In this double-blind, randomized, placebo-controlled study, we aim to investigate the effects of a long-term supplementation on insulin sensitivity, mitochondrial function and substrate metabolism in healthy overweight men and women.

In each group, 21 subjects consume 100mg Resveratrol (RSV) and 150mg Epigallocatechin-gallate (EGCG), respectively Placebo capsules, twice daily over a period of 12 weeks. The subjects receive the capsules after the last pre-measurement and continue to take them throughout the post-measurements.

Before and after the supplementation period, we perform a hyperinsulinemic-euglycemic clamp with a glucose-tracer infusion to assess hepatic and systemic insulin sensitivity. Simultaneously, substrate oxidation is measured throughout the clamp by indirect calorimetry. Furthermore, we perform a high-fat mixed meal test, in which we collect blood and measure substrate oxidation during fasted and postprandial conditions. During the meal tests, extra plasma is collected at the start (t=-30) and the end (t=240), of which the supernatant is stored in light-protected tubes (EGCG is mixed 1:1 with an EGCG buffer) for analyzing polyphenol concentrations in the blood.

In the male subgroup (21 men), we additionally place each 2 microdialysis probes in the subcutaneous adipose tissue and the gastrocnemius in order to assess local lipolysis and blood flow by means of ethanol infusion.

Furthermore, a dexa-scan is performed to assess body composition and biopsies are taken under fasted conditions from the subcutaneous adipose tissue and the quadriceps femoralis muscle. These samples are stored at -80C. Part of the adipose tissue samples is collected to measure adipocyte size. Of the skeletal muscle biopsy, one part is directly buffered and used for the oxygraph to measure mitochondrial function.

At last, feces samples are collected before and after the intervention in order to assess energy content, microbial composition and short-chain fatty acid content.

Based on previous human studies in our and other departments, we hypothesize that after 12 weeks of the combined polyphenol supplementation, insulin sensitivity and mitochondrial function improve. Furthermore, based on results of a short-term study performed by our group, that demonstrated an increase in energy expenditure, a positive effect on the regulation of body composition might be expected.

Inclusion Criteria:

• Overweight men and women (BMI≥25kg/m2-39.9kg/m2),
• Aged 20-35 and 35-50 years
• Caucasian
• Normal fasting glucose (< 6.1 mmol/L) and normal postprandial glucose (2h-glucose <7.8 mm)
• Normal blood pressure (systolic blood pressure 100-140 mmHg, diastolic blood pressure 60-90 mmHg)
• Weight stable in last 3 months (± 2kg)

Exclusion Criteria:

• Women lactating, pregnant or (post) menopausal
• Regular smokers
• People with intensive fitness training, eg. athletes (≥ 3 per week ≥ 1 hour training)
• Habitual consumption of green tea (more than 1 cup per day) or products containing green tea extract
• Total caffeine consumption > 300 mg/day (1 can of cola or 2 cups of regular coffee or 2 cups of black tea or 1 cup of coffee and 1 cup of black tea or other combinations)
• Alcohol intake >20 g/day (2 glasses of beer or wine)
• Any dietary vitamins or dietary supplements
• Diabetes mellitus (defined as FPG ≥ 7.0 mmol/l and/or 2hPG ≥ 11.1 mmol/l)
• Serious pulmonary, cardiovascular, hepatic or renal disease
• History of cardiovascular disease
• All other relevant medical disorders that potentially interfere with this trial (e.g. history of gastro-intestinal, liver or thyroid disorders)
• Current use of medication interfering with study intervention or interfering with study endpoints/hypotheses (e.g. medication containing caffeine like analgesics, anorectics and analeptics)
• Not to be able to understand the study information
• Subjects on a special diet or vegetarian
• Blood donation 2 months prior to the study and during the study
• Participation in other studies
• Drug use
• Coagulation disorders (i.e. hemophilia (type A, B and C), von Willebrand disease, vitamin K deficiency, afibrinogenemia, disseminated intravascular coagulation and thrombosis)
• Use of anti-coagulant medication
• Acute or history of gastrointestinal diseases (Morbus Crohn, Colitis Ulcerosa)
• Intake of Antibiotics for the last 3 months