Effects of an Apple Extract on Glycaemia: The GLU-Pomme Study

Study Overview
=================
Brief Summary
-----------------
Postprandial hyperglycaemia can lead to adverse modifications to functional proteins within the body and eventually lead to the development of type 2 diabetes. Previous research by this group has shown that an apple polyphenol extract reduced hyperglycaemia following a high-carbohydrate meal. The aim of this study is to investigate the effects of lower doses of the apple extract on postprandial glycaemia, insulinaemia and plasma gastric inhibitory polypeptide concentrations following a mixed carbohydrate test meal.

Detailed Description
-----------------
Introduction: Sharp peaks in blood glucose levels can lead to adverse modifications to functional proteins, oxidative stress and pancreatic beta cell dysfunction. It is therefore desirable to consume a diet that will allow more gradual rises in blood glucose levels after meals. Fruit polyphenols may help to limit the glucose excursion following a high carbohydrate meal. Previous research by this research group has demonstrated that 1200 mg of apple polyphenols (Appl'In™) inhibited the average incremental area under the curve (T+0 to T+30 min) of plasma glucose by 54% relative to placebo. Possible mechanisms include inhibition of intestinal enzymes and inhibition of intestinal glucose absorption by decreasing SGLT1/GLUT2 transport activity. The literature also suggests that foods rich in polyphenols exert beneficial effects on risk factors of cardiovascular disease such as hypertension, lipid metabolism and vascular function. Study design: A randomised, controlled, double-blind, cross-over study will be conducted. Four matched test drinks will be consumed in random order on separate study visits immediately before a mixed-carbohydrate test meal, containing either: 1) 1.2 g, 2) 0.9 g 3). 0.6 g of apple polyphenols, or 4). placebo. Postprandial changes in plasma glucose, insulin, NEFA, GIP, GLP-1 concentrations as well as changes in vascular function will be measured. Twenty-four hour urine samples will be collected for analysis of urinary polyphenol metabolites and glucose. In a sub sample of participants, a paracetamol absorption test will be incorporated via addition of 1.5 g paracetamol into the test drink.

Official Title
-----------------
Dose-response Effect of an Apple Extract on Postprandial Glycaemia: a Randomised Controlled Trial. The GLU-POMME Study.

