Fat, Inflammation and Insulin Resistance (FIRE)

• Effect of intervention on whole body insulin sensitivity [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
  

• Effect of intervention on systemic inflammation [ Time Frame: 1-6 hours ] [ Designated as safety issue: No ]
  
• Effect of intervention on cellular immune mechanisms [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
  

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.