The Effect of Lowered Physical Activity on Insulin Sensitivity and Lipid and Glucose Metabolism

The purpose of this study is to investigate the effects of lowered physical activity (resulting in decreased muscle mitochondrial oxidative capacity) alone and together with increased plasma free fatty acid availability (by infusion of a clinically widely used lipid emulsion (Intralipid)) on insulin sensitivity and glucose and lipid metabolism. To this end, we will compare skeletal muscle insulin sensitivity and glucose and lipid metabolism (within one subject) after 9 days of immobilization of one leg (unilateral lower limb suspension(ULLS))(decreased muscle mitochondrial oxidative capacity) versus an active control leg (unchanged muscle mitochondrial oxidative capacity). Further, changes in IMCL and fatty acid intermediates will be investigated in the immobilized vs the control leg, and this will be related to insulin sensitivity. The effectiveness of the ULLS intervention will be tested by measuring muscle mitochondrial oxidative capacity in both the immobilized and the control leg. All measurements will be performed both in the immobilized and control leg after 9 days of ULLS.

In the Netherlands and worldwide, the number of individuals suffering from obesity and type 2 diabetes mellitus is rising steadily. It is well established that obesity predisposes individuals to accumulation of excessive fat in non-adipose tissues such as the liver, the heart and skeletal muscle (called steatosis or ectopic fat accumulation). Furthermore, in sedentary humans ectopic fat accumulation in skeletal muscle is strongly associated with insulin resistance. However, paradoxically, IntraMyoCellular Lipid (IMCL) content is also increased in highly insulin sensitive endurance trained subjects (known as the athlete's paradox). This is suggesting that IMCL per se is not causative in skeletal muscle insulin resistance. The increased IMCL storage following endurance training serves to match training-induced increase in oxidative capacity and reliance on fat as a substrate during exercise, whereas in obesogenic/diabetogenic conditions the high fat availability is not matched by improved oxidative capacity. It is therefore speculated that under the latter conditions, the lipid intermediates of IMCL metabolism such as diacylglycerol (DAG), ceramides and fatty acyl-CoAs will accumulate and impede cellular insulin signalling. The rate of oxidative capacity is regulated by mitochondria, which are cellular organelles responsible for cellular energy production and cellular metabolism. Therefore, the overall hypothesis of this project is that a low muscle mitochondrial oxidative capacity can lead to muscle fat accumulation and/or accumulation of lipid intermediates when fatty acid availability is high, and this may result in insulin resistance in skeletal muscle.

Eligibility Criteria:
Inclusion Criteria:

* Men between 18-35 years of age at time of enrolment
* Non smoking
* No recent bone fractures of the limbs
* No cardiovascular medication or other medication
* No family history of thrombosis
* No engagement in programmed exercise for more than two hours a week
* Stable dietary habits
* No contra-indication for MRI

Exclusion Criteria:

* Regular smokers
* Participation in other studies
* Female sex
* Recent bone fractures of the limbs
* Medication use
* Cardiovascular disease
* Family history of type 2 diabetes mellitus
* Family history of thrombosis
* Contraindications for MRS scans:
* Electronic implants such as pacemakers or neurostimulator
* Iron-containing foreign bodies in eyes or brain
* Some hearing aids and artificial (heart) valves which are contraindicated for MRS
* Claustrophobia
* Participants, who do not want to be informed about unexpected medical findings, or do not wish that their physician will be informed, cannot participate in the study