Potential Mechanisms of Action of Polyphenols in Diabetes Risk

Tea and Coffee

In a meta-analysis of green tea or green tea extract of seven randomised controlled trials, the consumption of green tea did not decrease the levels of fasting plasma glucose, fasting serum insulin, 2-h oral glucose tolerance test (OGTT), glucose, glycated hemoglobin (HbA1c) or HOMA–IR index [90]. However the authors stated that limitations of the studies included the small sample sizes, poor quality and low evidence levels of the included studies. In contrast, another meta-analysis of 17 randomised controlled trials including seven high quality studies and 10 low quality studies, demonstrated that green tea had favourable effects significantly reducing the fasting glucose and HbA1c by 0.09 mmol/L (95% CI 0.15–0.03 mmol/L; p < 0.01) and 0.30% (95% CI 0.37%–0.22%; p < 0.01), respectively. Subgroup analyses from studies with high Jadad scores showed a significant reduction in fasting insulin (−1.16 μIU/mL, 95% CI −1.91 to −0.40 μIU/mL; p = 0.03) [91]. This study attributed these findings to measures of glucose control or insulin sensitivity not coming from primary outcomes, limited high quality studies, and concealment of null findings in most selected studies [91].

A third meta-analysis of 22 randomized controlled trials with 1584 subjects showed that green tea catechins (EGCG capsules or powder, whole green tea or green tea extract powder) with or without caffeine reduced fasting glucose (−1.48 mg/dL; 95% CI −2.57 to −0.40 mg/dL), whereas fasting insulin, HbA1c, and HOMA–IR were not affected. In subgroup analyses, the glucose-lowering effect was observed when the duration of follow-up was over a median of 12 weeks. This finding suggested that longer trials were required to support favourable effects of green tea consumption on glycemic control [92].

In summary, given the mixed results from interventions in contrast to epidemiological studies, it is still unclear if polyphenol-rich green tea has anti-diabetic effects.

A randomized cross over study investigating the effect of a single dose of espresso caffeinated coffee, decaffeinated coffee, or water on glucose tolerance and insulin sensitivity (Matsuda index) during an OGTT in 18 habitual coffee drinkers with T2D showed no difference in area under the curve AUC insulin, glucose or insulin sensitivity [31]. However, a three-way, randomized, crossover study of nine healthy subjects [93] showed that chlorogenic acid in coffee acutely modulated gastrointestinal hormone secretion and glucose uptake [93]. The consumption of 25 g glucose in either 400 mL water (control) or 400 mL caffeinated or decaffeinated coffee (equivalent to 2.5 mmol chlorogenic acid/L), did not affect glycemia or insulinemia but attenuated the postprandial increase of glucose-dependent insulinotropic-polypeptide (GIP) (p < 0.005) while glucagon-like peptide 1 secretion increased 0–120 min (p < 0.01) with a delayed intestinal glucose absorption compared with the control [93]. This finding suggested that chlorogenic acid in coffee decreased the rate of intestinal absorption of glucose or slowed gastric empting [93].

Overall, there is little evidence available to assess the effect of coffee on glucose homeostasis.

