Type 2 Diabetes
Conditions
Keywords
anthocyanin, blaeberries, bilberries, blueberries, mirtoselect, glucose AUC
Brief summary
Dietary strategies for alleviating health complications associated with type 2 diabetes (T2D) are being pursued as alternatives to pharmaceutical interventions. Berries such as bilberries that are rich in polyphenols may influence carbohydrate digestion and absorption and thus postprandial glycaemia. In addition berries have been reported to alter incretins as well as to have anti-oxidant and anti-inflammatory properties that may also affect postprandial glycaemia. This study investigated the acute affect of a standardised bilberry extract on glucose metabolism in T2D. Eight male volunteers with T2D controlling their diabetes by diet and lifestyle alone were given a single oral capsule of either 0.47g standardized bilberry extract (36% (w/w) anthocyanins) which equates to ∼50 g of fresh bilberries or placebo followed by a polysaccharide drink (equivalent to 75 g glucose) in a double blinded cross over intervention with a two week washout period. This study demonstrates that the ingestion of a concentrated bilberry extract reduces postprandial glycaemia and insulin in volunteers with T2D. The most likely mechanism for the lower glycaemic response involves reduced rates of carbohydrate digestion and/or absorption.
Detailed description
Dietary strategies for alleviating health complications, such as premature vascular disease, associated with type 2 diabetes (T2D) and obesity are actively being pursued as alternatives to pharmaceutical interventions. The genus Vaccinium (e.g. blueberry, bilberry, cranberry) has been used traditionally as a source of folk remedies for established diabetic symptoms. Berries from this genus are enriched in anthocyanins, polyphenols recognized for their ability to provide and activate cellular antioxidant protection and inhibit inflammatory gene expression, activities that may contribute to the efficacy of the Vaccinium genus as ameliorators for type 2 diabetes. Consumption of a freeze-dried blueberry beverage for an 8 week period for example decreased plasma concentrations of the cardiovascular risk factors oxidized LDL, malondialdehyde and hydroxynonenal. In another trial, bioactives from blueberries improved insulin sensitivity in obese insulin-resistant men and women. In both these studies the investigators reported no change in inflammatory markers following supplementation although bilberry juice was shown to modulate plasma markers of inflammation C-reactive protein and IL-6 in subjects with increased risk of cardiovascular disease. These beneficial responses from human studies are supported by data that demonstrate long-term beneficial effects of anthocyanins from mouse models of obesity and diabetes. There are also a number of studies in vitro and in vivo that suggest that polyphenols influence carbohydrate digestion and absorption, resulting in improved postprandial glycaemia in the short term. Polyphenols inhibit intestinal alpha glucosidase activity and glucose transport in vitro. In association with this, polyphenols administered to rodents suppress the elevation of blood glucose concentration after oral administration of mono- and di-saccharides. In humans, several studies have examined the effect of polyphenols on the post-prandial glycaemic response. In one study a test meal of mixed berry purée with sucrose showed a lower plasma glucose concentration after 15-30 min compared with a control matched for sugars. Overall, evidence suggests that consuming edible berries, particularly from the genus Vaccinium, that have high concentrations of anthocyanins could provide a supplementary intervention to improve glycaemia in subjects with T2D or impaired glucose tolerance. The object of this study was to investigate whether a single supplementation with a standardised (36% w/w anthocyanins) concentrated bilberry extract could alter glucose metabolism in overweight/obese volunteers with impaired glucose intolerance or T2D compared with a control capsule matched for sugars and to explore the possible mechanisms of action.
Interventions
DIETARY_SUPPLEMENTBilberry capsule first, then control cap
Male subjects aged \>40 and \<70 years, with type 2 diabetes controlling their diabetes by diet alone closely matched for adiposity as determined by waist circumference (n=8). Volunteers will be randomised double blinded into two groups (n=4 per group) and given a single capsule of either 0.47 grams of a bilberry extract (mirtoselect provided by Indena S.p.A (http://www.mirtoselect.info/) or a control capsule. Following a two week wash out period the volunteers will be asked to take a second single capsule of either of 0.47 grams of mirtoselect or a control capsule in a cross over study, the opposite of what they took the first time.
DIETARY_SUPPLEMENTControl capsule first then bilberry cap
Male subjects aged \>40 and \<70 years, with type 2 diabetes controlling their diabetes by diet alone closely matched for adiposity as determined by waist circumference (n=8). Volunteers will be randomised double blinded into two groups (n=4 per group) and given a single capsule of either 0.47 grams of a bilberry extract (mirtoselect provided by Indena S.p.A (http://www.mirtoselect.info/) or a control capsule. Following a two week wash out period the volunteers will be asked to take a second single capsule of either of 0.47 grams of mirtoselect or a control capsule in a cross over study, the opposite of what they took the first time.
