Healthy Adults With Normal BMI Clinical Trial
Official title:
Fat, Inflammation and Insulin Resistance (FIRE-Study)
The combination of impaired insulin sensitivity and insulin secretion is thought to be the
basis of type 2 diabetes. Increased free fatty acids levels impair insulin action in muscle
and liver, but also systemic inflammation processes play a role in the development of insulin
resistance.
This study compares the effects of fat and inflammation on insulin sensitivity, systemic
inflammation, energy metabolism, vascular system and neural function in healthy humans.
A dysregulation of lipid metabolism with increased levels of free fatty acids (FFA) is known
represent one key mechanism in the pathophysiology of insulin resistance, which is
subsequently known to be the basis of the development of type 2 diabetes. But also
inflammatory processes, also known as subclinical inflammation, have been shown to be
independently associated with insulin resistance and diabetes development. The aim of this
study is to analyse the causal relationship between FFA and inflammation in the induction of
insulin resistance in healthy humans.
It is known that the parenteral application of lipids over 4-6 hours results in an increase
of FFA and a subsequent induction of a transient insulin resistance in peripheral tissues.
Whether oral fat intake has similar effect is still unknown. On the other hand the oral
intake of a high fat meal acutely increases intestinal permeability and thereby the levels of
bacterial lipopolysaccharide (LPS) in the bloodstream. LPS is known to be a potent stimulator
of immune response on a subclinical level accompanied by elevated levels of immune mediators,
which in turn impair the insulin receptor signalling pathway leading to insulin resistance.
Thus, in this study the effects of fat, both by an oral or parenteral fat load, and by a
short-term LPS-infusion simulating the postprandial systemic LPS peak compared to a control
infusion (glycerol) on insulin resistance is analysed. Insulin resistance and hepatic glucose
production is determined by an hyperinsulinemic euglycemic clamp including glucose tracers.
To detect the effects on the immune system on different levels, we measure 1) circulating
levels of immune mediators by ELISA and bead-based mulitiplex assays, 2) gene expression of
leukocytes, 3) subfractions of circulating leukocytes by FACS and 4) the stimulatory capacity
of isolated lymphocytes and monocytes in vitro. Moreover, the effects of fat or inflammation
on the function of the autonomic nervous system and the vasculature are studied. A second
focus is the impact of the interventions on signal transduction and mitochondrial function in
muscle and as well as on the metabolism and inflammation in subcutaneous adipose tissue in
muscle and fat biopsies.
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