Chocolate and Cocoa

Meta-analyses of acute or short-term, chronic (≤18 weeks), randomized controlled trials showed that chocolate or cocoa reduced fasting insulin (−2.65 µU/mL) and insulin after glucose challenge (−17 µU/mL at 30 min; 95% CI −20.7 to −13.4 µU/mL) and improved insulin resistance (HOMA–IR −0.67; 95% CI −0.98 to −0.36). There was no effect on fasting glucose and HbA1c [94]. Dark chocolate (100 g bar containing approximately 500 mg of polyphenols) for 15 days decreased blood pressure and improved insulin sensitivity in healthy individuals as demonstrated by decreasing HOMA–IR (0.94 ± 0.42 vs. 1.72 ± 0.62; p < 0.001) and increasing quantitative insulin sensitivity check index (QUICKI) (0.398 ± 0.039 vs. 0.356 ± 0.023; p = 0.001), compared with 90 g white chocolate bar containing no polyphenols [95], and similar results were shown in hypertensive [96] and glucose-intolerant hypertensive individuals [97]. A four-week consumption of dark chocolate containing 500 mg polyphenols reduced blood pressure (BP), fasting glucose and HOMA–IR in lean and overweight females [98] compared with 20 g of placebo dark chocolate containing negligible polyphenol but similar nutritional composition. Consumption of cocoa flavanols (902 mg) for 12 weeks also improved insulin sensitivity in overweight and obese individuals compared with a low-flavanol cocoa drink [99]. In contrast, consumption of flavanol-rich cocoa drink (150 mL twice a day, containing approximately 900 mg flavanols) for two weeks did not improve insulin resistance or blood pressure in people with essential hypertension [100]. Daily consumption of 25 g dark chocolate for eight weeks did not improve fasting glucose, insulin and HbA1c levels in hypertensive diabetic subjects compared with 25 g white chocolate consumption [101]. Similarly, in acute studies [102,103], dark chocolate containing 450 mg of polyphenols did not improve insulin and glucose in hypertensive diabetic subjects given a 75 g oral glucose load 60 min after ingestion of either low (control) or a high polyphenol dark chocolate [102], and cocoa beverage containing 960 mg total polyphenols and 480 mg flavanols showed no effect on glucose and increased insulin levels in obese subjects with T2D given a high-fat breakfast (766 kcal; 50 g fat) compared with a placebo (110 mg total polyphenols; <0.1 mg flavanols) [103].

In summary, given conflicting results in interventions, current data is insufficient to recommend chocolate and cocoa for glycemic control. Therefore, large placebo controlled trials with good quality designs are required to clarify the effects of cocoa polyphenols.

Cinnamon

Cinnamon is known to contain polyphenols such as catechin, procyanidin, cinnamtannin trans-cinnamic acid and flavones (cinnamaldehyde and trans-cinnamaldehyde) [5,104,105]. Eleven studies have shown positive effects of cinnamon on glycemic control. Three studies [106,107,108] included subjects with T2D with baseline HbA1c levels >8%. Seven studies [109,110,111,112,113,114,115] included healthy normal subjects [111,112,113,114], subjects with impaired fasting glucose [109] and subjects with metabolic syndrome [115]. One study showed beneficial effects on improved insulin sensitivity in patients with polycystic ovary syndrome [105]. Two studies [116,117] showed positive effects on fasting blood glucose levels, but did not report baseline HbA1c levels [116] and no significant changes of HbA1c, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) or TG [117]. Five studies [118,119,120,121,122] showed no significant changes in fasting glucose, lipids, HbA1c, or insulin levels in 25 postmenopausal women with T2D taking 1.5 g of cinnamon daily for six weeks [120], in 43 subjects with T2D receiving 1 g of cinnamon daily for three months [118], in 60 subjects with T2D taking 1 g of cinnamon daily for 12 weeks [121], in 72 adolescents with Type 1 diabetes (T1D) taking 1 g of cinnamon daily [122] and in 11 healthy subjects taking 3 g of cinnamon daily for four weeks [119]. A randomized, controlled trial [108] (no placebo used with the concern that the strong taste of cinnamon capsules would preclude any blinding), investigating whether daily cinnamon plus usual care versus usual care alone lowers HbA1c in 109 patients with T2D (HbA1c > 7.0), showed that supplementation with 1 g of daily cassia cinnamon did not significantly lower HbA1c over 90 days [108]. A randomized, placebo-controlled, double-blind clinical trial of 58 subjects with T2D found that intake of 2 g daily of cinnamon for 12 weeks significantly reduced HbA1c (−0.36%; p < 0.005), systolic blood pressure—SBP (−4 mm Hg; p < 0.001) and diastolic blood pressure—DBP (−4 mmHg; p < 0.001) among 58 poorly controlled patients with T2D, compared with the placebo [107]. A randomized, double-blinded clinical study of 66 Chinese with T2D treated with gliclazide found significant reductions in HbA1c in those receiving 360 mg of cassia cinnamon extract (−0.92%; p = 0.0004) and 120 mg of cassia cinnamon extract (−0.67%; p = 0.003) after 90 days. No significant reductions were seen in the placebo group but the groups were not compared statistically. Fasting glucose levels were also significantly reduced over time in both treatment groups [106]. A study [116] in 60 subjects with T2D treated with sulfonylureas found significant reductions in fasting glucose (18%–29%), triglycerides (23%–30%), LDL (7%–27%), and total cholesterol (12%–26%), following supplementation with either 1, 3, or 6 g of cassia cinnamon daily for 40 days, while no change was observed in the placebo group but the groups again were not compared statistically. Significant effects were observed even after 20 days of washout [116]. A double-blind study [117] found that intake of 3 g daily cinnamon powder for 120 days significantly decreased fasting glucose but not HbA1c in 65 patients with T2D treated with oral antidiabetics or diet alone. Fasting glucose was reduced by 10.3% ± 13.2% in the treatment group and 3.37% ± 14.2% in the placebo group (p = 0.046). No significant changes in HbA1c, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) or triglycerides (TG) were observed. Baseline HbA1c values were below 7% [117]. Two recently updated meta-analyses showed that the intake of cinnamon/cinnamon extracts lowered fasting glucose levels [123,124]. A meta-analysis of 10 randomized controlled trials (543 patients) reported that the consumption of cinnamon ranging from 120 mg/day to 6 g/day for 4–18 weeks decreased levels of fasting glucose, total cholesterol, LDL, and triglyceride and increased levels of HDL. No significant effect on HbA1c was observed [124]

