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Pathophysiology of Prediabetes

Our goal is to understand the causes and consequences of impaired metabolic health in obesity and normal weight and the role of metabolic dysfunction-associated steatotic liver disease (MASLD) in the pathogenesis of prediabetes, type 2 diabetes and cardiovascular diseases.

In this respect, in 2008, we published the first large cohort study addressing precise phenotyping in metabolically healthy obesity (MHO) and then extended our research to subphenotypes of impaired metabolic in normal weight. To address the mechanisms how MASLD impacts on cardiometabolic diseases, in 2008, we were the first to introduce the concept of hepatokines and are studying their cardiometabolic role in the organ cross-talk.

Our goal is to understand the causes and consequences of impaired metabolic health in obesity and normal weight and the role of metabolic dysfunction-associated steatotic liver disease (MASLD) in the pathogenesis of prediabetes, type 2 diabetes and cardiovascular diseases.

In this respect, in 2008, we published the first large cohort study addressing precise phenotyping in metabolically healthy obesity (MHO) and then extended our research to subphenotypes of impaired metabolic in normal weight. To address the mechanisms how MASLD impacts on cardiometabolic diseases, in 2008, we were the first to introduce the concept of hepatokines and are studying their cardiometabolic role in the organ cross-talk.

Scientists at Pathophysiology of Prediabetes

Prof_Stefan_ Porträt 1(1)
Prof. Dr. Norbert Stefan

Head of Section

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Fritz_Schick_Med_Mitarbeiter_ 74
Prof. Dr. Dr. Fritz Schick

Group Leader, Scientist

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Juergen_Machann_Med_Mitarbeiter_ 15
Prof. Dr. Jürgen Machann

Senior Scientist

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Costas_Kartazis
Dr. Konstantinos Kantartzis

Physician Scientist

Portraitfoto Angela_Lehn_Stefan
Dr. Angela Lehn-Stefan

Physician Scientist

Dr. Sebastian Schuth

Physician Scientist

Karin Waneck

TA

Our Topics

Causes, consequences, and treatment of metabolically unhealthy fat distribution

 

Energy storage capacity under positive energy balance is important for metabolic health. An increased energy intake, particularly after consuming increased amounts of glucose, fructose, and saturated fat, and when energy expenditure is low, results in the storage of energy mostly in the form of triglycerides in adipose tissue.

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Causes and cardiometabolic consequences of NAFLD

 

An unhealthy diet results in increased hepatic de novo lipogenesis and hepatic inflammation. This process is amplified by a lipodystrophy-like phenotype with expansion of visceral adipose tissue. By increased secretion of very low-density lipoproteins, ceramides, pro-coagulants, glucose, and dysregulated secretion of microRNAs and hepatokines, the fatty liver impacts metabolically important organs and tissues and the cardiovascular system.

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Treatment of NAFLD

 

Pathophysiological targeted treatment of hepatic steatosis, e.g. by inhibiting cortisol production in metabolically active tissues, such as the liver, is effective to fight the epidemic of NAFLD.

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Recent Publications

Lancet Diabet. Endocrinol., DOI: 10.1016/S2213-8587(25)00295-5 (2025)

Vazquez Arreola, E. ; Gong, Q. ; Hanson, R.L. ; Wang, J. ; Sandforth, L. ; He, S. ; Sandforth, A. ; Qian, X. ; Giacca, M. ; Bornstein, S.R. ; Fritsche, A. ; Stefan, N. ; Preissl, H. ; Gregg, E.W. ; Marx, N. ; Jumpertz von Schwartzenberg, R. ; Li, G. ; Birkenfeld, A.L.

Prediabetes remission and cardiovascular morbidity and mortality: Post-hoc analyses from the Diabetes Prevention Program Outcome study and the DaQing Diabetes Prevention Outcome study.
Diabetologia, DOI: 10.1007/s00125-025-06632-y (2025)

Wang, Y. ; Ram, J. ; Bianchi, C. ; Fiorentino, T.V. ; Kim, S.S. ; Kim, J. ; Ryang, S. ; Del Prato, S. ; Sesti, G. ; Sandforth, L. ; Preissl, H. ; Jumpertz von Schwartzenberg, R. ; Stefan, N. ; Fritsche, A. ; Ha, J. ; Birkenfeld, A.L. ; Bergman, M.

