The Effect of Lowered Physical Activity on Insulin Sensitivity and Lipid and Glucose Metabolism
Condition: Insulin Sensitivity
MeSH terms: Insulin Resistance; Hypersensitivity
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): unilateral lower limb suspension
Intervention type(s): Other
Intervention description(s): This is an intervention study, where each subject will undergo 12 days of unilateral lower limb suspension. Randomly, the dominant or the non-dominant leg of the subject will be suspended by attachment of a sling to a non-rigid ankle brace and to a harness on the upper body and unloaded from all weight bearing. The knee will be slightly flexed at an angle of 130°. Hip, knee and ankle will be fully mobile. The sling will be used during all locomotory activity, and the subjects will use crutches for walking.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science