In summary, the consumption of cinnamon may have glycaemic-lowering effects, but more intervention studies covering different types and amounts of cinnamon and types of subjects, are required as not all studies have shown positive effects of cinnamon on insulin resistance and many have been poorly analysed. The usual dose of cinnamon used was 1–2 g/day but some studies used larger doses of 6 g/day which would be difficult to maintain long term.

Grape Polyphenols

A double-blinded, randomized, crossover trial of 32 subjects with T2D showed positive effects of grape seed extract intake of 600 mg/day for four weeks on fructosamine, whole blood glutathione (GSH; p < 0.01), high sensitivity C reactive protein hsCRP, (p = 0.0006) and total cholesterol concentration (p = 0.05), but did not show significant changes in HOMA–IR [125]. Another study showed protective effects of grape polyphenols on fructose-induced oxidative stress and insulin resistance in first-degree relatives of patients with T2D. Subjects were randomised to eight weeks of supplementation with 2 g/day grape polyphenols or placebo and then ingested 3 g fructose/kg fat free mass/day as a 20% fructose solution with the three meals during the six days preceding muscle biopsies and a two-step hyperinsulinemia-euglycemic clamp. After six-day fructose loading, the placebo group showed a 20% decrease in hepatic insulin sensitivity (11.9 ± 1.5 vs. 9.6 ± 0.9; p < 0.05) associated with an 11% decrease in glucose infusion rate (p < 0.05). However, the grape polyphenol group did not show these deleterious effects of fructose. Moreover, grape polyphenol supplementation showed protective effects against fructose-induced oxidative stress markers of urinary F2-isoprostanes, muscle thiobarbituric acid reactive substances (TBARS), while fructose load induced a downregulation of mitochondrial genes and decreased mitochondrial respiration in permeabilized muscle fibers [126]. In a randomized, controlled study of 38 males with at least one component of metabolic syndrome [127], the daily consumption of 20 g of wine grape pomace flour containing 10 g of dietary fiber, 822 mg of polyphenols for 16 weeks showed a significant reduction (p < 0.05) in postprandial insulin and fasting glucose levels compared with the baseline, but there were no significant differences in fasting insulin, postprandial glucose, insulin, glycosylated haemoglobin and HOMA–IR between a wine grape pomace flour group and a control group [127].

In summary, there is little persuasive evidence of an effect of mixed grape polyphenols on glucose homeostasis.

Resveratrol (3, 5, 4′-trihydroxy-trans-stilbene) is a phytoallexin naturally synthesized by plants in response to infection and injury pathogens such as bacteria or fungi. Berries, grape skins, red wine, Japanese knotweed, peanuts, and the roots of rhubarb are sources of resveratrol. Resveratrol exists in two isomeric forms. The main form is trans-resveratrol mainly found in red grape juice (3.38 mg/L) [128]. The levels of resveratrol in food vary. Its levels in red wine are higher (5.8 mg/L vs. 0.2 mg/L) than white wine as red wine is fermented with skins [129].

