Cranberries improve postprandial glucose excursions in type 2 diabetes

Abstract

Recent research supports a favorable role of cranberries on cardiometabolic health. Postprandial metabolism, especially hyperglycemia, has been shown to be an independent cardiovascular risk and few clinical studies have reported the role of berries in improving postprandial dysmetabolism. We investigated the postprandial effects of dried cranberries following a high-fat breakfast challenge in obese participants with type 2 diabetes (T2DM), in a randomized crossover trial. Blood draw and vascular measurements were conducted at fasting, 1, 2 and 4 hours (h), following the consumption of a fast-food style high-fat breakfast (70 g fat, 974 kcal) with or without cranberries (40 g). Analyses of our data (n = 25; BMI (kg m⁻²) (mean ± s.d.) = 39.5 ± 6.5; age (years) = 56 ± 6) revealed that postprandial increases in glucose were significantly lower in the cranberry vs. control at 2 & 4 h (p < 0.05). No significant differences were noted in insulin, insulin resistance evaluated by homeostasis model assessment, lipid profiles and blood pressure between the cranberry and control groups. Among the biomarkers of inflammation and oxidation, postprandial serum interleukin-18 and malondialdehyde were significantly lower at 4 h, and serum total nitrite was higher at 2 h in the cranberry vs. control group (all p < 0.05). No effects were noted on C-reactive protein or interlukin-6. Overall, dietary cranberries had notable effects in improving high-fat breakfast induced postprandial glucose and selected biomarkers of inflammation and oxidation in participants with T2DM. These findings provide evidence that adding whole cranberries to a high-fat meal may improve postprandial blood glucose management and warrant further investigation.

1. Introduction

Abnormalities in the postprandial (fed) state, especially in type 2 diabetes, are considered a significant risk factor for cardiovascular disease (CVD).^1,2 In type 2 diabetes, the postprandial phase is mostly characterized by increases in plasma glucose and triglycerides, which contribute to endothelial dysfunction, oxidative stress and inflammation.^2–5 Thus, reducing the magnitude of postprandial hyperglycemia, hypertriglyceridemia, as well as oxidative stress and inflammation has been the target of food-based nutritional interventions. While meals high in fats and refined carbohydrates have been shown to elicit a higher postprandial response,^6–8 co-administration of antioxidant micronutrients, as well as dietary bioactive compounds, such as fruit and wine polyphenols, has been shown to ameliorate such adverse metabolic changes.^9–12 These studies have been mostly conducted in non-diabetic subjects at risk for CVD. In a few reported studies of patients with type 2 diabetes, dietary patterns, such as adherence to a Mediterranean diet which was associated with favorable postprandial glucose levels,¹³ and administration of plant compounds, such as nopal extracts¹⁴ and spice mix,¹⁵ and antioxidant nutrients, such as vitamin C,¹⁶ have been shown to delay postprandial excursions of blood glucose and improve endothelial function in diabetic patients. Thus, there is a substantial lack of studies that address the role of bioactive dietary compounds, especially polyphenolic flavonoids, in the modulation of postprandial metabolism in diabetes.

In recent years, cranberries have gained much attention as a rich source of polyphenolic flavonoids and other bioactive constituents in improving the features of metabolic syndrome, diabetes and CVD.¹⁷ Such studies in the context of diabetes are quite limited. In two 12-week studies in patients with type 2 diabetes, cranberry juice showed a significant decrease in fasting glucose,¹⁸ while cranberry extracts decreased total and LDL-cholesterol but failed to show any effects on glycemic control when compared to the control group.¹⁹ In the context of postprandial hyperglycemia in type 2 diabetes, Wilson et al. reported a lower glycemic response with low calorie cranberry juice and low calorie dried cranberries when compared to the normal calorie control groups.^20,21 However, these studies did not report changes in postprandial lipids, blood pressure and any of the biomarkers of inflammation and lipid oxidation associated with endothelial dysfunction.

Thus, we examined the hypothesis that commercially available dried whole cranberries will reduce postprandial hyperglycemia, hypertriglyceridemia and inflammation in obese adults with type 2 diabetes following a high-fat meal challenge. We specifically examined the postprandial effects of cranberries in the presence of a high-fat fast food style breakfast representing a typical western dietary pattern consumed in the US.

