs [28], [29], [30], [31] as demonstrated in Table 2. In healthy individuals, a moderate supplementation of fish oil did not affect glycemic parameters after consuming a diet rich in either saturated or monounsaturated fat, or when parameters were adjusted for dietary intake of omega-6 and omega-3 FAs [28]. Yet in another study with older individuals, high omega-3 FAs consumption increased insulin sensitivity and reduced inflammatory markers [29]. In overweight individuals, supplementation with fish oils improved a number of biomarkers used to assess risk of CVD, including insulin sensitivity [30]. Ramel et al. also concluded that omega-3 FAs consumption during energy reduction regime exerts positive effects on insulin resistance in overweight individuals [31]. Indeed, omega-3 FAs may potentially improve markers of glycemic control in for the “at risk” populations such as overweight or older individuals.

Table 2. Recent intervention studies on omega-3 FAs supplementation on glycemic control in healthy and type 2 diabetes populations.

	Study design	Study diet	Results
	Woodman et al. [35]	Randomly assigned to consume 4g EPA, DHA, or olive oil/d while continuing to consume their usual diet for 6 weeks	↑ FBG in the EPA and DHA groups in comparison with the change from baseline in fasting glucose in the control group
	59 obese type 2 diabetic subjects in a placebo-controlled trial of parallel design		↔ Fasting insulin, insulin sensitivity or secretion, or HbA1c levels
			↓ TG
			↔ TC, LDL-C, or HDL-C
	Mostad et al. [34]	Intake in the intervention group was 17.6mL fish oil/d (5.9g total n-3 FAs) and the control group received 17.8mL corn oil/d (8.5g 18:2n-6) for 9 weeks	↔ Body weight
	26 subjects with type 2 diabetes without hypertriacylglycerolemia in a controlled study of parallel design		↑ Daytime blood glucose concentrations and FBG
			↔ Fasting insulin or HbA1c levels
			↓ Glucose utilization
			↑ Tendency glucagon-stimulated C-peptide (measure of insulin secretion)
			↔ TC, LDL-C, HDL-C, TG, leptin, adiponectin, glucagon or insulin
	Krebs et al. [33]	Randomized (1) 39 women to a weight-loss program with n-3 FA, (2) 38 to a weight-loss programme with placebo oil, and (3) 39 to receive placebo oil with no weight-loss program (control) for 24 weeks	↓ Body weight and anthropometric measures
	93 overweight insulin-resistant women in controlled study of parallel design		Weight-loss improved insulin sensitivity, HbA1c levels, glucose excursion during OGTT and lipids levels
			Weight-loss with n-3 FAs improved non-significantly fasting insulin, glucose during OGTT and lipids levels
	Kabir et al. [32]	Randomly allocated to 3g/d of either fish oil (1.8g n-3 FAs) or placebo (paraffin oil) for 2 months	↔ Body weight and energy intake
	27 women with type 2 diabetes without hypertriglyceridemia in a parallel design		↔ FBG, fasting insulin and HbA1c levels
			↓ Atherogenic risk factors: TG, the ratio of TG to HDL cholesterol, and plasma plasminogen activator inhibitor
	Giacco et al. [28]	Randomly assigned to follow either diets: (1) rich in monounsaturated fats and (2) rich in saturated fats. Within each group there was a second randomization to fish oil (n-3 FAs 3.6g/d) or placebo for 3 months	↔ Body weight
	162 healthy individuals in a parallel design		↔ Insulin sensitivity, insulin secretion, and glucose tolerance in either diet
	Waite et al. [30]	All subjects being placed on fish oil supplements (n-3 FA (100%); 440mg DHA, 660mg EPA) for 60 days	↔ Anthropometric measurements
	5 subjects selected in a intervention study		↑ Insulin sensitivity
			↓ Plasma glucose response
			Non-significant ↓ in serum TG's and TC
	Ramel et al. [31]	Randomized to 1 of 4 energy-restricted diets (−30% energy intake) of identical macronutrient composition but different n-3 FA content: control (no seafood); lean fish (150g cod, three times/week); fatty fish (150g salmon, three times/week); (4) fish oil (daily DHA/EPA capsules, no other seafood) for 8 weeks	Fish oil intake with weight loss diet exerts positive effects on fasting insulin and insulin resistance independent from weight loss, change in TG, erythrocyte membrane EPA/DHA or adiponectin concentrations
	278 overweight subjects in a parallel design		Weight loss was also a predictor of improvement
	Tsitouras et al., 2008 [29]	Consumed an isocaloric control diet for 6 weeks, followed by experimental diet, which included 720 g of fatty fish weekly plus 15 ml of sardine oil daily for 8 weeks	↑ Insulin sensitivity
	6 men and 6 women aged over 60 years for intervention study		↓ Serum C-reactive protein
			Tendency ↓ IL-6
			↔ Other metabolic parameters, adiponectin levels, or hormone responses