A randomized, double-blind, crossover study of 11 healthy, obese men showed that resveratrol supplementation of 150 mg/day for 30 days reduced glucose, insulin, HOMA–IR and leptin, decreased inflammatory markers (TNF-α, leukocyte count, alanine aminotransferase) and SBP by 5 mmHg, improved muscle mitochondrial respiration on a fatty acid-derived substrate from the vastus lateralis muscle biopsy (~30 mg), and decreased adipose tissue lipolysis and plasma fatty acid and glycerol in the postprandial state [130]. However, there was no control group or placebo period. Nineteen subjects with T2D took 5 mg trans-resveratrol daily for four weeks and showed improved insulin sensitivity as assessed by HOMA–IR, decreased glucose levels and a delayed glucose peak following a standard meal. There was no control group or placebo used. This study considered these favourable effects were attributed to decreased oxidative stress leading to more efficient insulin signalling via the Akt pathway, with an increase in the ratio of phosphorylated vs. total Akt (pAkt: Akt) ratio in platelets [131]. However, a combination of other polyphenolic compounds found in red wine may contribute to the many beneficial effects, as resveratrol is known to have low bioavailability [104].

In summary, it is hard to conclude that resveratrol has anti-diabetic effects. More clinical trials of resveratrol are required to confirm the findings described above in this article.

Red Wine

In a randomized, controlled study, red wine significantly improved insulin sensitivity, lipid profiles and endothelial function compared with other alcoholic beverages [132,133].

A study [134] comparing the acute effects of red wine, beer and vodka on oxidative stress reported that only red wine demonstrated protection against oxygen-induced oxidative stress, while all three alcoholic beverages provided similar protection against oxygen-induced (via hyperoxia) increase in arterial stiffness. Ten males randomly consumed one of four tested beverage of red wine, vodka, beer (0.32 g ethanol/kg body weight) and water (control). Every beverage was consumed once, a week apart in a cross-over design. The volunteers breathed 100% normobaric O2 between 60th and 90th min of 3-h study protocol. Plasma lipid peroxides (LOOH—biochemical marker of oxidative stress) and uric acid (UA) concentration, blood alcohol concentration (BAC) and arterial stiffness—indicated by augmentation index (AIx)—were measured before and 30, 60, 90, 120 and 180 min after beverage consumption [134]. Moreover, 2 g/day of grape seed extract (1 g of polyphenols) also improved endothelial function in subjects with high vascular risk [135].

However, overall, there is little evidence of an effect of wine polyphenols on glucose and insulin.

Pomegranate

Fresh pomegranate juice is comprised of phenolic acids, including gallic acid, chlorogenic acid, caffeic acid, ferulic acid, and coumaric acids, as well as flavonoids, such as catechin, phloridzin, and quercetin. Other flavan-3-ols such as epicatechin and epigallocatechin are present in pomegranate [136]. Various in vivo and in vitro studies have demonstrated favourable effects of pomegranate on insulin sensitivity, inhibition of a-glucosidase and reduced oxidative stress and lipid peroxidation [136,137]. Very limited human studies have focused on the effects of pomegranate juice on T2D [137]. One hundred and twenty milliliters of pomegranate juice/day in obese subjects did not modify insulin secretion and sensitivity after one month of administration in a fasted state [138]. Similarly, 50 mL of pomegranate juice/day for four weeks in subjects with T2D induced no changes in fasting glucose, insulin and HbA1c [139]. Overall, there appears to be little benefit of pomegranate juice.

Berries

In a randomized, cross-over, double-blind, placebo-controlled acute meal study of 20 healthy subjects, no significant effects were observed on plasma glucose, plasma triacylglycerol, plasma non esterified fatty acids, as well as markers of vascular inflammation, intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) after consumption of a black currant (20% juice), compared with consumption of placebo juice devoid of polyphenols and Vitamin C. Both drinks contained 50% citric acid solution, 1% aspartame and 8% acesulfame K. However, an increase in plasma insulin levels was detected [140]. Freeze-dried blueberry beverage containing 50 g of blueberry powder (equivalent to approximately 350 g fresh blueberries) was given daily to 48 individuals with metabolic syndrome for eight weeks in a randomized controlled trial. The serum glucose concentration, lipid profiles, fasting plasma hs-CRP, IL-6, adiponectin, sICAM-1 and sVCAM-1 were not changed significantly, whereas blood pressure decreased in the blueberry-supplemented group compared with the 960 mL water control group [141]. Insulin sensitivity improved more in a 22.5 g blueberry group (22.2% ± 5.8%) than in the placebo group (4.9% ± 4.5%) (p = 0.02) as measured by a high-dose hyperinsulinemic-euglycemic clamp [142]. The thirty-two obese, nondiabetic, and insulin-resistant participants of this study showed no significant changes in adiposity, energy intake, and inflammatory biomarkers.