2. Materials and methods

2.1. Participants

This was a randomized crossover trial in which adults with type 2 diabetes as defined by the American Diabetes Association²² and elevated waist circumference (>89 cm for women or >102 cm for men) were enrolled in the study. Enrollment criteria also required the following: established and stable diabetes for at least 5 years but not on insulin therapy, the absence of preexisting conditions, such as any type of cancer or coronary heart disease, abnormal liver, renal, or thyroid function, anemia, not taking antioxidants or fish oil supplements on a regular basis, and not currently enrolled in a weight-loss program. In addition, current smokers, those consuming alcohol on a regular basis (except for social drinking, 1–2 drinks per week), or pregnant or lactating women were also excluded from the study. The study protocol was approved by the Institutional Review Board at the Oklahoma State University (OSU). All participants provided written informed consent. Study procedures were conducted in the Clinical Assessment Unit of the Department of Nutritional Sciences at OSU.

2.2. Study design

Participants were recruited via fliers in the OSU community, campus e-mail lists, and a university research website. This was a randomized crossover study in which each participant made 2 separate visits to the study site, arriving in a fasting state (10–12 h), and each visit lasted ∼6–7 h. As shown in Fig. 1, the 2 study days were separated by a 1-week washout phase. On each day of the study, blood draw, blood pressure, and vascular measurements were conducted in the fasting state (baseline), then again at 60 (1 h), 120 (2 h), and 240 (4 h) postprandial time points, starting from the time of completion of the breakfast meal intake. After the measurements in the fasting state, participants were administered a high-fat fast-food-style breakfast with or without cranberries. The breakfast was prepared at the clinic, and all participants underwent supervised consumption of the test meals. Participants were asked to avoid alcohol and caffeine for 24 h as well as polyphenol-containing foods, such as other berries, tea, red wine, soy products, citrus juices, nuts, chocolate, and cocoa-containing products, or dietary supplements of these food extracts for 48 h before each study visit. Otherwise, participants were asked to maintain their usual diet, medications, and lifestyle during the entire course of the study. Three-day food records (2 weekdays and 1 weekend day) were collected at the baseline before the start of the study, and nutrient intake was analyzed with Nutritionist Pro version 3.2 (Axxya Systems).

Fig. 1.

Overview of the study design.

2.3. Meal interventions

The nutrient composition of the breakfast meals with or without cranberries is shown in Table 1. The fast-food-style breakfast meal consisted of 2 scrambled eggs, 2 tsp butter, hash brown potatoes (70 g), 2 buttermilk biscuits, and a sausage patty (57 g). The control meal had 80 g ripe banana to match the calorie (100 kcal) and carbohydrate content (28 g) of the cranberries. The cranberry breakfast meal had added 40 g dried reduced calorie cranberries (Ocean Spray Cranberries, Inc.) which were purchased in a single lot from the local grocery store and their macronutrient and polyphenol composition were analyzed at the Robert M. Kerr Food & Agricultural Products Center at Oklahoma State University. The commercial brand of reduced sugar cranberries (Crasins®) is made from North American cranberries (Vaccinium macrocarpon) and has the following carbohydrate composition in the 40 g dose used in our study: fructose (4 g), sucrose (2.4 g), dextrose (6 g), maltose (0.2 g), total sugars (12 g), polydextrose (7 g), total organic acids (1 g), soluble fiber (8 g), insoluble fiber (2 g), total fiber (10 g), and total carbohydrates (30 g). All breakfast meal ingredients were purchased from a local grocery store and prepared in the metabolic kitchen at the clinic each morning on the 2 trial days.

Table 1.

Nutrient composition of breakfast meals

Nutrient	Control meal (meal +80 g ripe banana)	Cranberry meal (meal +40 g dried cranberries)a
Calories (kcal)	974	974
Total fats (g)	70	70
Total carbohydratesb (g)	56	55
Proteins (g)	31	31
Saturated fats (g)	40	40
Monounsaturated fats (g)	10	10
Polyunsaturated fats (g)	20	20
Cholesterol (mg)	465	465
Fiber (g)	5.5	12.5
Total polyphenols (mg)	—	178c
Quercetin-3-rhamnoside (mg)	—	32
Quercetin-3-galactoside (mg)	—	29
Proanthocyanidins (mg)	—	35

^aCrasins® (Ocean Spray Cranberries, Inc.).

