Mechanistic Role of Inadequate Hyperinsulinemia in Mitochondrial Dysfunction and Fibrosis Development Across Metabolic Tissues

• Applicant: Dr. Ekaterina von Rauchhaupt
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 582079017

The project investigates how inadequate hyperinsulinaemia—insulin secretion disproportionate to metabolic demand—impairs metabolic flexibility, induces mitochondrial stress, and promotes tissue fibrosis. The project then tests whether these processes are reversible after weight loss in humans. A 12-month training and mechanistic exploration phase at Columbia University Irving Medical Center (CUIMC), NY, during which the candidate will master and apply advanced techniques for the metabolic characterization of hyperinsulinemia (WP1) will build the foundation for the subsequent implementation and translational phase in Heidelberg as a post-fellowship continuation of Phase 1. The acquired methodologies will be embedded in existing cohorts: the Free Fatty Acid-Induced Insulin Resistance (FFAIR) clamp study and the Characterization of Metabolic Remodelling after Bariatric Surgery (ChARMeD) bariatric cohort study. The work programme (WP1–3) therefore distinguishes between the funded training phase at CUIMC (WP1–2) and the planned post-fellowship implementation in Heidelberg (WP3). Phase 1 (12-Month Training Phase, CUIMC) focuses on the development of multi-tracer insulin-suppression protocols—Diazoxide Suppression Test (DzST), Graded Insulin Suppression Test (GIST), and Pancreatic Clamp (PC)—to quantify insulin- versus glucose-dependent contributions to oxidative stress and mitochondrial function in obese individuals with and without metabolic dysfunction–associated steatotic liver disease (MASLD), and to develop oral glucose tolerance test (OGTT)- based modelling of insulin suppression. Phase 2 (Implementation Phase, Heidelberg) applies these methodologies to two distinct clinical cohorts (ChARMeD and FFAIR) using oGTT-based modelling, phenotype allocation, and tissue-level integration within a liver–adipose crosstalk framework. The FFAIR clamp study provides dynamic phenotyping under lipid overload and stratification by endogenous hyperinsulinemia, as well as the investigation of sex-specific differences. The ChARMeD bariatric cohort study characterizes the chronic consequences of sustained hyperinsulinemia on mitochondrial stress and fibrogenic activation. This combined design provides the framework for transitioning from the analysis of acute mechanistic processes to the characterization of chronic tissue alterations and their clinical reversibility.

• DFG Programme: Fellowship
• International Connection: USA
• Host: Professor Joshua Cook