Polyphenol-rich berries may reduce sucrose digestion and absorption leading to delayed glycaemic response [143,144]. In a randomised, controlled, cross-over study of two 3-h meal tests in healthy subjects, a berry puree (150 g) made of equal amounts (37.5 g) of bilberries, blackcurrants, cranberries and strawberries, and sweetened with 35 g sucrose lowered glucose levels at 15 (p < 0.05) and 30 min (p < 0.01) compared with the control meal including 250 mL water, 35 g sucrose, 4.5 g glucose and 5.1 g fructose which are similar in glycemic profile and amounts of available carbohydrates. The berry meal and the control meal showed the peak glucose concentration at 45 and 30 min, respectively. No significant difference in the 3-h area under the glucose response curve was observed. These findings indicated that berries rich in polyphenols delayed digestion of sucrose and/or absorption of glucose from the berry meal or slowed gastric empting [144]. In three randomised, controlled, cross-over, 2-h meal studies [143], healthy female volunteers underwent four 2-h meal tests on separate visits, at least three days apart with a mix of berries and bread strawberries, and a berry mix reduced insulin but not glucose to both wheat and rye breads [143].

A randomized, single-blind, placebo-controlled, cross-over trial in an acute-meal setting showed beneficial effects of polyphenolic- and antioxidant-rich strawberry (Fragaria) on postprandial inflammation and insulin sensitivity. Twenty-four overweight subjects consumed two isocaloric meals of high-carbohydrate, moderate-fat (HCF) accompanied by either a strawberry or a strawberry-flavoured beverage that served as a placebo. The strawberry beverage significantly attenuated the postprandial inflammatory response as measured by hsCRP and IL-6 (p < 0.05) and reduced postprandial insulin response (p < 0.05). In addition to polyphenolic compounds, Vitamin C and glutathione were also suggested to contribute to the antioxidant activity of strawberry. The test meals including strawberry and placebo beverage did not contain any soluble fibre [145]. The same team conducted an extended study [146] to investigate the effects of six weeks of strawberry consumption (~95 mg total strawberry phenols/day) on HCF meal-induced increases in glucose, insulin and indicators of inflammation and homeostasis over 6 h. Twenty-four overweight subjects consumed either a strawberry beverage or a placebo beverage for six weeks after a seven-day run-in of low/no berry consumption. Strawberry consumption attenuated postprandial plasminogen activator inhibitor-1,plasminogen activator inhibitor-1 (PAI-1) (p = 0.002), IL-1 β (p = 0.05) with moderate suppression of IL-6, but no significant changes in platelet aggregation, hsCRP, TNF-α, insulin, or glucose were observed compared with the placebo [146]. Consumption of a beverage of 50 g freeze-dried strawberries (2006 mg polyphenols) for eight weeks decreased total cholesterol and LDL-C, small LDL particles and VCAM-1, whereas waist circumference, SBP/DBP, fasting glucose, triglycerides, and HDL-C were not affected, compared with control (equivalent amounts of water) in 27 obese subjects with metabolic syndrome after eight weeks [147]. Daily consumption of two cups of a strawberry drink for four weeks in women with metabolic syndrome (each cup had 25 g of freeze-dried strawberry powder equivalent to approximately 3.5 cups or 500 g fresh strawberries) decreased total cholesterol and LDL-C levels by 5% and 6%, respectively (p < 0.05) and decreased lipid peroxidation in the form of malondialdehyde and hydroxynonenal by 14% (p < 0.01) at four weeks versus baseline. There was no control group or control period. This study suggested that phytosterol, dietary fiber (8 g/day), or polyphenolic flavonoids content of strawberries might contribute to the hypocholesterolemic effects of freeze dried strawberry powder [148].

