Insulin Sensitivity Clinical Trial
Official title:
The Effect of Dietary Fat Load and Physical Exercise on the Flexibility and Partitioning of Ectopic Lipids.
This study aims at assessing the effect of standardized dietary fat load and short-term
aerobic exercise on systemic lipolysis, flexibility and partitioning of ectopic fat stores
(intramyocellular = IMCL, intrahepatocellular = IHCL, intramyocardial lipids = IMCaL) in
relation to FFA in endurance trained athletes and hypopituitary patients compared to
sedentary healthy control subjects.
Exercise is a powerful stimulation for growth hormone (GH) secretion in health. A
standardised exercise test can, therefore, be discriminative for the diagnosis of
GH-deficiency in adults. This will be assessed.
Hypothesis (ectopic fat stores)
1. Ectopic fats stores are flexible fuel stores and are influenced by diet and physical
activity.FFA availability may play an important regulatory role.
2. There is a tissue specific partitioning of triglycerides and/or FFA among non-adipose
organs after fat load and physical exercise
3. The flexibility of ectopic fat stores is related to insulin sensitivity
4. Lipolytic and anti-lipolytic hormones are critical for regulating FFA availability (at
rest or during exercise) and therefore also for the regulation of ectopic fat stores.
5. GH is a lipolytica hormone. Lack of GH in adulthood is related to decreased FFA
availability thereby influencing ectopic lipid stores Hypothesis diagnosis of GHD
6. A short intensive physical exercise shows a good discriminative power to diagnose GHD.
Background
Obesity, in particular visceral obesity, is associated with impaired insulin action on target
tissues (insulin resistance or metabolic syndrome) that, in turn, is related to an increased
risk for cardiovascular mortality and morbidity. Pathophysiological mechanism remains
unclear. Interventions in patients with impaired glucose tolerance/impaired fasting glucose
have consistently demonstrated that by increasing physical activity and reducing calorie
intake the risk to convert to frank type 2 diabetes is decreased, even more efficiently than
by early medical therapy with metformin.
Physically inactive and overweight subjects do not only store the excess of fat in the
intra-abdominal or subcutaneous department but also in non-adipose tissue (="ectopic"
tissues), such also skeletal muscle, liver and myocardium, also called intramyocellular
lipids (IMCL), intrahepatocellular lipids (IHCL) and intramyocardial lipids (IMCaL).This
ectopic lipid accumulation occurs either by increased free fatty acids (FFA) uptake, increase
synthesis in the involved tissues or reduced FFA oxidation.
The relative contribution of these factors to ectopic lipid accumulation varies in different
physiological conditions (i.e. physical exercise, fasting, postprandial condition) and in
different tissues. In addition, it may be influenced by hormones that regulate lipid
metabolism. There is increasing evidence that ectopic fat and its intermediate metabolites
interfere with insulin signalling, thereby contributing to the impaired insulin action on
target tissues such as liver and skeletal muscle. It has been well showed that high fat
oxydation capacity allows to keep a lower lipolytic activity and therefore low levels of
lipolyse degradation products. Strong evidence is accumulating that these intermediates
interact with insulin signalling finally resulting in insulin resistance.
There is still scarce data about the behaviour of ectopic fat stores in the presence of
positive(nutritional fat excess) or negative energy balance (physical activity) and the role
of hormones in regulating these fat depots.
Additionally,we have previously shown that GH values obtained during a 2h standardized
aerobic exercise of moderate intensity revealed a high diagnostic accuracy in predicting
severe GHD in adult individuals. Whether a shorter exercise on higher intensity may lead to
comparable results has to be assessed.
Objective
The study aims to comprehensively assess the flexibility and partitioning of ectopic fat
deposition and to define the role of relevant hormones (especially GH and insulin) in
relation to the availability of FFAs as well as their role in the process of ectopic fat
deposition and consumption. Another objective is to investigate the role of a standardized
fat load and aerobic exercise on IMCaL.
Methods
Using the two-step hyperinsulinaemic-euglycaemic clamp technique hepatic and peripheral
insulin sensitivity is assessed.
Lipid depots (skeletal muscle and liver) are repeatedly measured by MR-spectroscopy,
subcutaneous and visceral fat mass by whole body MR-imaging.
Exercise capacity ist measured on a bicycle (incl. spiroergometry). Counterregulatory
hormones, glucose and free fatty acids are measured during a 2h physical exercise at 50-60
VO2max.
Blood samples to evaluate GH will be taken immediately before and after the Vo2 max-test, as
well as 15, 30 and 45minutes after the end of the exercise test.
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