Sponsors
University of Aberdeen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
40 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male subjects * Aged \>40 and \<70 * Clinical diagnosis of Type 2 diabetes controlling their diabetes by diet alone * All subjects must live in the Aberdeenshire area of Scotland
Exclusion criteria
* Medical
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Glucose iAUC (Incremental Area Under the Curve; mM*Min) | Plasma was collected at -15, -10 and -5 (fasted) and at 15, 30, 45, 60, 90, 120, 150 and 300 min post capsule | Volunteers were fasted (10-12 h) overnight before the OGTT. Venous blood samples were taken through an indwelling cannula inserted into a forearm vein at -15, -10 and -5 (fasted) and at 15, 30, 45, 60, 90, 120, 150 and 300 min after consuming 75 g of Polycal liquid (carbohydrate, 61·9%; polysaccharide, 49·2 %; sugars, 12·2%; glucose, 0·6%; maltose, 11·6%; http://www. nutricia.co.uk). Polycal was selected as the main carbohydrate as it is in the form of polysaccharides and this is closer to normal dietary consumption than glucose only.The volunteers consumed the appropriate capsule (0 min), glucose load and a further sample of water (70 ml) within 3 min. For those volunteers taking the control capsule, additional sugar (fructose and dextrose/glucose) was added double-blinded to the water to match the free sugar content of the Mirtoselect® capsules. Movement during the 300 min OGTT was kept to a minimum. |
| Plasma Insulin iAUC (Incremental Area Under the Curve; ng/ml*Min) | Plasma was collected at -15, -10 and -5 (fasted) and at 15, 30, 45, 60, 90, 120, 150 and 300 min after the capsule | Volunteers were fasted (10-12 h) overnight before the OGTT. Venous blood samples were taken through an indwelling cannula inserted into a forearm vein at -15, -10 and -5 (fasted) and at 15, 30, 45, 60, 90, 120, 150 and 300 min after consuming 75 g of Polycal liquid (carbohydrate, 61•9%; polysaccharide, 49•2 %; sugars, 12•2%; glucose, 0•6%; maltose, 11•6%; http://www. nutricia.co.uk). Polycal was selected as the main carbohydrate as it is in the form of polysaccharides and this is closer to normal dietary consumption than glucose only.The volunteers consumed the appropriate capsule (0 min), glucose load and a further sample of water (70 ml) within 3 min. For those volunteers taking the control capsule, additional sugar (fructose and dextrose/glucose) was added double-blinded to the water to match the free sugar content of the Mirtoselect® capsules. Movement during the 300 min OGTT was kept to a minimum. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bioavailability in Plasma | Plasma will also be collected -15,-10, -5, 15, 30, 45, 60, 90, 120, 150, and 300 minutes and 24 hours post intervention | To measure the amount of anthocyanins and phenolic-derived metabolites by liquid chromatography mass spectrometry (LC-MS) being absorbed from the gut and excreted following the single intervention. |
| Bioavailability in Urine | Urine will also be collected (if possible) 0, 1, 3 and 5 hours, with all urine collected within the 24 hour time period post intervention | To measure the amount of anthocyanins and phenolic-derived metabolites by liquid chromatography mass spectrometry (LC-MS) being absorbed from the gut and excreted following the single intervention. |
Countries
United Kingdom
Participant flow
Recruitment details
Eight male volunteer subjects with T2D controlled by diet and lifestyle alone or with impaired glucose tolerance were recruited from the Aberdeen area of the UK. Subjects were only included if they were not on any special religious or prescribed diet and had a stable weight.
