Prof. Dr. Burkhard Kleuser

University of Potsdam, Germany

Abstract

The Role of Sphingolipids on Insulin Resistance and ß-cell Dysfunction

Insulin resistance is a complex metabolic disorder in which insulin-sensitive tissues fail to respond to the physiological action of insulin. There is a strong correlation of insulin resistance and the development of type 2 diabetes both reaching epidemic proportions.

The dysfunction of pancreatic ß-cells and the development of insulin resistance are multifaceted with their interdependence for triggering the pathogenesis of type 2 diabetes. The fundamental role of pancreatic ß-cells is to secrete insulin in response to a glucose stimulus, which is essential for maintaining plasma glucose homeostasis. Thus, ß-cells must respond appropriately. An increased metabolic demand for insulin due to insulin resistance in several tissues usually precedes the development of hyperglycemia. But in an early phase pancreatic ß-cells compensate for insulin resistance by hypersecretion of insulin due to modulation of ß-cell function. In this manner ß-cell mass is enhanced by proliferation, neogenesis, hyperplasia and hypertrophy. However, chronic exposure to elevated plasma glucose levels results in the dysfunction of ß-cells and the manifestation of hyperglycemia. The ß-cell failure that follow the period of compensation may result from inadequate expansion of ß-cell mass or failure of existing ß-cells cells to respond to glucose. Thus, ß-cell mass is decreased by cell death through apoptosis, necrosis and autophagy, hypoplasia and hypotrophy.

Dysfunctional lipid metabolism is a hallmark of insulin resistance and numerous studies in humans and rodents have shown that insulin resistance is associated with elevations of non-esterified fatty acids in the plasma. Moreover, it is well established that especially the saturated fatty acid palmitate is disadvantageous in its attitude to influence ß-cell viability compared to fatty acids. This may be explained by the fact that not the fatty acids themselves but secondary metabolites may contribute to the modulation of ß-cell function. Noteworthy, the saturated fatty acid palmitate is required for the de novo biosynthesis of sphingolipids. Indeed, sphingolipid metabolites have been postulated as critical mediators of glucolipotoxicity. In particular, ceramides have been identified to contribute to the dysfunction of ß-cells. Nevertheless, ceramides can be further metabolized to the bioactive sphingolipid sphingosine 1-phosphate. It has previously been shown that plasma levels of sphingosine 1-phosphate are increased in animal models of diabetes. Moreover, plasma levels of sphingosine 1-phosphate are also increased in HFD-fed obese mice and more importantly in obese humans., Moreover the sphingosine 1-phosphate content is positively correlated with clinical outcomes of the metabolic syndrome. However, whether sphingosine 1-phosphate seems to be only a biomarker of the metabolic syndrome or whether it possesses a central function in the progression of insulin resistance and type 2 diabetes is still a matter of debate. Here, the current state of knowledge about sphingolipids and insulin signaling in pancreatic ß-cells is presented. A specific focus is put on the action of ceramides and sphingosine 1-phosphate on pancreatic ß-cells. In particular, modulation of sphingolipid signaling can be considered as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.

Profile

Burkhard Kleuser is the chairperson of Toxicology at the Institute of Food Science. At the same time Prof. Kleuser is also the managing director of the Institute of Nutritional Science. Prof. Kleuser is a certified food chemist with a PhD in Biochemistry and Molecular Biology and a Habilitation in toxicology and pharmacology.

After studying Food Chemistry at the University of Wuppertal Burkhard Kleuser completed a practical year at the Food and Veterinary Office of the federal state Schleswig Holstein. He obtained a Ph.D in Biochemistry and Molecular Biology from the University of Hamburg. At the department of Biochemistry and Molecular Biology he worked on the biological functions of ether lipids. A grant from the German Research Association (DFG) allowed him to work at the Medical Center of Georgetown University in Washington DC. There he worked in the group of Prof. Dr. Sarah Spiegel, who discovered sphingosine 1-phosphate as a novel biological signalling molecule. Today it is known that this molecule is a blood borne lipid mediator, in particular in association with lipoproteins such as high density lipoprotein (HDL). A gradient of sphingosine 1-phosphate from lymph node, lymph and plasma is essential for immune cell trafficking. After the stay at Georgetown University, Prof. Kleuser returned to the Institute of Pharmacy at the Freie Universität Berlin, where he habilitated in 2002 and received the Venia legendi in the field of Toxicology and Pharmacology. In 2006 he accepted a position as W2 Professorship of Pharmacology and Toxicology at the Institute of Pharmacy at Freie Universität Berlin. Since 2009 Burkhard Kleuser is Professor and Chair of Toxicology at the Institute of Nutritional Science at the University of Potsdam.

His research interests include studies on the role of sphingolipids in the pathophysiology of diseases such as diabetes mellitus as well as infections and immunological diseases. Moreover, epigenetic processes are investigated at the Department of Toxicology. The working group also has a distinguished expertise in the field of sphingolipidomics, the identification and quantification of sphingolipid metabolites.

Professional Experience

  • since 07/2011: Director of the Institute of Nutritional Science at the Faculty of Mathematics and Natural Science, Universität Potsdam (Germany)
  • since 10/2009: W3-Professor and Chair of Toxicology, Faculty of Mathematics and Natural Science, Universität Potsdam (Germany)
  • 10/2006 – 08/2009: W2 Professor of Pharmacology and Toxicology at the Institute of Pharmacy, Freie Universität Berlin (Germany)
  • 08/2002 – 09/2006: Associate Professor of Pharmacology and Toxicology at the Institute of Pharmacy, Freie Universität Berlin (Germany)
  • 01/1997 – 07/2002 Assistant Professor of Pharmacology and Toxicology at the Institute of Pharmacy, Freie Universität Berlin (Germany)
  • 09/1995 – 12/1996 Fellow of the German Research Foundation (DFG) at the Medical Center of the Georgetown University (Washington, D.C., USA) with Prof. Dr. Sarah Spiegel
  • 10/1994 – 08/1995 Post-Doc at the department of Pharmacology and Toxicology at the Institute of Pharmacy, Freie Universität Berlin (Germany)
  • 04/1990 – 09/1994 Research Associate at the Institute of Food Chemistry and Biochemistry, Department of Biochemistry and Molecular Biology, Universität Hamburg (Germany)

Educational Background

  • 10/1984 – 09/1988: Studies of Food Chemistry at Universität Wuppertal (Germany)
    (state examination)
  • 01/1989 – 02/1990: Practical training at the Institute of Veterinary and Food Chemistry at the Federal State Schleswig-Holstein (Germany)
  • 04/1990 – 04/1994: Studies of Biochemistry and Molecular Biology at Universität Hamburg (Germany)

Scientific Degrees

  • 10/1995 – 05/2002: Habilitation in Pharmacology and Toxicology at Freie Universität Berlin (Germany). Mentor: Prof. Dr. M. Schäfer-Korting
  • 04/1990 – 03/1994: Doctorate in Biochemistry and Molecular Biology with Prof. Dr. G. Gercken, Universität Hamburg (Germany)