Identification of Novel Marker Candidates Associated with the Progression of Prediabetes to Diabetes or Its Remission to Normoglycemia
People with prediabetes often develop diabetes, but many of them manage to reverse to normoglycemia. What determines these distinct outcomes? Can we identify biomarkers to predict the different trajectories of prediabetes? To address the questions above, researchers from the Paul Langerhans Institute Dresden of the German Center of Diabetes Research (DZD) and other collaborators made use of the DZD multicenter study PLIS (Prediabetes Lifestyle Intervention Study) to compare the proteomic and metabolomic signatures of patients with prediabetes following opposite trajectories, i.e. progressing to diabetes versus reversing to normoglycemia. The outcome of this work has now been published in the renowned journal Diabetes Care.
The progression of prediabetes to type 2 diabetes has been associated with pancreatic beta cell dysfunction, whereas its remission to normoglycemia has been related to improvement of insulin sensitivity. To understand the mechanisms and identify potential biomarkers related to prediabetes trajectories, the researchers conducted an explorative case-control study with participants from the PLIS study to compare the proteomic and metabolomic profile of people with prediabetes progressing to diabetes or reversing to normoglycemia within one year.
The team, led by Prof. Nikolaos Perakakis, included in the analysis 1389 proteins and 152 metabolites from plasma samples of individuals in prediabetes state, as well as one-year later, when some of the individuals have reversed to normoglycemia, while others have progressed to diabetes. Significant differences were found in 14 proteins in new-onset diabetes compared to normoglycemia, with six of them being reported for the first time. Elevated concentrations of two of the proteins Dicarbonyl/L-xylulose reductase (DCXR) and Glutathione S-transferase A3 (GSTA3) at prediabetes state were associated with profoundly increased risk for developing diabetes one year later.
Another aspect of the study highlighted the role of inflammation and immune system pathways in glucose homeostasis. Here the scientists found that pathways related to leukocyte chemotaxis, chemokines signaling, cytokine interactions and immune responses to infections were associated with prediabetes progressing to diabetes.
Metabolomic signatures in new-onset diabetes were characterized by increased concentrations of intermediate density lipoproteins, branched-chain amino acids, apolipoprotein A2 and glutamate. Metabolomic and proteomic signatures differentiating between prediabetes trajectories correlated stronger with markers of insulin sensitivity and to a lesser extent with markers of beta cell function.
“We were able to successfully identify new candidates associated with the progression of prediabetes to diabetes or vice versa as well as that we were also able to show that pathways which are regulating immune responses are strongly associated with prediabetes trajectories”, summarizes Prof. Perakakis. “Now, the new candidate proteins may in the future serve as biomarkers of prediabetes trajectories or targets for assessing their role in glucose homeostasis in mechanistic studies.”
Original Publication:
Barovic M, Hahn JJ, Heinrich A, Adhikari T, Schwarz P, Mirtschink P, Funk A, Kabisch S, Pfeiffer AFH, Blüher M, Seissler J, Stefan N, Wagner R, Fritsche A, Jumpertz von Schwartzenberg R, Chlamydas S, Harb H, Mantzoros CS, Chavakis T, Schürmann A, Birkenfeld AL, Roden M, Solimena M, Bornstein SR, Perakakis N. Proteomic and Metabolomic Signatures in Prediabetes Progressing to Diabetes or Reversing to Normoglycemia Within 1 Year. Diabetes Care. 2025 Jan 2:dc241412. doi: 10.2337/dc24-1412.
About the PLIS study:
Conventional lifestyle intervention is not sufficient to prevent type 2 diabetes in all people with prediabetes. Only individually tailored prevention can be effective here. In the completed multicenter Prediabetes Lifestyle Intervention Study (PLIS), the DZD set itself the goal of developing such personalized preventive measures. After extensive phenotyping, the PLIS study participants underwent different lifestyle programs with nutritional counseling and supervised physical activity. 1,145 patients were recruited for the PLIS study. To scientifically follow up this valuable cohort, the follow-up of the study participants was extended to a long-term observation over a period of 12 years after the intervention. Cluster analyses of the PLIS study identified first subtypes of prediabetes that have a particularly high risk of secondary diseases.
The Technische Universität Dresden (TU Dresden) is one of Germany's Universities of Excellence, esteemed for its exceptional standards in research and teaching spanning diverse fields. The Faculty of Medicine at TU Dresden is dedicated to propelling medical science and healthcare forward through interdisciplinary collaboration and pioneering research. https://www.uniklinikum-dresden.de/en
The Paul Langerhans Institute of Helmholtz Munich at the University Hospital Carl Gustav Carus and the Faculty of Medicine at TU Dresden (PLID) contributes decisively to a better understanding of the mechanisms of the disease and to explore new therapeutic options. The institute is a founding-partner of the German Center for Diabetes Research (DZD e.V.) and has been a satellite institute of Helmholtz Munich since January 2015. Its program comprises research into the pathophysiology of type 1 and type 2 diabetes mellitus. The main focus is on the mechanisms which cause the destruction and/or limited function of pancreatic beta cells and insufficient insulin secretion. In addition, the PLID also plays an outstanding role as only German transplant center for human pancreatic islet cells. https://tu-dresden.de/med/mf/plid
The German Center for Diabetes Research (DZD) 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 Munich – 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 Helmholtz Munich at the University Medical Center Carl Gustav Carus of the TU Dresden and the Institute for Diabetes Research and Metabolic Diseases of Helmholtz Munich at the Eberhard-Karls-University of Tuebingen together with associated partners at the Universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich. www.dzd-ev.de/en
