Elevated Circulating FFA and Intrahepatic Lipid Content
Condition: Diabetes; Hepatic Steatosis
MeSH terms: Fatty Liver
Study type: Interventional

Summary: 
      There is increasing evidence that hepatic lipid content (IntraHepatic Lipid, IHL) markedly
      increases the risk of metabolic complications, including insulin resistance and
      cardiovascular events. The investigators hypothesize that the liver is passively taking up
      free fatty acids (FFA) when the availability is high, thereby leading to an increased
      storage. To test this hypothesis, the investigators want to manipulate FFA levels, by means
      of a fasted exercise and recovery protocol, and monitor IHL content and hepatic Adenosine
      triphosphate (ATP) and inorganic phosphate (Pi) concentrations.
    

Detailed description: 
      In the Netherlands and worldwide, the number of individuals suffering from type 2 diabetes
      mellitus is rising steadily. As a consequence, a dramatic increase in diabetes-related
      morbidity and mortality can be expected over the next few decades. Accordingly, a concerted
      effort aimed at reducing diabetes rates and towards effective diabetes management is needed.

      One of the earliest hallmarks of type 2 diabetes is resistance of the peripheral tissues
      liver and muscle to the action of insulin, which is generally referred to as insulin
      resistance. Development of insulin resistance is strongly promoted by obesity. In fact
      obesity is the major risk factor for insulin resistance, and 80% of all type 2 diabetic
      patients are overweight or obese. Whereas obesity is by definition characterized by an
      excessive accumulation of fat in the body, it is specifically the accumulation of fat within
      peripheral tissues (called steatosis or ectopic fat accumulation), which is associated with
      the development of insulin resistance. Indeed, type 2 diabetic patients and their
      first-degree relatives are characterized by excessive accumulation of fat in skeletal muscle.
      Similarly, the presence of fatty liver in patients with type 2 diabetes and obesity has long
      been reported. This accumulation of fat in the liver markedly increases the risk for
      metabolic complications, including insulin resistance and cardiovascular events. Despite the
      well-known detrimental effects of ectopic fat accumulation, it is not completely understood
      why fat accumulates in muscle and liver.

      In recent years, non-invasive methods like proton magnetic resonance spectroscopy (1H-MRS)
      have been developed for quantifying lipid content in skeletal muscle and the liver, and were
      frequently applied by us and others. These measurements can be combined with other Magnetic
      Resonance techniques to investigate hepatic ATP- and Pi concentrations, determined by
      phosphorus magnetic resonance spectroscopy (31P-MRS). Furthermore, it has been shown that
      ATP- and Pi concentrations are lower in subjects with type 2 diabetes mellitus, who are
      characterized by hepatic lipid accumulation and hepatic insulin resistance. It has been
      suggested that a decreased ATP and Pi concentration may be an underlying factor for hepatic
      lipid accumulation.

      Human studies using hepatic 1H-MRS reported that intrahepatic lipid (IHL) content is
      associated with obesity, the metabolic syndrome and diabetes. Furthermore, a period of 36
      hours of fasting increased IHL dramatically. These conditions are characterized by elevated
      plasma FFA levels. We hypothesize that an increased passive uptake of FFAs can lead to a
      mismatch between uptake and oxidation when FFA availability is high.

      Interestingly, results in skeletal muscle show that elevation of FFA levels by lipid infusion
      result in increased lipid content after 4 hours. Similarly, we showed that skeletal muscle
      lipid content is increased in the inactive arm muscle after prolonged cycling exercise in the
      fasted state, where FFA typically increase to up to 1450 mmol. These results suggest that
      high circulatory FFA levels lead to unrestrained uptake of these FA in skeletal muscle,
      independent of oxidative needs. Whether IHL accumulation is also the resultant of elevated
      plasma FFA levels is currently unknown.

      Please note that in the study cited above, whereas skeletal muscle lipid content increased in
      the inactive arm muscle, it decreased in the active vastus lateralis muscle, reflecting the
      use of intramuscular lipid stores as substrate during prolonged muscular activity. Whether
      intensified use of IHL during exercise also leads to a decrease in IHL is presently unknown.
    

Intervention name(s): exercise
Intervention type(s): Other
Intervention description(s): 2 hours cycling exercise at 50 % of maximal power output
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: FFA; Liver; steatosis; exercise