Participants by arm
| Arm | Count |
|---|---|
| Bilberry Capsule First, Then Control Capsule In a cross-over design, eight volunteers were randomised and double-blinded into two groups matched for BMI as well as age and given a single capsule of either 0·47 g of Mirtoselect® (a standardised bilberry extract (36 % (w/w) anthocyanins)) which equates to about 50 g of fresh bilberries formulated in gelatin capsules or a control capsule consisting of microcrystalline cellulose in an opaque gelatin capsule, followed by oral glucose tolerance testing (OGTT). The reverse procedure was conducted following a 2-week washout period. The volunteers were asked to consume a low-phytochemical diet 3 d before taking the capsule and for the 24 h after taking the capsule on both occasions. In addition the volunteers were asked to record what they ate over the same period in a food diary to ensure that they adhered to the low-phytochemical diet. Subjects were reimbursed travelling expenses on completion of the study. | 4 |
| Control Capsule First, Then Bilberry Capsule In a cross-over design, eight volunteers were randomised and double-blinded into two groups matched for BMI as well as age and given a single capsule of either 0·47 g of Mirtoselect® (a standardised bilberry extract (36 % (w/w) anthocyanins)) which equates to about 50 g of fresh bilberries formulated in gelatin capsules or a control capsule consisting of microcrystalline cellulose in an opaque gelatin capsule, followed by oral glucose tolerance testing (OGTT). The reverse procedure was conducted following a 2-week washout period. The volunteers were asked to consume a low-phytochemical diet 3 d before taking the capsule and for the 24 h after taking the capsule on both occasions. In addition the volunteers were asked to record what they ate over the same period in a food diary to ensure that they adhered to the low-phytochemical diet. Subjects were reimbursed travelling expenses on completion of the study. | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | Bilberry Capsule First, Then Control Capsule | Control Capsule First, Then Bilberry Capsule | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Continuous | 62 years STANDARD_DEVIATION 5 | 62 years STANDARD_DEVIATION 5 | 62 years STANDARD_DEVIATION 5 |
| BMI | 30 Kg/m2 STANDARD_DEVIATION 4 | 30 Kg/m2 STANDARD_DEVIATION 4 | 30 Kg/m2 STANDARD_DEVIATION 4 |
| Region of Enrollment United Kingdom | 4 participants | 4 participants | 8 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Plasma Glucose iAUC (Incremental Area Under the Curve; mM*Min)
Volunteers were fasted (10-12 h) overnight before the OGTT. Venous blood samples were taken through an indwelling cannula inserted into a forearm vein at -15, -10 and -5 (fasted) and at 15, 30, 45, 60, 90, 120, 150 and 300 min after consuming 75 g of Polycal liquid (carbohydrate, 61·9%; polysaccharide, 49·2 %; sugars, 12·2%; glucose, 0·6%; maltose, 11·6%; http://www. nutricia.co.uk). Polycal was selected as the main carbohydrate as it is in the form of polysaccharides and this is closer to normal dietary consumption than glucose only.The volunteers consumed the appropriate capsule (0 min), glucose load and a further sample of water (70 ml) within 3 min. For those volunteers taking the control capsule, additional sugar (fructose and dextrose/glucose) was added double-blinded to the water to match the free sugar content of the Mirtoselect® capsules. Movement during the 300 min OGTT was kept to a minimum.
Time frame: Plasma was collected at -15, -10 and -5 (fasted) and at 15, 30, 45, 60, 90, 120, 150 and 300 min post capsule
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Placebo Capsule | Plasma Glucose iAUC (Incremental Area Under the Curve; mM*Min) | 836 glucose iAUC (mM*min) | Standard Error 97 |
| Single Blaeberry Capsule | Plasma Glucose iAUC (Incremental Area Under the Curve; mM*Min) | 693 glucose iAUC (mM*min) | Standard Error 103 |
p-value: 0.003t-test, 2 sided
Primary
Plasma Insulin iAUC (Incremental Area Under the Curve; ng/ml*Min)
Volunteers were fasted (10-12 h) overnight before the OGTT. Venous blood samples were taken through an indwelling cannula inserted into a forearm vein at -15, -10 and -5 (fasted) and at 15, 30, 45, 60, 90, 120, 150 and 300 min after consuming 75 g of Polycal liquid (carbohydrate, 61•9%; polysaccharide, 49•2 %; sugars, 12•2%; glucose, 0•6%; maltose, 11•6%; http://www. nutricia.co.uk). Polycal was selected as the main carbohydrate as it is in the form of polysaccharides and this is closer to normal dietary consumption than glucose only.The volunteers consumed the appropriate capsule (0 min), glucose load and a further sample of water (70 ml) within 3 min. For those volunteers taking the control capsule, additional sugar (fructose and dextrose/glucose) was added double-blinded to the water to match the free sugar content of the Mirtoselect® capsules. Movement during the 300 min OGTT was kept to a minimum.
Time frame: Plasma was collected at -15, -10 and -5 (fasted) and at 15, 30, 45, 60, 90, 120, 150 and 300 min after the capsule
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Placebo Capsule | Plasma Insulin iAUC (Incremental Area Under the Curve; ng/ml*Min) | 358 insulin iAUC (ng/ml*min) | Standard Error 131 |
| Single Blaeberry Capsule | Plasma Insulin iAUC (Incremental Area Under the Curve; ng/ml*Min) | 294 insulin iAUC (ng/ml*min) | Standard Error 113 |
p-value: 0.028t-test, 2 sided
Secondary
Bioavailability in Plasma
To measure the amount of anthocyanins and phenolic-derived metabolites by liquid chromatography mass spectrometry (LC-MS) being absorbed from the gut and excreted following the single intervention.
Time frame: Plasma will also be collected -15,-10, -5, 15, 30, 45, 60, 90, 120, 150, and 300 minutes and 24 hours post intervention
Secondary
Bioavailability in Urine
To measure the amount of anthocyanins and phenolic-derived metabolites by liquid chromatography mass spectrometry (LC-MS) being absorbed from the gut and excreted following the single intervention.
Time frame: Urine will also be collected (if possible) 0, 1, 3 and 5 hours, with all urine collected within the 24 hour time period post intervention