A small study suggested that dried cranberries might lower the glycemic response for people with T2D [149], but other studies did not find glucose-lowering effects, despite antioxidant, anti-inflammatory, and HDL-raising and LDL-lowering effects of cranberry juice supplementation [150,151,152,153].

In summary, berries appear to reduce the insulin response to a glucose load and have anti-inflammatory effects. However, the results are very mixed and there is limited data.

Extra Virgin Olive Oil

In the PREDIMED study of 3541 patients with high cardiovascular risk with a 4.1-year follow-up period, a Mediterranean diet rich in extra virgin oil showed a 40% reduction (95% CI 15–57) in the risk of T2D compared with the control group [154]. An olive-rich Mediterranean diet also improved glucose metabolism and reduced body weight in subjects with T2D. Insulin resistance was measured by HOMA–IR, adiponectin/leptin and adiponectin/HOMA–R ratios after one year of follow-up, but HbA1c was not measured [155]. Moreover, the Mediterranean diet supplemented with virgin olive oil or nuts showed an anti-inflammatory effect by decreasing CRP, IL-6 and adhesion molecules, chemokines and T-lymphocytes (CD49d) and monocytes (CD 11b, CD49d, CD40) [156]. In contrast, in a study of a six-week olive oil supplementation in healthy adults, fasting glucose and HDL-C increased compared with baseline in both the low- and high-phenolic olive oil group. There was no change in fructosamine, or plasma total phenols within either group. No significance in a proteomic biomarker score for diabetes was observed with either low- or high-phenolic olive oil [157]. Phenolic components such as oleuropein and hydroxytyrosol abundant in olive leaves as well as oil may protect against diabetes and metabolic disorders [158]. Only two intervention studies of olive leaf polyphenols [159,160] have been conducted so far. Supplementation with olive leaf polyphenols (51.1 mg oleuropein and 9.7 mg hydroxytyrosol per day) for 12 weeks significantly improved insulin sensitivity and pancreatic β-cells secretory capacity after oral glucose challenge in overweight, middle-aged men at the risk of developing the metabolic syndrome [159]. Similarly, in a randomized, placebo-controlled trial in subjects with T2D, supplementation of a 500 mg olive leaf extract tablet once daily for 14 weeks was shown to significantly lower HbA1c and fasting insulin with no significant changes in postprandial insulin levels [159,160].

More clinical studies evaluating the potential effects of olive oil or leaf polyphenols on insulin sensitivity and glycaemic control should be conducted to confirm these beneficial effects.

Whole Grains, Nuts and Seeds

Whole grains such as wheat, rye, soy and flaxseed are a good source of polyphenols as are nuts such as chestnuts, hazelnuts, pecans and almonds [161]. Whole grain intake is associated with a reduced risk of T2D but the mechanism of the protection is not clear [162]. Whole grain intake is also associated with a lower body weight, lower waist circumference and lower fasting insulin in the Framingham offspring study [163]. However, interventions comparing whole grain with refined grain cereals for 12 weeks have shown no effect on insulin sensitivity or insulin release in 146 individuals with the metabolic syndrome [164] although 2- and 3-h postprandial insulin and triglyceride was lower after the whole grain intervention [165] compared with a standard test meal during the run-in period. A large study with 316 individuals compared usual diet (<30 g/day of whole grains) to 60 and 120 g/day for four months. No effects were seen on glucose, insulin, inflammatory, coagulation or endothelial markers [166]. It would appear despite the epidemiology that increasing whole grain intake with more fibre and polyphenols has little effect on metabolic risk. However, in the Predimed study, nuts reduced the incidence of T2D assessed annually by OGTT by 52% in the Reus Substudy over four years [167].

Fruits and Vegetables

Most prospective studies have shown no effect of vegetables and fruits on insulin resistance or the risk of T2D [168,169,170,171]. Only a high daily consumption of green leafy vegetables was inversely associated with T2D [169,170], while a high intake of berries was associated with a 35% lower risk of T2D (HR 0.65; 95% CI 0.49–0.88; p = 0.15) [171].

Dietary Patterns