Yet in patients with type 2 diabetes, omega-3 FAs supplementation fails to reverse or displays mixed effects on glycemic control or insulin sensitivity for unclear reason [32], [33], [34], [35]. A moderate dose of omega-3 FAs for 2 months reduced atherogenic markers and adiposity without deteriorating insulin sensitivity [32]. Similarly, omega-3 FAs had additional benefits on lipid profile without changing insulin sensitivity, when added to a weight loss program [33]. However, a high intake of fish oil (6g/d omega-3 FAs) moderately increased blood glucose and decreased insulin sensitivity [34]. In addition, a study by Woodman et al. showed that supplementation with individual FAs, EPA and DHA had adverse effects on short-term glycemic control, without changing long-term parameter, HgbA1C [35]. Overall, recent studies have not resolved the issues regarding omega-3 FAs and glycemic control.

In conclusion, omega-3 FAs including fish oil may be able to modulate insulin action more than revert an established insulin resistance; therefore, the beneficial effects may be more evident in healthy people and not in diabetic patients. However, the effects of fish oil supplements on glycemic control or insulin sensitivity are insufficiently clear in type 2 diabetes. Future, long-term intervention studies are recommended. In addition, it is possible that the consumption of omega-3 FAs in fish matrix may modulate the glycemic control differently than a capsule of omega-3 FAs. Overall, modest amounts of omega-3 FAs in the range of 1–2g/d appear to pose no significant risk to glucose control in persons with type 2 diabetes. The ADA recommends two or more servings of fish per week (except commercially fried fish filets) to provide the omega-3 FAs [3].

4. Cinnamon 

Cinnamon extracts containing polyphenol type-A polymers, have demonstrated insulin-mimetic properties. In vitro and in vivo animal studies have reported strong insulin-like or insulin-potentiating effects after cinnamon administration [36], [37], [38]. A summary of recent studies with cinnamon extracts is made in Table 3. The first clinical trial by Khan showed that relatively low amounts of cinnamon powder supplementation (1g/d) reduced FBG concentration and improved the blood lipid profile in postmenopausal patients with type 2 diabetes [39]. Likewise, in a study with men and women with the metabolic syndrome, the results support the efficacy of cinnamon supplementation in reducing FBG and improving body composition [40]. Also a high dose (6g/d) of cinnamon with rice pudding reduces postprandial blood glucose and delays gastric emptying without affecting satiety [41]. Yet, some studies failed to replicate these findings [42], [43]. First, Vanschoonbeek et al. conclude that cinnamon supplementation (1.5g/d) did not improve whole-body insulin sensitivity, oral glucose tolerance or blood lipid profile in postmenopausal patients with type 2 diabetes [42]. Secondly, Tang et al. also demonstrated no changes in FBG and blood lipids after a 4-week supplementation with cinnamon in healthy young patients [43]. Finally, a recent meta-analysis by Baker et al. examining five prospective randomized controlled trials indicates that the use of cinnamon does not confirm to improve FBG, HbgA1C, or lipid parameters in patients with type 1 or type 2 diabetes [44].

