What role do omega-6 fatty acids play in cardiovascular disease and diabetes? Scientists from Mannheim, together with researchers from Heidelberg, Frankfurt and Hangzhou in China, have investigated the breakdown of omega-6 fatty acids and gained new insights into how their oxidation products influence the metabolism. Under the leadership of Professor Dr. Jens Kroll from the European Center for Angioscience (ECAS) of the Medical Faculty Mannheim, Heidelberg University, the researchers identified a breakdown product of omega-6 fatty acids and developed a model in zebrafish to examine the undesirable effects of this oxidation product, known as tt-DDE (for trans,trans-2,4-decadienal).

While omega fatty acids are generally considered healthy, doubts are arising. Epidemiological studies and a so-called Red Hand Letter, in which eight pharmaceutical companies provide information on the risks associated with omega-3 fatty acids (source: BfArM, 16.11.2023), suggest that the issue is more complex than thought.

Like omega-3 fatty acids, omega-6 fatty acids are polyunsaturated fatty acids. And like these, they have various functions in the body and must be supplemented through diet.

The role of omega-6 fatty acids in relation to cardiovascular disease is contradictory. On the one hand, omega-6 fatty acids likely reduce the risk of developing cardiovascular diseases such as heart attacks or strokes by positively influencing lipid (fat) levels and blood pressure. However, an excess of these essential fatty acids is suspected of inducing early stages of vascular calcification through their pro-inflammatory effect and thus in turn promoting cardiovascular disease.

New cause of side effects discovered
Professor Kroll's research group at the Medical Faculty Mannheim, Heidelberg University, together with scientists from Heidelberg University Hospital (UKHD), the University of Frankfurt and Zhejiang University Hangzhou, China, approached the topic from a new perspective by investigating the oxidation product tt-DDE, which is also abundant in cooking oil fumes. In order to understand what increased tt-DDE levels can do, they first had to identify which enzyme is responsible for breaking down tt-DDE. They discovered that aldehyde dehydrogenase 9a1b performs this task: When this enzyme is inhibited, tt-DDE levels rise.

With this information, the scientists successfully developed a zebrafish model to explore the effects of high tt-DDE levels. They found that increased tt-DDE level is associated with a disruption of the sugar metabolism, similar to mild diabetes, as well as an impaired function and formation of blood vessels, which is also typical of diabetes.

The researchers also discovered the mechanism. They were able to prove that tt-DDE inhibits the function of the insulin receptor by binding to it. The blood sugar-lowering effect of insulin, which in a healthy individual activates the transport of glucose from the blood into the cell, cannot develop and is presumably responsible for the hyperglycemia observed in the blood.

Cooking oils contain large amounts of omega-6 fatty acids, which can be converted into the oxidation product tt-DDE through heating (frying, deep-frying) or oxidative stress in the body. If tt-DDE is not broken down by the enzyme ALDH9a1b (in humans it is called ALDH9a1), its concentration in the body increases. tt-DDE inhibits insulin action and the uptake of glucose into the cells, which can subsequently lead to increased blood sugar and damage to the eyes (diabetic retinopathy). © Jens Kroll

Professor Kroll says: “We discovered a new function of aldehyde dehydrogenase 9a1b while investigating a breakdown product of omega-6 fatty acids. Since the enzyme regulates tt-DDE levels, it is also an important regulator of glucose metabolism and could be an important component in the development of diabetes. We now want to investigate whether there is a subgroup of people with diabetes who develop secondary damage due to excessive tt-DDE levels - either because tt-DDE breakdown is too low or tt-DDE accumulation due to oxidation of omega-6 fatty acids is too high.”

This is followed by an important question that the scientists also want to investigate: Are there people with mild diabetes caused by a disorder of aldehyde dehydrogenase 9a1 function - and could aldehyde dehydrogenase 9a1 be the key to a new therapy?

With this work, Professor Kroll’s research group has achieved an important milestone in understanding how oxidation products of omega-6 fatty acids influence the metabolism, which may also shed some light on the somewhat more complex effects of omega fatty acids.
 

Original publication:
Xin Qian, [...], Julia Szendroedi, Peter Paul Nawroth, Jens Kroll. Impaired Detoxification of Trans, Trans-2,4-Decadienal, an Oxidation Product from Omega-6 Fatty Acids, Alters Insulin Signaling, Gluconeogenesis and Promotes Microvascular Disease. Adv. Sci. 2023, 2302325. doi: 10.1002/advs.202302325

Press contact:
Medical Faclty Mannheim
Heidelberg University
Science communication
Dr. Eva Maria Wellnitz
Phone:  +49 621 383-71115
eva.wellnitz(at)medma.uni-heidelberg.de

The German Center for Diabetes Research (DZD) e.V. is one of the seven German Centers for Health Research. It brings together experts in the field of diabetes research and interlinks basic research, epidemiology and clinical application. The aim of the DZD is to make a significant contribution to the successful, tailor-made prevention, diagnosis and therapy of diabetes mellitus through a novel, integrative research approach. Members of the network are Helmholtz Munich - German Research Center for Environmental Health, the German Diabetes Center DDZ in Düsseldorf, the German Institute of Human Nutrition DIfE in Potsdam-Rehbrücke, the Institute for Diabetes Research and Metabolic Diseases of Helmholtz Munich at the Eberhard Karls University of Tübingen and the Paul Langerhans Institute Dresden of Helmholtz Munich at the Carl Gustav Carus University Hospital of the TU Dresden, as well as associated partners at the universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich and other project partners. www.dzd-ev.de/en