Project 1:

Targeting mitochondrial function in pre-diabetic subjects: a role for SIRT1 activation by resveratrol?

It is well known that exercise and calorie restriction are the two most potent non-pharmacological therapies to improve metabolic health in humans, mainly through positive effects on mitochondrial metabolism. Unfortunately, these therapies do not receive widespread enthusiasm in the general population.. . .

This stresses the need for alternative therapies to improve mitochondrial function. Recently we showed that resveratrol – a natural compound and activator of the AMPK-SIRT1-PGC1a axis – has positive effects on mitochondrial metabolism and metabolic health in obese subjects. These first promising results urge the need for further studies in humans with compromised metabolic health. For example it will be of utmost importance to examine if people at risk for developing type 2 diabetes, such as first-degree relatives of type 2 diabetic patients (FDR) – who are characterized by lower mitochondrial function– benefit from resveratrol supplementation.

The aim of the current proposal is to investigate if resveratrol supplementation – both on short and longer term – can be beneficial in the prevention of type 2 diabetes. To this end we aim to supplement FDR subjects with resveratrol or placebo for 30 days– in a double-blind randomized cross over design – and examine metabolic health in great detail, including assessment of mitochondrial function and insulin sensitivity. The longer-term efficacy of resveratrol supplementation will be investigated in a placebo-controlled intervention trial in overweight subjects for a period of 6 months, with glucose homeostasis and substrate oxidation as major outcome parameters. Underlying mechanisms will be investigated in muscle biopsies and primary myotubes. We anticipate that the results of this project will provide further insight in the potential of resveratrol and SIRT1 activation in the prevention of type 2 diabetes mellitus.

This project is financed by a grant from the Dutch Diabetes Research Foundation (DFN)
PhD-student: Marlies de Ligt
Collaborators: Prof. Dr. Johan Auwerx, EPFL Lausanne, Switzerland