Table 3. Recent intervention studies on cinnamon supplementation on glycemic control in healthy and type 2 diabetes populations.

	Study design	Study diet	Results
	Khan et al. [39]	Randomly divided into six groups: Groups 1, 2, and 3 consumed 1, 3, or 6g of cinnamon daily (Cinnamomum cassia), respectively, and groups 4, 5, and 6 were given placebo capsules corresponding to the number of capsules consumed for the three levels of cinnamon for 40 days	↓ FBG in all three levels of cinnamon
	60 people with type 2 diabetes in controlled study of parallel design		↓ TG, LDL-C, and TC levels in all three levels of cinnamon
			↔ HDL-C
	Ziegenfuss et al. [40]	Randomly assigned to supplement their diet with either Cinnulin PF® (500mg/d which is equivalent of 10g of whole cinnamon powder) or a placebo for 12 weeks	↓ Body fat and ↑ lean body mass
	22 subjects with prediabetes and the metabolic syndrome in study of parallel design		↓ FBG
			↔ HbA1c levels
			↓ Systolic blood pressure
			↔ Blood lipids
	Vanschoonbeek et al. [42]	Supplemented with either cinnamon (Cinnamomum cassia, 1.5g/d) or a placebo for 6 weeks	↔ FBG, fasting insulin or HbA1c levels
	25 postmenopausal patients with type 2 diabetes in study of parallel design		↔ Whole-body insulin resistance/sensitivity
			↔ Blood lipids
	Hlebowicz et al. [41]	Randomly ingested of 300g rice pudding or 300g rice pudding and 6g cinnamon	↓ Postprandial glucose response
	14 healthy subjects using a crossover trial in 1 session		Delayed gastric emptying
			↔ Satiety
	Wang et al. [45]	Randomized to daily oral cinnamon extract (1g/d) or placebo for 8 weeks	↓ FBG
	15 women with polycystic ovary syndrome in study of parallel design		↔ Fasting insulin and insulin index
			↓ Insulin resistance
	Blevins et al. [46]	Randomized to receive either cinnamon (Cinnamomum cassia, 1g/d) or placebo (wheat flour) for 3 months	↔ Body weight
	58 subjects with type 2 diabetes in study of parallel design		↔ FBG or HbA1c levels
			↔ Blood lipids
	Tang et al. [43]	Randomized to be supplemented doses of cinnamon (3g/d) and turmeric (2.8g/d) for 4 weeks each	↔ FBG
	11 young and healthy subjects participated in randomly assigned, crossover study		↔ TC and TG

In conclusion, not all studies have reported beneficial effects of cinnamon. More research is needed before cinnamon can be recommended for treatment of type 2 diabetes. Therefore, studies should be conducted to determine how specific variables, such as diet, population type, body mass index (BMI), glucose levels, cinnamon type/dose, and concurrent medication affect cinnamon responsiveness.

5. Conclusion 

In overweight and obese insulin-resistant individuals, modest weight loss has been shown to improve insulin resistance [3], [4], [5], [6]. Thus, weight loss is recommended for all such individuals who have, or are at risk for diabetes. In addition, people with diabetes are encouraged to consume a variety of fiber-containing foods. Studies also show that in individuals consuming a high-glycemic index diet, low-glycemic index diets can produce a modest benefit in controlling postprandial hyperglycemia [3]. To lower the glycemic index, nuts and peanuts can be potentially included in a healthy diet. However, more long-term studies are needed to demonstrate the effects of nuts and peanuts on glycemia. Also, given the potential benefits of omega-3 FAs on CVD risk, regular fish consumption is recommended to assure the intake of omega-3 FAs. Finally, studies of patients with type 2 diabetes also show that cinnamon may have the potential to lower glucose levels. Yet, more research on the proposed health benefits of cinnamon supplementation is warranted before unambiguous recommendations can be made. In conclusion, a growing number of individuals are adding functional foods and natural health products to their diet to help control blood glucose; however, a large amount of research still needs to be done before benefits can be confirmed, and before these foods can be recommended routinely for glycemic control.