Diabetes Clinical Trial
Official title:
Effects of Acute Elevation of Circulating Fatty Acids on Hepatic Lipid Accumulation and Metabolism in Healthy Overweight and Obese Men
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.
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.
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Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Basic Science
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