SFB 1118:  Reactive metabolites as a cause of diabetes complications

According to current figures, one in ten adults has diabetes and an equally large number has the precursor to it, prediabetes. Diabetes is the leading cause of blindness, chronic kidney failure, heart attack, stroke and leg amputations. These diabetic complications often determine the mortality of patients with diabetes. Diabetic complications are evident in subtypes of diabetes as early as the manifestation of the disease itself. However, no therapeutic approaches are currently available that specifically target intracellular metabolic pathways underlying the development of diabetic complications. In addition, it is still not possible to reliably determine the risk of late onset diabetes or to induce remission of established late complications.The SFB1118 aims to understand diabetes complications by studying the intracellular effects of reactive metabolites (RM), such as reactive oxygen species (ROS), dicarbonyls (DC), or glucose metabolites (O-Glc-NAc), which are generated during energy metabolism.Work in the first funding periods identified novel molecular pathomechanisms of diabetic complications as well as specific targets of RM in the development of insulin resistance, retinopathy, sensory and autonomic neuropathy, nephropathy, and diabetic cardiopathy. Paradigm-shifting findings of this SFB demonstrated that synergistic enzyme systems and autoregulatory feedback loops determine the accumulation of RM. RM induce post-translational modifications of proteins and DNA with functional changes that are followed by cellular compensatory mechanisms, insulin resistance, DNA damage and/or senescence and can lead to tissue fibrosis and organ failure (multiple-hit concept).The aim of the 3rd funding period is to test the causality and reversibility of the newly identified mechanisms underlying the complications, by utilizing targeted interventions in different animal models and to transfer the new findings to the clinic. The SFB will test whether, and in which subtypes of diabetes these mechanisms are relevant for the development of diabetes complications and which biomarkers indicate them. The new molecular mechanisms will be translated into clinical stages according to the progression of diabetic damage, which will help validate intervention options and better define subgroups of patients.Our ultimate goal is to achieve long-term targets for prevention and remission of existing late complications in diabetes.

DFG Programme Collaborative Research Centres

• A01 - Targeting of TSC22D4 to counteract diabetic liver fibrosis (Project Heads Ekim, Ph.D., Bilgen ;  Herzig, Stephan )
• A02 - Diabetes late complications caused by iron-induced reactive oxygen radicals (Project Head Muckenthaler, Martina )
• A03 - Regulation of PDH activity by MG and the impact on diabetes complications (Project Head Teleman, Aurelio A. )
• A04 - Methylglyoxal Metabolism and its Cellular Consequences (Project Heads Fleming, Thomas Henry ;  Nawroth, Peter )
• B01 - Functional interplay of reactive metabolites in diabetic organ damage (Project Head Kroll, Jens )
• B02 - TRPC cation channels in hypoglycemia-associated autonomic nervous system failure in diabetes models (Project Head Freichel, Marc )
• B03 - Epigenetic regulation of adaptive and maladaptive effects of O-GlcNAc modifications in the diabetic heart (Project Heads Backs, Johannes ;  Müller, Oliver J. )
• B04 - Regulation of endothelial aquaporin-1 channels by reactive glucose metabolites (Project Head Schwenger, Vedat )
• B05 - The three levels of structural nerve damage in the pathogenesis of diabetic polyneuropathy: defining therapeutic target markers using MR-Neurography (Project Heads Bendszus, Martin ;  Heiland, Sabine ;  Schwarz, Daniel )
• B06 - Functional roles and mechanisms of ROS-dependent sumoylation in diabetic neuropathy (Project Heads Agarwal, Nitin ;  Kuner, Rohini )
• B07 - Regulation of tubular metabolism, senescence and renal regeneration by coagulation proteases in the context of diabetic kidney disease (Project Head Isermann, Berend )
• C03 - Glucose and reactive metabolites in the diabetic retina - preventive approaches against Vasoregression (Project Head Hammes, Hans-Peter )
• C04 - Reactive metabolites in the progression of the diabetic tubulopathy and its association to mitochondrial dysfunction und lipid droplets (Project Heads Gröne, Hermann-Josef ;  Hoffmann, Ph.D., Sigrid )
• C05 - The functional impact of dipeptide metabolism in protection from reactive metabolite induced, late diabetes complications (Project Heads Peters, Verena ;  Schmitt, Claus Peter )
• C06 - RAGE mediated DNA repair at the interface between damage by reactive metabolites and repair of diabetic complications (Project Heads Mendler, Michael ;  Nawroth, Peter )
• C07 - Loss of the MG-induced cellular defense mechanism leads to the development of diabetic complications (Project Head Zemva, Johanna )
• KS01 - Metabolic effects of fasting interventions on liver and kidney in type 2 diabetes (Project Heads Herzig, Stephan ;  Nawroth, Peter ;  Szendrödi, Julia )
• S01 - Liquid-Chromatography Tandem Mass Spectrometry (LC-MS/MS) Core Facility (Project Heads Fleming, Thomas Henry ;  Hell, Rüdiger )
• S02 - Diabetes-specific biobank (Project Heads Herpel, Esther ;  Poth, Tanja ;  Schwab, Constantin )
• S03 - Platform for CRISPR/Cas technology and AAV atherosclerosis model (Project Heads Freichel, Marc ;  Medert, Rebekka ;  Schumacher, Dagmar )
• Z - Central Tasks (Project Heads Nawroth, Peter ;  Szendrödi, Julia )

Applicant Institution Ruprecht-Karls-Universität Heidelberg

Participating Institution Deutsches Krebsforschungszentrum (DKFZ); Helmholtz Zentrum München
Deutsches Forschungszentrum für Gesundheit und Umwelt

Participating University Universität Leipzig

Spokespersons Professor Dr. Stephan Herzig, from 9/2021 until 6/2022; Professor Dr. Peter Nawroth, until 8/2021; Professorin Dr. Julia Szendrödi, since 7/2022