^bDried cranberries (40 g Craisins® provided a total of 30 g carbohydrates including 10 g fiber and 12 g total sugars).

^cGallic acid equivalent (GAE) measured by the Folin–Ciocalteu method.

2.4. Anthropometrics and vascular measurements

Body weight (±0.05 kg) was measured on a calibrated scale with participants wearing light clothing and shoes removed, and the height (±0.05 cm) was measured with the use of a stadiometer. Waist circumference (±0.05 cm) was measured at the superior iliac crest. On each day of the trial, systolic and diastolic blood pressures and arterial compliance were measured in a quiet, temperature-controlled laboratory after an overnight fast and before blood sampling. With the subject supine, radial arterial waveforms were recorded for 30 s. The pressure transducer amplifier system was connected to a specially designed device (Model CR-2000; Hypertension Diagnostics Inc.). This technique has been previously validated^23,24 and provides separate assessment of the large artery or capacitive compliance and small artery reflective or oscillatory compliance. These measures were performed at the baseline and at 1, 2, and 4 h postprandially.

2.5. Biochemical variables

On each study day, blood samples were sent to the Stillwater Medical Center Laboratory for analyses of serum glucose, insulin, lipid profiles (total cholesterol, TGs, LDL cholesterol, and HDL cholesterol) and high-sensitivity CRP (hs-CRP). Analyses for glucose, insulin, and lipids were conducted with the use of automated diagnostic equipment (Abbott Architect Instruments) by enzymatic colorimetric methods that used commercially available kits according to the manufacturer’s protocols. hsCRP was assayed by ultrasensitive nephelometry (Dade Behring). Serum glycated hemoglobin was analyzed with the use of a DCA 2000+ Analyzer (Bayer). Insulin resistance was evaluated by HOMA-IR and was calculated as follows: [insulin (mU L⁻¹) × glucose (mmol L⁻¹)]/22.5. Among the serum biomarkers of inflammation and lipid peroxidation, interleukin-6 (IL-6) and interleukin-18 (IL-18) were measured using commercially available ELISA kits (R&D Systems) according to the protocols of the manufacturer. The inter-assay CVs were 4.5% and 7.6%, respectively. Lipid peroxidation was measured in serum as combined malondialdehyde and hydroxynonenal using a colorimetric assay according to the protocol of the manufacturer (Oxis Health Products) with a mean inter-assay CV of 5.5%. Serum nitrite was measured using the Griess Reagent System (Promega Corporation) with a mean CV of 3.3% for samples.

2.6. Statistical analysis

The primary objective of the study was to examine the effects of a high-fat meal with cranberries on postprandial glucose and lipids, and biomarkers of inflammation and oxidation when compared to the no cranberry group. Data are presented as means ± SEMs for serum biochemical variables, biomarkers of inflammation and lipid peroxidation, blood pressure and measures of arterial compliance. Treatment effects of the test meal with or without cranberries on outcome variables were analyzed using a mixed model ANCOVA using treatment and the time point as repeated measures and the baseline as a covariate. The area under the curve (AUC) for serum glucose was calculated for each subject and meal intervention using the trapezoid model. GraphPad Prism (version 6, GraphPad Software, San Diego, CA, USA) was used for graph plotting and calculation of AUC. A power calculation was done and it was estimated that a sample size of 20 individuals would be sufficient to detect a one SD difference in postprandial glucose with α = 0.05 and β = 0.80. Data analyses were conducted with the use of IBM SPSS Statistics version 20.0 (IBM Corp.). The results corresponding to P < 0.05 are described as significant for the purposes of discussion.

3. Results

3.1. Baseline characteristics

Among the 40 participants who were screened for our study, 25 qualified and completed the 2-week postprandial crossover study (Fig. 1). The study interventions were well tolerated and compliance was 100% among the enrolled participants. Table 2 shows the baseline characteristics of the participants of whom all had clinical diagnosis of type 2 diabetes as defined by ADA.²² Among these 25 participants, all were obese and on oral hypoglycemic agents and none were taking insulin. In general, these participants had the above normal blood pressure but mostly optimal serum lipids at the baseline. Macronutrient distribution based on habitual dietary analyses revealed an intake of 37% fat, 47% carbohydrates and 17% proteins by these participants.

Table 2.