Superiority of 1 h plasma glucose vs fasting plasma glucose, 2 h plasma glucose and HbA1c for the diagnosis of type 2 diabetes.

Tao, R. ; Stöhr, O. ; Tok, O. ; Andres-Hernando, A. ; Qiu, W. ; He, B. ; Wang, C. ; Grøntved, L. ; Burant, C.F. ; Hui, S.T. ; Lanaspa, M.A. ; Stefan, N. ; Copps, K.D. ; White, M.F.

Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance.
JAMA, DOI: 10.1001/jama.2025.19615 (2025)

Tilg, H. ; Petta, S. ; Stefan, N. ; Targher, G.

Metabolic dysfunction-associated steatotic liver disease in adults: A review.

Wang, Y. ; Sandforth, A. ; Jumpertz von Schwartzenberg, R. ; Ganslmeier, M. ; Cheng, Y. ; Sandforth, L. ; Katzenstein, S. ; Machann, J. ; Schick, F. ; Kantartzis, K. ; Preissl, H. ; Fritsche, A. ; Stefan, N. ; Bergman, M. ; Birkenfeld, A.L.

Lifestyle intervention is more effective in high 1-hour post-load glucose than in prediabetes for restoring β-cell function, reducing ectopic fat, and preventing type 2 diabetes.

Grieger, J.A. ; Takele, W.W. ; Vesco, K.K. ; Redman, L.M. ; Hannah, W. ; Bonham, M.P. ; Chen, M. ; Chivers, S.C. ; Fawcett, A.J. ; Habibi, N. ; Liu, K. ; Mekonnen, E.G. ; Pathirana, M. ; Quinteros, A. ; Taylor, R. ; Ukke, G.G. ; Zhou, S.J. ; ADA/EASD PMDI (Stefan, N.)

Participant characteristics in the effectiveness of lifestyle interventions to optimize gestational weight gain: A systematic review and meta-analysis.
Nat. Med. 31, 3330-3340 (2025)

Sandforth, A. ; Vazquez Arreola, E. ; Hanson, R.L. ; Wewer Albrechtsen, N.J. ; Holst, J.J. ; Ahrends, R. ; Coman, C. ; Gerst, F. ; Lorza-Gil, E. ; Cheng, Y. ; Sandforth, L. ; Katzenstein, S. ; Ganslmeier, M. ; Seissler, J. ; Hauner, H. ; Perakakis, N. ; Wagner, R. ; Machann, J. ; Schick, F. ; Peter, A. ; Lehmann, R. ; Weigert, C. ; Maurer, J. ; Preissl, H. ; Heni, M. ; Szendrödi, J. ; Kopf, S. ; Solimena, M. ; Schwarz, P. ; Blüher, M. ; Häring, H.-U. ; Hrabě de Angelis, M. ; Schürmann, A. ; Kabisch, S. ; Mai, K. ; Pfeiffer, A.F.H. ; Bornstein, S. ; Stumvoll, M. ; Roden, M. ; Stefan, N. ; Fritsche, A. ; Birkenfeld, A.L. ; Jumpertz von Schwartzenberg, R.

Prevention of type 2 diabetes through prediabetes remission without weight loss.

Mantovani, A. ; Morandin, R. ; Fiorio, V. ; Lando, M.G. ; Stefan, N. ; Tilg, H. ; Byrne, C.D. ; Targher, G.

Glucagon-like peptide-1 receptor agonists improve MASH and liver fibrosis: A meta-analysis of randomised controlled trials.
Diabetes Care 48, 1042-1052 (2025)

Mantovani, A. ; Morandin, R. ; Lando, M.G. ; Fiorio, V. ; Pennisi, G. ; Petta, S. ; Stefan, N. ; Tilg, H. ; Byrne, C.D. ; Targher, G.

Sodium-glucose cotransporter 2 inhibitor use and risk of liver-related events in patients with type 2 diabetes: A meta-analysis of observational cohort studies.

Contact

Prof_Stefan_ Porträt 1(1)
Prof. Dr. Norbert Stefan

Head of Section

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Networks and Affiliations

University of Florida

University of Florida

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Boston Children’s Hospital

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National Institutes of Health

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Stratification of obese phenotypes to optimize future obesity therapy

SOPHIA IMI EU Consortium

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German Center for Diabetes Research

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