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Personalized Medicine

Smart drug clears fat from liver and blood

Scientists of Helmholtz Zentrum München and Technical University of Munich have developed a ‘smart’ drug that safely clears the liver of fat and prevents blood vessels from clogging up. Similar to a trojan horse, the drug enters the liver with a trick: It uses the pancreatic hormone glucagon as vehicle to shuttle thyroid hormone T3 the live while keeping it away from other organs, thereby improving cholesterol and lipid metabolism while avoiding typical side effects of thyroid hormone.

Dr. Timo Müller (left), Prof. Dr. Matthias Tschöp; Source: HMGU

Drawing: Dr.Timo Müller; Source: HMGU; click to enlarge

The constant rise in obesity and diabetes represents a major burden of our society. Fatty liver and atherosclerosis are frequent consequences of these metabolic diseases, but an efficient and safe medicine, which would reverse obesity, insulin resistance, fatty liver and atherosclerosis remains a major scientific challenge of global priority.

An international team led by metabolism experts Matthias Tschöp (Helmholtz Zentrum München / Technical University of Munich), Richard diMarchi (Indiana University) and Timo Müller (Helmholtz Zentrum München) report in the current issue of the journal ‘Cell’ that liver-specific delivery of the thyroid hormone T3 using glucagon corrects obesity, glucose intolerance, fatty liver disease and atherosclerosis without causing adverse effects in other tissues. “While the ability of T3 to lower cholesterol is known for centuries, deleterious effects, in particular on the skeleton and the cardiovascular system, do so far limit its medicinal utility”, says Brian Finan, the first author of the manuscript.  

Toward precision medicines of the future 

“Part of our trick is, that we use the pancreatic hormone glucagon as a vehicle to deliver thyroid hormone only into cells carrying a glucagon receptor”, says Christoffer Clemmensen, who led several of the key experiments.  He explains: “Since there are lots of glucagon receptors in the liver, but almost none in heart or bone, our molecule concentrates thyroid hormone action to the liver while keeping it away from places where it would be harmful.” “The next task is to see whether this drug candidate will reach the same level of targeted tissue-selectivity in clinical studies”, says diMarchi. “If the molecule shows equal efficacy and safety in humans, then this particular ‘smart’ drug design may indeed offer perspectives for metabolic precision medicine”, summarizes Tschöp.

Further information

* The team of Matthias Tschöp (Director of the Helmholtz Diabetes Center and Professor for Metabolic Diseases at the Technical University of Munich) and  Richard DiMarchi (Indiana University) already reported in 2015 the development and evaluation of a single hormone triple agonist, which effectively corrects obesity and insulin resistance. In another study (with a similar working mechanism as in this study) the scientists showed the targeted delivery of estrogen to only cells that express the receptor for GLP-1, thereby improving systems metabolism by concentration the action of estrogen to only the hypothalamus and the pancreas.

The newly developed glucagon/T3 molecule delivered the T3 selectively to the liver and thereby safely improved within a few days cholesterol metabolism in diet-induced obese mice. The molecule further decreased body weight, corrected non-alcoholic fatty liver disease, and improved glucose metabolism without deleterious effects of T3 in the heart and bone. Notably, the molecule failed to improve metabolism in mice lacking either the glucagon receptor or which lack the thyroid hormone receptor in only the liver, demonstrating the liver-specific signal specificity of this new molecule.

Finan, B.& Clemmensen, C. et al. (2016): Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease. Cell, DOI: 10.1016/j.cell.2016.09.014

The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.

The Institute for Diabetes and Obesity (IDO) studies the diseases of the metabolic syndrome by means of systems biological and translational approaches on the basis of cellular systems, genetically modified mouse models and clinical intervention studies. It seeks to discover new signaling pathways in order to develop innovative therapeutic approaches for the personalized prevention and treatment of obesity, diabetes and their concomitant diseases. IDO is part of the Helmholtz Diabetes Center (HDC).

The research objective of the Institute of Experimental Genetics (IEG) is to elucidate the causes and pathogenesis of human diseases. Due to its prominent role in interdisciplinary and international consortia, the IEG is a global leader in the systemic study of mouse models for human diseases and the elucidation of involved genes. The main focus is on metabolic diseases such as diabetes. The IEG is part of the Helmholtz Diabetes Center (HDC).

The German Center of Diabetes Research e.V. is a national association that brings together experts in the field of diabetes research and combines basic research, translational research, epidemiology and clinical applications. The aim is to develop novel strategies for personalized prevention and treatment of diabetes. Members are Helmholtz Zentrum München – German Research Center for Environmental Health, the German Diabetes Center in Düsseldorf, the German Institute of Human Nutrition in Potsdam-Rehbrücke, the Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Medical Center Carl Gustav Carus of the TU Dresden and the Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard-Karls-University of Tuebingen together with associated partners at the Universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich

TheTechnical University of Munich (TUM)  is one of Europe’s leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 39,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, reinforced by schools of management and education. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany. 

As one of Europe's leading research universities,LMU Munich is committed to the highest international standards of excellence in research and teaching. Building on its 500-year-tradition of scholarship, LMU covers a broad spectrum of disciplines, ranging from the humanities and cultural studies through law, economics and social studies to medicine and the sciences. 15 percent of LMU‘s 50,000 students come from abroad, originating from 130 countries worldwide. The know-how and creativity of LMU's academics form the foundation of the University's outstanding research record. This is also reflected in LMU‘s designation of as a "university of excellence" in the context of the Excellence Initiative, a nationwide competition to promote top-level university research.