Baseline characteristics

Variable	Value
N	25
Age, years	56 ± 6
Gender, M/F	5/20
Weight, kg	105 ± 13
BMI, kg m−2	39.5 ± 6.5
Waist circumference, inches	45 ± 1.8
Glucose, mg dL−1	138 ± 21
Insulin, mU L−1	12.5 ± 3.6
Insulin resistance (HOMA-IR)	3.7 ± 0.9
HbA1c, %
8.6 ± 0.8
Total cholesterol, mg dL−1	176 ± 11
LDL-cholesterol, mg dL−1	108 ± 11
HDL-cholesterol, mg dL−1	43 ± 2.5
Triglycerides, mg dL−1	155 ± 13
hs CRP, mg L−1	5.1 ± 1.2
Systolic blood pressure, mmHg	136 ± 8.5
Diastolic blood pressure, mmHg	88 ± 4.0
Small artery elasticity index, mL mmHg−1 × 100	5.8 ± 3.6
Large artery elasticity index, mL mmHg−1 × 10	22 ± 7.4
Medication/supplement use n (%)
Insulin	0 (0)
Oral hypoglycemic agents	25 (100)
Statins/fibrates	5 (20)
CCBs	3 (12)
ACEIs/ARBs	10 (40)
Diuretics	2 (8)
Aspirin	6 (24)
Multivitamins/minerals	6 (24)
Macronutrient intake
Energy, kcal	2220 ± 200
Carbohydrates, g	265 ± 38
Total fats, g	95 ± 8
Proteins, g	88 ± 9
Fiber, g	15 ± 9

Values represented as means ± SE unless otherwise indicated. ACEI/ARB, angiotensin converting enzyme inhibitor/angiotensin receptor blocker; CCB, calcium channel blocker; HbA1c, glycated hemoglobin; hsCRP, high-sensitivity C-reactive protein.

3.2. Postprandial serum glucose, insulin, HOMA-IR and lipids

As shown in Table 3, postprandial serum glucose was found to be significantly lower after cranberry intervention at 2 and 4 hours when compared to the control phase (p < 0.05). The mean AUC (0–240 min) of serum glucose responses also revealed significantly lower values for cranberry vs. the control phase at these time points (0.56 vs. 0.88 at 2 hours, and 0.48 vs. 0.78 at 4 hours, respectively, all p < 0.05). On the other hand, serum insulin and insulin resistance as assessed by HOMA-IR were not significantly different following cranberry vs. control intervention. Postprandial lipid profiles, especially total, LDL- and HDL-cholesterol, LDL:HDL and triglycerides were not significantly different following cranberry vs. the control phase at any time point (Table 3).

Table 3.

Postprandial measures of serum biochemical profiles, blood pressure and vascular measurements in patients with type 2 diabetes fed a high-fat breakfast with and without dried whole cranberries in a randomized crossover study (n = 25)

