Duality of Lipids: the Athlete's Paradox
Condition: Insulin Resistance, Diabetes; Lipid Metabolism Disorders
MeSH terms: Insulin Resistance; Metabolic Diseases; Lipid Metabolism Disorders
Study type: Interventional

Summary: 
      Accumulation of intramyocellular lipids (IMCLs) due to increased supply of fatty acids can
      induce defects in the insulin signaling cascade, causing skeletal muscle insulin resistance.
      However, the causes for muscle insulin resistance are not well understood. The association of
      elevated IMCLs and insulin resistance has been shown in obese humans and individuals with
      type 2 diabetes as well as several animal models of insulin resistance. Despite the strong
      relationship between IMCLs and insulin resistance, this suggested relationship disappears
      when well-trained endurance athletes are included into this consideration as this group is
      highly insulin sensitive. This metabolic enigma has been termed the 'athlete's paradox'. The
      aim of this project is to resolve the mechanisms contributing to the athlete's paradox.
    

Detailed description: 
      Type 2 diabetes (T2D) is characterized by an increasing insensitivity of muscle, fat and
      liver cells to the hormone insulin. About 9% of the global population is affected by this
      condition and mortality risk is twice as high in individuals with diabetes compared to
      similar-aged people without diabetes.

      Muscle is of particular importance for glucose homeostasis, since in healthy subjects it
      accounts for 80-90% of postprandial insulin-stimulated glucose disposal. After cellular
      uptake of glucose by the specialized glucose transporter 4 (GLUT4), glucose is phosphorylated
      and stored as glycogen. In individuals with obesity or T2D, the capacity for insulin to
      facilitate glucose uptake and glycogen synthesis is impaired. This reduced response of a
      given insulin concentration to exert its biological effect is termed insulin resistance.
      Subsequent diminished insulin secretion due to β-cell failure results in fasting
      hyperglycemia and overt diabetes. Importantly, muscle insulin resistance is the initial
      defect occurring in the development of T2D and precedes the clinical development of the
      disease by up to 20 years. Intracellular defects in glucose transport have been identified as
      the limiting step for insulin-mediated glucose uptake into skeletal muscle. Impaired muscle
      glucose transport activity is likely a consequence of ectopic lipid accumulation and
      subsequent dysregulation of intramyocellular fatty acid metabolism. Indeed, results from
      normal weight, nondiabetic adults suggest that intramyocellular triglyceride content is a
      strong predictor for muscle insulin resistance. Of note, the development of insulin
      resistance occurred without changes in intramyocellular triglyceride content, thus
      dissociating the amount of these neutral storage lipids from insulin resistance. Instead, the
      bioactive lipid species diacylglycerols (DAG) and ceramides have been implicated in
      interfering with insulin signaling and glucose homeostasis in obese and insulin resistant
      individuals and individuals with T2D by activating members of the protein kinase C (PKC)
      family while ceramides mediate an increase in protein phosphatase 2A (PP2A) and an
      association of PKCζ and protein kinase B (PKB)/Akt2. To add another layer of complexity, DAGs
      seem to exert their detrimental intracellular effects in a subspecies- (mostly C18:0, C18:1,
      or C18:2 DAGs) and stereo-selective manner (sn-1,2 stereoisomer DAG). Taken together,
      excessive amounts of bioactive intramyocellular lipids (IMCLs) contribute to defective
      insulin signaling in obese individuals and patients with T2D. Surprisingly, endurance
      athletes have comparable amounts of IMCLs, but remain highly insulin sensitive. This
      metabolic conundrum has been termed "athlete's paradox".

      This study therefore aims at resolving this conundrum with mass-spectrometry based
      state-of-the-art methodology by analysing lipid subspecies in endurance-trained athletes,
      untrained healthy individuals and insulin-resistant individuals.
    

Intervention name(s): Acute bout of endurance exercise
Intervention type(s): Procedure
Intervention description(s): Individuals will undergo an acute bout of endurance exercise for 90 min at 75% of maximal oxygen uptake.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science