Effect of resveratrol on insulin sensitivity and metabolic profile in type 2 diabetics

There is now a general consensus that the combination of excessive energy
intake and a low capacity to oxidize fat will lead to muscular fat accumulation
and insulin resistance. It is known for many years that physical activity and
diet therapy are the most powerful treatment to combat obesity and insulin
resistance, but it is also known that it is difficult to get people to exercise
and follow diets. A major breakthrough in this field has come from the
nutrition field, with the finding that resveratrol, a natural polyphenolic
compound, could serve as an *calory restriction mimetic*, as a recent study of
S. Timmers et al. in Cell metabolims (2011) showed that resveratrol mimiced the
effect of caloric restriction in healthy obese man (lowering liver fat
accumulation and increasing fat oxidation, thereby improving metabolic health
in these subjects). These findings were similar to those found earlier in
animal studies, where it was found that resveratrol protected mice from many
detrimental effects of diet-induced obesity. Therefore we would like to
investigate if resveratrol has the same effects in obese humans with type 2
diabetes as it does in healthy obese man.
This information can then be used to develop new treatment for obesity and type
2 diabetes. Therefore, we would like to investigate whether ResvidaTM can
increase mitochondrial number together with an increased intrinsic activity and
whether this will lead to a better insulin sensitivity in type 2 diabetic
patients.

To examine whether resveratrol supplementation in type 2 diabetic patients
improves overall and muscle-specific insulin sensitivity by affecting
mitochondrial fat oxidative capacity. Furthermore, we are interested is this
also affects liver and muscle fat storage.

24 obese (BMI 27-35 kg/m2) male subjects with type 2 diabetes, aged between 40
and 70 years, who are not engaged in regular programmed exercise are included
in a randomized, double blind cross over design. Each subject will participate
in two interventions, in random order, and separated by a wash-out period of at
least 4 weeks. Each intervention includes a 30 days (4 week) suppelementation
with resveratrol or placebo. Before the start of the study, subjects will be
screened to assess elegibility., which will include a medical questionnaire, a
measurement of body weight and composition (DEXA scan) to determine fat
content, and drawing of a fasted blood sample. On day 0, subjects will come to
the university for withdrawal of a fasted blood sample and a measurement of
body weight. Hereafter, heart rate and blood pressure will be checked and an
ECG will be made by an experienced physician. Thereafter, subjects can go home
and they will receive enough capsules for the first week of the intervention.
Additional blood samples will be drawn on a weekly basis as well as
measurements of body weight (day 7, 14, 21). During these weekly visits,
subjects will receive enough capsules for the next week. On day 27, subjects
will report to the university for a maximal aerobic capacity test under the
supervision of a physician. An ECG will be made during the cycling test. On day
29, hart function will be measured by echocardiography, and in vivo
mitochondrial function and liver fat content will be measured with MR
spectroscopy. Thereafter, subjects will stay in the respiration chamber for 12
hours (evening day 29 and night day 29) during which their energy expenditure
and fat oxidation will be measured. On day 30 in the morning, subjects will
leave the respiration chamber, and a fasting blood sample will be drawn. An ECG
will be made and blood pressure and heart rate will be measured. Then, fat
content in the heart will be measured by MR spectroscopy and a muscle biopsy
will be taken. Hereafter, the insulin sensitivity measurement will be started
to determine overall and muscle and liver specific insulin sensitivity. After
the test, a second muscle biopsy will be taken.

Subjects will be asked to take two pills of resveratrol 75 mg, or placebo,
twice daily (lunch and diner), for 30 days, which will be randomized.
Resveratrol (resvidaTM) is a food supplement and is regulated in the body as a
food component. ResvidaTM and placebo are provided by DSM Nutritional Products
Ltd. For the resveratrol product, the maximal approved daily dose in humans is
150 mg/day. For higher doses the safety concerns are not yet investigated.
Therefore, we have chosen to supplement the subjects with a dose of 150 mg/day
spread out over two doses of 75 mg twice a day with lunch and diner.

Before the start of the study, subjects will be screened to access eligibility
which will include a medical questionnaire, measurement of body weight and body
composition (DEXA scan). A fasted bloodsample will also be drawn (duration: 1
hour). Thereafter, they will be randomized and undergo two intervention periods
of 30 days separated by a wash-out period of at least 4 weeks. The subjects
will come to the University 6 times (day 0, 7, 14, 21, 27, 29). During these
visits at the University, a bloodsample will be taken weekly as well as a
weekly measurement of body weight (day 0, 7, 14, 21), a maximal aerobic
capacity test will be performed (day 27) and heart function will be measured by
echocardiography, in vivo mitochondrial function and liver fat content will be
measured with MRS (day 29). In addition, subjects will stay in the respiration
chamber for 12 hours (1 evening and night) (day 29-30) after which the fat
content of the heart will be measured by MR spectroscopy (day 30), and a muscle
biopsy will be taken (day 30). Hereafter, the insulin sensitivity test will be
started (day 30). After this test is finished, a second muscle biopsy will be
taken (day 30).