Variable	Fasting	1 h	2 h	4 h
Total cholesterol (mg dL−1)
Control	180 ± 5.4	177 ± 5.5	177 ± 5.5	179 ± 5.3
Cranberry	172 ± 6.2	172 ± 6.7	177 ± 5.9	177 ± 6.2
LDL cholesterol (mg dL−1)
Control	100 ± 4.7	97 ± 4.8	94 ± 4.9	92 ± 5.1
Cranberry	101 ± 5.3	95 ± 6.7	94 ± 5.1	91 ± 5.3
HDL cholesterol (mg dL−1)
Control	44 ± 1.9	43 ± 1.8	42 ± 1.8	43 ± 1.9
Cranberry	41 ± 1.6	41 ± 1.5	41 ± 1.7	41 ± 1.6
LDL/HDL
Control	2.4 ± 0.15	2.4 ± 0.15	2.3 ± 0.15	2.3 ± 0.18
Cranberry	2.6 ± 0.16	2.4 ± 0.18	2.4 ± 0.16	2.3 ± 0.16
Triglycerides (mg dL−1)
Control	161 ± 19	183 ± 14	188 ± 15	196 ± 16
Cranberry	151 ± 14	171 ± 13	179 ± 13	183 ± 15
Glucose (mg dL−1)
Control	140 ± 7.2	175 ± 9.8	191 ± 7.7	176 ± 5.9
Cranberry	137 ± 5.3	151 ± 8.0	161 ± 8.7*	152 ± 8.5*
Insulin (mU L−1)
Control	11.6 ± 0.87	31.0 ± 3.7	33.0 ± 3.6	23.0 ± 1.9
Cranberry	12.1 ± 0.93	35.5 ± 5.7	36.0 ± 4.0	24.8 ± 2.5
HOMA-IR
Control	3.9 ± 0.29	12.6 ± 1.5	14.7 ± 1.4	9.7 ± 0.7
Cranberry	4.1 ± 0.40	13.1 ± 2.0	13.5 ± 1.8	8.9 ± 0.9
Systolic blood pressure (mmHg)
Control	138 ± 3	141 ± 3	139 ± 5	142 ± 3
Cranberry	131 ± 4	135 ± 4	130 ± 4	131 ± 4
Diastolic blood pressure (mmHg)
Control	90 ± 4	87 ± 4	91 ± 3	89 ± 5
Cranberry	85 ± 5	78 ± 5	86 ± 6	82 ± 7
Small artery elasticity index (ml mmHg−1)
Control	6.5 ± 2.1	5.8 ± 2.2	6.8 ± 2.0	7.7 ± 3.1
Cranberry	5.7 ± 1.5	5.1 ± 1.8	6.4 ± 1.6	5.9 ± 2.5
Large artery elasticity index (ml mmHg−1)
Control	18 ± 5	23 ± 6	26 ± 5	28 ± 4
Cranberry	21 ± 3	19 ± 4	23 ± 3	21 ± 5

^*p value <0.05 vs. control. Values represented as means ± SE. P values obtained from repeated measures ANOVA. HOMA-IR: homeostasis model assessment of insulin resistance; h: hour.

3.3. Postprandial blood pressure and vascular measures

Among the measures of blood pressure and vascular compliance, systolic and diastolic blood pressure and small and large artery elasticity indices did not differ significantly between the cranberry and control phases of intervention (Table 3).

3.4. Postprandial serum markers of inflammation and oxidation

As shown in Table 4, among the biomarkers of inflammation and lipid oxidation, serum IL-18 and MDA were significantly lower at 4 hours (p < 0.05), and MDA tended to be lower at 2 hours following cranberry vs. control intervention (p < 0.1). Serum nitrite was significantly higher at 2 hours (p < 0.05) and tended to be higher at 4 hours (p < 0.1) in the cranberry vs. control phase. We observed no significant differences in postprandial levels of hs-CRP and IL-6 between the two phases (Table 4).

Table 4.

Postprandial measures of serum inflammatory markers and lipid peroxidation in patients with type 2 diabetes fed with a high-fat breakfast with and without dried whole cranberries in a randomized crossover study (n = 25)

Variable	Fasting	1 h	2 h	4 h
hs-CRP (mg L−1)
Control	4.7 ± 0.6	3.8 ± 0.5	3.6 ± 0.4	4.6 ± 0.4
Cranberry	4.9 ± 1.2	5.9 ± 1.2	3.5 ± 1.1	4.2 ± 1.3
IL-6 (pg mL−1)
Control	22.5 ± 1.2	28.7 ± 1.0	31.8 ± 1.1	34.7 ± 1.2
Cranberry	20.6 ± 1.4	22.4 ± 6.2	27.1 ± 6.9	28.2 ± 6.8
IL-18 (pg mL−1)
Control	333.4 ± 10.7	360.0 ± 10.3	347.8 ± 10.2	341.7 ± 12.7
Cranberry	327.7 ± 10.8	333.2 ± 12.5	325.2 ± 11.9	308.2 ± 11.2*
Nitrite (µM)
Control	6.6 ± 0.9	6.5 ± 0.9	5.2 ± 0.7	6.0 ± 0.7
Cranberry	6.8 ± 1.1	7.0 ± 2.2	8.4 ± 2.6*	8.0 ± 2.4#
MDA & HNE (µM)
Control	3.6 ± 1.2	3.8 ± 1.0	3.0 ± 0.8	3.3 ± 1.1
Cranberry	4.3 ± 1.1	3.5 ± 1.3	2.2 ± 0.7#	1.6 ± 0.8*

^*p value <0.05 vs. control.

