Effects of lipids on cellular metabolism

Impaired insulin action (insulin resistance) is the central feature of obesity and type 2 diabetes which became an epidemic with enormous socioeconomic consequences during last decades. Plasma concentrations of free fatty acids (FFA) are typically increased in insulin resistant states and even predict the development of type 2 diabetes. In human skeletal muscle elevation of FFA rapidly causes insulin resistance which is mediated through impairment of insulin signaling transduction and results in decreased glucose uptake and storage as glycogen. In liver FFA increase the synthesis of new glucose (gluconeogenesis) without affecting glucose production. However, the cellular mechanism of FFA action in humans is still under debate. Recent developments in non-invasive nuclear magnetic resonance spectroscopy (NMRS) now make it possible to assess glucose uptake in muscle as well as cellular energy coupling in the mitochondria between glucose oxidation (tricarboxylic acid cycle) and synthesis of energy-rich phosphates (ATP synthesis) in muscle and liver. The aims of this proposal are to examine the effect of FFA (i) on glucose transport/phosphorylation and possible intracellular mediators such as long chain fatty acyl CoA and protein kinase C in muscle, (ii) on mitochondrial energy coupling in muscle and (iii) on oxidative glucose metabolism and deposition of triglycerides in liver. To this end studies will be performed in healthy volunteers and type 2 diabetic patients employing non-invasive 1 H, 31P, 13C NMRS, infusion of glucose and/or acetate labeled with stable isotopes and muscle biopsies under conditions of low and high plasma FFA. The results of this proposal will help to further delineate the contribution of FFA to common insulin resistance and type 2 diabetes. The findings of this proposal could therefore be of particular importance for evaluation of new therapeutic strategies and monitoring of the efficacy of antidiabetic treatment.

Obesity and type 2 diabetes mellitus are of worldwide increasing epidemiologic and socioeconomic relevance. The central feature of these disorders is the impairment of insulin action (insulin resistance) to which both inherited and acquired factors contribute. Increased availability of fat derived from nutrients or body fat depots raises the blood concentration of free fatty acids which can cause insulin resistance. The mechanism of action of free fatty acids in humans was yet unclear. We studied metabolism in healthy and type-2 diabetic humans using methods of functional biology. To this end, we further developed on-invasive magnetic resonance spectroscopy (MRS) for tracing metabolic fluxes within cells of the human body without taking tissue biopsies. We demonstrated that elevation of free fatty acids not only directly decrease sugar transport into muscle cells but primarily impair energy metabolism in the cellular power plants (mitochondria) by inhibiting synthesis of adenosine trisphosphate (ATP). Furthermore we showed that a comparable defect occurs in liver and relates to the development of fatty liver. Fatty liver disease was detected already in children and adolescents suffering from obesity. The disorders of energy metabolism are present also in only slightly overweight type-2 diabetic patients. Based on this results a hypothesis was developed stating that "mitochondrial dysfunction" underlies insulin resistance and the development of type-2 diabetes and non-alcoholic fatty liver. This project also examined whether other nutrients interfer with insulin action. We described fort he first time how amino acids cause insulin resistance in muscle and increased glucose production in liver. Characteristic alterations in insulin signal transduction (serine phosphorylation of insulin receptor subtrate-1) were identified as the critical steps. During this project we further reported on the regulation of liver glycogen metabolism in healthy and type-2 diabetic humans and effects of appetite regulating hormones in severely obese humans. The results of this project delivered novel insights into the development of type-2 diabetes using newly developed methods. This will help to improve the detection of high risk groups as well as contribute to individual prevention and therapy by new assessment of diets and nutrients fro diabetes and obesity.