Fat, Inflammation and Insulin Resistance (FIRE)

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.

Fat infusion (Intralipid) over 6 hours Fat orally (Soy bean oil) single dose LPS infusion for 10 minutes Glycerol infusion over 6 hours

Inclusion Criteria: Healthy male and female subjects Age 20-40 BMI 20-25 mg/m2 Exclusion Criteria: Hyperlipidemia Smoking Pregnancy Acute infection Anaemia Taking drugs influencing lipid or glucose metabolism, the immune system or antihypertensive medication Malignancies Any chronic disease Autoimmune or immune compromising diseases including HIV/AIDS Allergies against study drugs Hepatitis Gall bladder diseases Renal failure Psychiatric diseases or addiction

Ziegler D, Strom A, Strassburger K, Nowotny B, Zahiragic L, Nowotny PJ, Carstensen-Kirberg M, Herder C, Szendroedi J, Roden M. Differential Patterns and Determinants of Cardiac Autonomic Nerve Dysfunction during Endotoxemia and Oral Fat Load in Humans. PLoS One. 2015 Apr 20;10(4):e0124242. doi: 10.1371/journal.pone.0124242. eCollection 2015.

Nowotny B, Zahiragic L, Krog D, Nowotny PJ, Herder C, Carstensen M, Yoshimura T, Szendroedi J, Phielix E, Schadewaldt P, Schloot NC, Shulman GI, Roden M. Mechanisms underlying the onset of oral lipid-induced skeletal muscle insulin resistance in humans. Diabetes. 2013 Jul;62(7):2240-8. doi: 10.2337/db12-1179. Epub 2013 Mar 1.