^#p value <0.1 vs. control. Values represented as means ± SE. P-Values obtained from repeated measures ANOVA. Hs-CRP: high sensitivity C-reactive protein; IL-6: interleukin-6; IL-18: interleukin-18; MDA & HNE: malondialdehyde and hydroxynonenal; h: hour.

4. Discussion

To our knowledge, this is the first report assessing the postprandial effects of whole cranberries in the presence of a high-fat breakfast challenge in obese adults with type 2 diabetes. In our study, dried low calorie cranberries were shown to improve high-fat meal challenge-induced postprandial glycemia, and inflammation and lipid peroxidation in diabetes. Cranberries on the other hand had no effects on postprandial insulin and lipid levels, as well as blood pressure and arterial elasticity. The dose of cranberries administered in our study is of practical importance as this amount can be easily incorporated into a daily diet and was observed to be consumed by our participants without any discomfort at one sitting.

The role of dietary berries in improving postprandial hyperglycemia, hypertriglyceridemia, oxidative stress and inflammation has been reported by previous studies using a mixture of different berries, or individual berry fruits and juices, such as blueberries, cranberries and strawberries.^{9,12,20,21,25,26} Among these studies, only a few address postprandial metabolism in diabetes,^20,21 or involve a meal challenge in examining the counteracting effects of berries in adults with cardiovascular risks.^9,25 We observed a generally lower postprandial glucose response in the cranberry phase which reached significance at 2 and 4 hours when compared to the no cranberry or control phase. Wilson et al. have previously reported the effects of different cranberry products, especially reduced calorie sweetened dried cranberries and raw cranberries, as well as reduced calorie cranberry juice in improving postprandial glycemic and insulinemic responses in participants with type 2 diabetes.^20,21 In our study, using a similar dose and participant characteristics with diabetes as previously reported by Wilson et al. we report the effects of cranberries in reducing postprandial hyperglycemia following a high-fat meal challenge. These findings are also in agreement with some long-term studies demonstrating the effects of cranberry juice in lowering fasting glucose and improving insulin resistance in healthy but overweight adults,²⁷ and in those with diabetes.¹⁸ The role of cranberries in glucoregulation has been explained by mechanistic studies showing the effects of proanthocyanidins, the principal cranberry polyphenols in inhibiting carbohydrate digestive enzymes and improving cellular glucose uptake and metabolism,²⁸ as well as inhibiting intestinal glucose transporters by berry extracts and thus reducing the uptake of glucose in the circulation.²⁹

The carbohydrate content of cranberries deserves attention in explaining the lower postprandial glucose levels observed in our study. Based on our nutritional analyses, of the 30 g total carbohydrate in cranberries, only 12 g was digestible carbohydrate, the remainder consisting of indigestible carbohydrates such as 10 g fiber, 7 g polydextrose and 1 g organic acids. Thus the cranberry test meal contained about 27% less digestible carbohydrate than the control meal (37 vs. 50.5 g) which likely accounts for about half of the reduction in glycemic response. This together with the 8 g soluble fiber and the polyphenols they contain may explain the effects of cranberries in suppressing the postprandial increase of blood glucose in comparison with the control meal observed in our diabetic participants.

We did not observe the effects of cranberries on postprandial lipids and blood pressure at any time point. These could be explained by the postprandial design and optimal lipid profiles of our study participants, as well as the high-fat meal challenge, which might mask or blunt the effects of cranberries on these metabolic and vascular variables. There are a few long-term studies that have shown the effects of cranberry juice in lowering blood pressure and improving lipid profiles in otherwise healthy participants,^27,30 and in those with diabetes,¹⁸ though results have been largely inconsistent. Keeping in view the magnitude of postprandial hyperglycemia in atherosclerotic conditions in diabetes, our data deserve further investigation in larger trials.

