The Health Effects of Blueberry Anthocyanins in Metabolic Syndrome (the CIRCLES-study) (CIRCLES)

The Effects of Blueberry Anthocyanins on Insulin Resistance and Vascular, Lung and Cognitive Function in a Population With Metabolic Syndrome.

The purpose of this study is to determine the dose-dependent impact of 6 month freeze-dried blueberry powder intake on insulin sensitivity and resistance, cardiovascular disease risk factors, and lung and cognitive function in overweight and obese participants with metabolic syndrome. We will also examine acute post-prandial effects of blueberry intake (at baseline and at 6-months).

Study Overview

• Status: Completed
• Conditions: Insulin Resistance; Metabolic Syndrome X
• Intervention / Treatment: Other: Full dose blueberry; Other: Half dose blueberry; Other: Control

• Study Type: Interventional
• Enrollment (Anticipated): 144
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Addenbrooke's Hospital
  • Norfolk
    • Norwich, Norfolk, United Kingdom, NR4 7UY
      • Norfolk and Norwich University Hospital
    • Norwich, Norfolk, United Kingdom, NR4 7TJ
      • Norwich Medical School University of East Anglia
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Harvard School of Public Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 74 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and postmenopausal women (≥ 1 year since last menstruation)
• 50 to 75 years old
• BMI of ≥ 25 kg/m2
• 3 characteristics of metabolic syndrome i.e: Waist circumference ≥ 102 cm for men, ≥ 88 cm for women; Triglycerides ≥ 1.7 mmol/L (or drug treatment for elevated triglycerides); HDL-cholesterol < 1.0 mmol/L for men, < 1.3 mmol/L for women (or drug treatment for low HDL-cholesterol); Blood pressure ≥ 130 mm Hg systolic and/or ≥ 85 mm Hg diastolic blood pressure; Fasting blood glucose ≥ 5.56 mmol/L
• Successful biochemical, haematological and urinalysis assessment at screening

Exclusion Criteria:

• Current smokers, or ex-smokers ceasing < 6 months ago
• Existing or significant past medical history of vascular disease or medical conditions likely to affect the study measures
• Fructose intolerance or known allergies to the intervention treatments
• On therapeutic diets or having experienced substantial weight loss within 3 months of screening
• Taking flavonoid containing supplements (and unwilling to cease intake during, and 1 month preceding the trial)
• Planning on altering consumption of vitamin supplements / fish oil capsules during the course of the study.
• Prescribed hypoglycaemic, vasodilators or HRT medication.
• Unsatisfactory biochemical, haematological or urinary assessment at screening, or measures considered to be counter indicative for the study
• < 3 characteristics of the metabolic syndrome.

NB: REC approved NoSA granted to include those on anti-hypertensives (29JUL2014)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Full dose blueberry; 26g of freeze dried blueberry powder; equivalent to 2 portions of fresh blueberries per day. Frequency: 26g per day. Total duration: 6-month.	Other: Full dose blueberry; Full dose: 26g of freeze dried blueberry powder to be incorporated into the habitual diet. Dietary restrictions will be observed (i.e. avoidance of blueberry, and restricted intake of anthocyanin rich foods) for 21 days prior to the first assessment visit and throughout the study.
ACTIVE_COMPARATOR: Half dose blueberry; 26g of freeze dried powder; containing 13g of freeze dried blueberry powder and 13g of placebo comparator material; equivalent to 1 portion of fresh blueberries per day. Frequency: 26g per day. Total duration: 6-month.	Other: Half dose blueberry; Half dose: 26g of freeze dried powder (containing 13g of freeze dried blueberry powder and 13g of placebo comparator material) to be incorporated into the habitual diet. Dietary restrictions will be observed (i.e. avoidance of blueberry, and restricted intake of anthocyanin rich foods) for 21 days prior to the first assessment visit and throughout the study.
PLACEBO_COMPARATOR: Control; Matched control powder; matched for appearance, taste and sugar content. Frequency: 26g per day. Total duration: 6-month.	Other: Control; Control: 26g of placebo comparator material to be incorporated into the habitual diet. Dietary restrictions will be observed (i.e. avoidance of blueberry, and restricted intake of anthocyanin rich foods) for 21 days prior to the first assessment visit and throughout the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin resistance	Assessed, in the fasted state, via HOMA-IR calculation in all participants; indirect assessment.	Chronic (0 to 6 month)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin resistance	Assessed in a sub-group via hyperinsulinemic euglycaemic clamp.	Chronic (0 to 6 month)
Blood pressure and blood vessel regulation	Measurements taken of arterial stiffness, endothelial function and blood pressure.	Chronic (0 to 6 month)
Lung function	Assessed via standard spirometry techniques and biological assessment of exhaled samples.	Chronic (0 to 6 month)
Cognitive function	Assessed via a validated cognitive test battery.	Chronic (0 to 6 month)
Liver fat and blood flow assessment	Assessment via 3T MRI in a sub-group of participants.	Chronic (0 to 6 month)
Bio-availability	Flavonoid and metabolite levels will be assessed in blood and 24 hour urine samples.	Chronic (0 to 6 month)
Metabolite phenotype effects	The gut microbiome will be assessed from faecal sample collection and the impact on metabolism and of genotype, will be assessed via a targeted approach.	Chronic (0 to 6 month)
Acute +24 hour effect of single (26g) intervention intake, given with high fat challenge	Insulin resistance, lipaemia, vascular, cognitive and lung function measured pre- and post-intervention in combination with a high fat challenge in a sub-group of participants. Urine samples and blood samples (over a 24 hour period) will be taken for biomarker analysis.	Chronic (0 to 6 month)

Collaborators and Investigators

• Sponsor: University of East Anglia
• Collaborators: Harvard School of Public Health (HSPH)

Publications and helpful links

General Publications

• Curtis PJ, Berends L, van der Velpen V, Jennings A, Haag L, Chandra P, Kay CD, Rimm EB, Cassidy A. Blueberry anthocyanin intake attenuates the postprandial cardiometabolic effect of an energy-dense food challenge: Results from a double blind, randomized controlled trial in metabolic syndrome participants. Clin Nutr. 2022 Jan;41(1):165-176. doi: 10.1016/j.clnu.2021.11.030. Epub 2021 Nov 27.
• Curtis PJ, van der Velpen V, Berends L, Jennings A, Feelisch M, Umpleby AM, Evans M, Fernandez BO, Meiss MS, Minnion M, Potter J, Minihane AM, Kay CD, Rimm EB, Cassidy A. Blueberries improve biomarkers of cardiometabolic function in participants with metabolic syndrome-results from a 6-month, double-blind, randomized controlled trial. Am J Clin Nutr. 2019 Jun 1;109(6):1535-1545. doi: 10.1093/ajcn/nqy380. Erratum In: Am J Clin Nutr. 2019 Nov 1;110(5):1262.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (ACTUAL): November 7, 2016
• Study Completion (ACTUAL): November 7, 2016

Study Registration Dates

• First Submitted: January 10, 2014
• First Submitted That Met QC Criteria: January 10, 2014
• First Posted (ESTIMATE): January 14, 2014

Study Record Updates

• Last Update Posted (ACTUAL): September 29, 2017
• Last Update Submitted That Met QC Criteria: September 28, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Hyperinsulinism; Syndrome; Metabolic Syndrome; Insulin Resistance
• Other Study ID Numbers: R21478-C