Conditions
-----------------
Prevention of Hyperglycaemia

Intervention / Treatment
-----------------
* Dietary Supplement: Apple polyphenols
* Dietary Supplement: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age: 18-70 y Male and female Healthy (free of diagnosed diseases listed in the exclusion criteria) Body Mass Index 18-35 kg/m2 Able to understand the information sheet and willing to comply with study protocol Able to give informed written consent Exclusion Criteria: Those diagnosed with Phenylketonuria (PKU) Those with known or suspected food and/or paracetamol intolerances, allergies or hypersensitivity Women who are known to be pregnant or who are intending to become pregnant over the course of the study Women who are breast feeding Participation in another clinical trial Those who have donated blood within 3 months of the screening visit and participants for whom participation in this study would result in having donated more than 1500 millilitres of blood in the previous 12 months. Full Blood Counts and Liver Function test results outside of the normal range. Current smokers, or reported giving up smoking within the last 6 months History of substance abuse or alcoholism Reported history of Cardiovascular disease, diabetes (or fasting glucose ≥ 7.1 mmol/L), cancer, kidney, liver or bowel disease, gastrointestinal disorder or use of drug likely to alter gastrointestinal function Unwilling to restrict consumption of specified high polyphenol foods for 48 h before the study Weight change >3kg in preceding 2 months and body mass index <18 or >35 kg/m2 Blood pressure ≥160/100 mmHg Total cholesterol ≥ 7.5 mmol/L; fasting triacylglycerol concentrations ≥ 5.0 mmol/L Medications that may interfere with the study: alpha-glucosidase inhibitors (acarbose: Glucobay), insulin sensitizing drugs (metformin: Glucophage, Glucophage SR, Eucreas, Janumet; thiazolidinediones: Actos, Competact), sulfonylureas (Daonil, Diamicron, Diamicron MR, Glibenese, Minodiab, Amaryl Tolbutamide), and lipid lowering drugs (statins, nicotinic acid, colestyramine anhydrous, ezetimibe, fibrates); and medications that may react unpredictably with paracetamol: ketoconazole, metoclopramide, carbamazepine, phenobarbital, phenytoin, primidone, warfarin and other products containing paracetamol. Other medications should be reviewed by medical representative from KCL on a case by case basis. Nutritional supplements that may interfere with the study: higher dose vitamins/minerals (>200% Recommend Nutrient Intake), B vitamins, Vitamin C, calcium, copper, chromium, iodine, iron, magnesium, manganese, phosphorus, potassium and zinc. Subjects already taking vitamin or minerals at a dose around 100% or less up to 200% of the RNI, or evening primrose/algal/fish oil supplements will be asked to maintain habitual intake patterns, ensuring that they take them every day and not sporadically. They will be advised not to stop taking supplements or start taking new supplements during the course of the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.2 g apple polyphenols<br>1200 mg apple polyphenols delivered in a low sugar drink. | Dietary Supplement: Apple polyphenols<br>* Drinks will be delivered in random order at 4 separate study visits immediately before a high-carbohydrate meal. Seven days wash-out period will be required between study days.<br>|
| Experimental: 0.9 g apple polyphenols<br>900 mg apple polyphenols delivered in a low sugar drink. | Dietary Supplement: Apple polyphenols<br>* Drinks will be delivered in random order at 4 separate study visits immediately before a high-carbohydrate meal. Seven days wash-out period will be required between study days.<br>|
| Experimental: 0.6 g apple polyphenols<br>600 mg apple polyphenols delivered in a low sugar drink. | Dietary Supplement: Apple polyphenols<br>* Drinks will be delivered in random order at 4 separate study visits immediately before a high-carbohydrate meal. Seven days wash-out period will be required between study days.<br>|
| Placebo Comparator: Placebo<br>No polyphenols delivered in a low sugar drink. | Dietary Supplement: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postprandial Glycaemia | Primary outcome: Area over baseline t+0-30 min for plasma glucose | 30 min following the test drink | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postprandial Insulinaemia | Peak postprandial insulin concentrations (Cmax) t +0-30 min and change from baseline data and areas over baseline t+0-30 min and t+0-240 min. | baseline and 10, 20, 30, 45, 60, 75, 90, 120, 150, 180, 240 min following the test drink | 
| Postprandial Glucose-dependent Insulinotropic Polypeptide (GIP) Concentrations | Peak postprandial GIP concentrations (Cmax) t +0-30 min and change from baseline data and areas over baseline t+0-30 min and t+0-240 min. | baseline and 10, 20, 30, 45, 60, 75, 90, 120, 150, 180, 240 min following the test drink | 
| Postprandial Glucagon-like Peptide-1 (GLP-1) Concentrations | Peak postprandial GLP-1 concentrations (Cmax) t +0-30 min and change from baseline data and areas over baseline t+0-30 min and t+0-240 min. | baseline and 10, 20, 30, 45, 60, 75, 90, 120, 150, 180, 240 min following the test drink | 
| Postprandial C-peptide Concentrations | Peak postprandial C-peptide concentrations (Cmax) t +0-30 min and change from baseline data and areas over baseline t+0-30 min and t+0-240 min. | baseline and 10, 20, 30, 45, 60, 75, 90, 120, 150, 180, 240 min following the test drink | 
| Postprandial Non-esterified Fatty Acid (NEFA) Concentrations | Peak postprandial NEFA concentrations (Cmax) t +0-30 min and change from baseline data and areas over baseline t+0-30 min and t+0-240 min | baseline and 10, 20, 30, 45, 60, 75, 90, 120, 150, 180, 240 min following the test drink | 
| Postprandial Triglyceride (TAG) Concentrations | Peak postprandial TAG concentrations (Cmax) t +0-30 min and change from baseline data and areas over baseline t+0-30 min and t+0-240 min. | baseline and 10, 20, 30, 45, 60, 75, 90, 120, 150, 180, 240 min following the test drink | 
| Postprandial Paracetamol Concentrations | Peak postprandial paracetamol concentrations (Cmax) t +0-30 min and change from baseline data and areas over baseline t+0-30 min and t+0-240 min (1.5 g paracetamol will be added to all test drinks in a sub-group of participants). | baseline and 10, 20, 30, 45, 60, 75, 90, 120, 150, 180, 240 min following the test drink | 
| Postprandial Polyphenol Metabolite Concentrations | Peak postprandial polyphenol metabolites concentrations (Cmax) t +0-30 min and change from baseline data and areas over baseline t+0-30 min and t+0-240 min. | baseline and 10, 20, 30, 45, 60, 75, 90, 120, 150, 180, 240 min following the test drink | 
| Vascular Endothelial Function by Flow-mediated Dilation (FMD) | Change in FMD after the consumption of test drink. | baseline and 120, 240, 300 min following the test drink | 
| Vascular Function (Arteriograph Measurement) | Change in augmentation index following the test drink. | Baseline and 60, 90, 120, 180, 240 min following the test drink | 
| Blood Pressure | Change in blood pressure following the test drink. | Baseline and 60, 90, 120, 180, 240 min following the test drink | 
| Urinary Polyphenol Metabolites | Change in urinary polyphenol metabolite concentration following the test drink. | 0-4 h, 4-8 h, 8-24 h following the test drink | 
| Urinary Glucose | Change in urinary glucose concentration following the test drink. | 0-4 h, 4-8 h, 8-24 h following the test drink | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Polyphenol, Apple, Fruit, Hyperglycaemia, Metabolic