High-fat meal has been shown to induce postprandial inflammation, oxidative stress and endothelial activation, and only a few studies have shown their reversal with berries but not in the context of diabetes.^9,25,26 Among the inflammatory biomarkers, CRP, IL-6 and IL-18 have been shown to be modulated by meal composition, and have been significantly associated with insulin resistance and diabetes, as well as coronary events in adults.^31,32 In a recently reported systematic review on the magnitude of changes in inflammatory markers in healthy adults, researchers examined five most commonly measured inflammatory markers in postprandial studies as follows: CRP, IL-6, −1β, −8 and tumor necrosis factor (TNF)-α. Among these five biomarkers, the review highlights IL-6 to be the most responsive to postprandial meal composition in healthy participants.³³ However, postprandial studies on inflammation based on high-fat meals are lacking in adults with diabetes, and hence the scientific consensus on the selection of inflammatory biomarkers in this population. In our study in diabetic adults, though CRP levels were quite similar between cranberry and control phases at each postprandial time point, IL-6 remained lower in the cranberry phase vs. controls though it did not reach significance. IL-18 is a pro-inflammatory cytokine and epidemiological studies reveal significant associations of IL-18 with postprandial glucose control and energy metabolism in adults with type 2 diabetes.³¹ Consequently, in our study IL-18 was found to be the most responsive to the high-fat meal with cranberries vs. the control meal. These findings deserve further investigation in the postprandial studies of diabetes in response to the meal composition with different bioactive compounds, such as dietary berries.

We also observed the effects of cranberries in increasing postprandial serum nitrite and decreasing serum MDA vs. the control phase. While feeding studies have reported the effects of dietary blueberries, cranberries and strawberries in reducing postprandial oxidative stress and improving the plasma antioxidant capacity,^9,34–36 few of these studies have examined their effects on the markers of inflammation. In a postprandial study using a high-carbohydrate/fat meal, strawberry beverage showed no differences in IL-6 and CRP, but significantly decreased postprandial increases in IL-1β and a pro-thrombotic factor plasminogen activator inhibitor-1 (PAI-1) in over-weight adults.²⁵ In another postprandial study using a moderately high-fat breakfast with two different doses of blueberries, IL-1β and IL-6 production was suppressed by blueberries in ex vivo treated blood samples with lipoprotein lipase.²⁶ Thus, reported data on the role of berries in postprandial inflammation are limited and conflicting. We also observed an increase in serum nitrite at 2 and 4 hours in the cranberry phase, which is in agreement with some previous studies showing the effects of polyphenols in increasing circulating nitric oxide.³⁷ The postprandial decrease in MDA, a marker of lipid peroxidation is in agreement with our previous studies showing decreases in lipid peroxidation following interventions with cranberry juice, blueberries and strawberries.^35,38,39 MDA is a stable end product of lipid peroxidation that has been shown to be elevated in diabetes, and is a commonly measured biomarker of oxidative stress.^40,41 Thus, future studies must further evaluate the effects of dietary bioactive compounds on postprandial MDA levels in diabetes.

The limitations of our study include a small sample size, and the absence of non-diabetic controls as well as dose response effects of different cranberry products on the biomarkers of postprandial metabolism that must be considered in future studies. Though we measured biomarkers that have been shown to be modulated by berries in previous studies, there are other key biomarkers, such as IL-1β and TNF-α related to inflammation, carotenoids and glutathione related to antioxidant status,⁴² and of hormonal control such as C-peptide reflecting beta cell function that regulate postprandial metabolism⁴³ that were not examined in our study, and must be investigated in future studies of dietary berry intervention. Furthermore, no formal adjustment was made for multiple testing and therefore, the results should be interpreted cautiously given the concern for an inflated Type I error rate beyond the nominal 0.05 alpha level. Overall, keeping in view the emerging evidence on the role of postprandial metabolism in cardiovascular risks and events, our data shed light on how cranberries can counteract the metabolic challenges of a high-fat meal at dietary achievable doses.

5. Conclusions

In a randomized crossover postprandial study, we demonstrate the effects of dried low calorie cranberries in improving postprandial hyperglycemia at multiple time points in adults with type 2 diabetes. In addition, cranberries were also shown to modulate selected but key markers of inflammation such as IL-18 and nitrite, as well as decrease lipid peroxidation in response to a high-fat meal challenge. These effects of cranberries on postprandial glycemia may be explained by carbohydrates, especially high fiber and lower amounts of digestible carbohydrates as well as the polyphenol composition of whole cranberries. Our results add to the limited available literature on the role of berry fruits in postprandial metabolism in diabetes. Based on our observations at dietary achievable doses of cranberries, these findings may support recommendations to add dried low calorie cranberries as means to control hyperglycemia in diabetes. Overall, cranberries as a rich source of polyphenols and fiber deserve further investigation in the management of diabetes which indeed is a public health problem of high costs and health complications.