Studying hypothalamic-pancreatic crosstalk to dissect pathophysiology of monogenic diabetes patients

• Applicants: Professor Dr. Alexander Kleger; Professor Dr. Stefan Liebau
• Subject Area: Endocrinology, Diabetology, Metabolism ; General Genetics and Functional Genome Biology ; Developmental Biology ; Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568388869

Diabetes affects over 350 million individuals globally, with Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D) being the most common forms. A small subset of juvenile onset diabetes (JOD) has a monogenic etiology, contrasting with the general multifactorial inheritance of common diabetes. About 30 monogenic diabetes genes have been identified to date, and these affect beta-cell development, function and survival through a variety of mechanisms. Several of these genes responsible for monogenic diabetes (rare variants) are also associated with multigenic diabetes (frequent variants) suggesting shared disease mechanisms and biological pathways. Tailoring treatment based on specific genetic defects is critical, especially for monogenic forms, underlining the public health relevance. Our previous studies identified that ONECUT1/HNF6 variants are associated with monogenic as well as multifactorial diabetes. We characterized the consequences of ONECUT1 mutations using a human pluripotent stem cell (hPSC) pancreatic differentiation model. Loss of ONECUT1 disrupts pancreatic progenitor formation and endocrine development by affecting transcription factor binding and enhancer activity, underscoring its role in diabetes pathogenesis. Nevertheless, most studies including our own work focused their analysis on the mere exploration of genes that have a direct impact on pancreatic development or beta-cell function. In our current proposal, we hypothesize that this concept falls short in understanding the complex pathomechanisms and that likely varying processes beyond dysfunctional beta-cells disturb glucose homeostasis. SEROTONIN extends our previous successful project (MONODIA-POP) to characterize new monogenic entities of JOD by in-depth functional understanding. Here, a novel functional analysis pipeline will be applied to characterize a candidate gene in terms of beta-cell function and crosstalk mechanisms along the hypothalamic-pancreatic axis. Gene-edited hPSC differentiated into beta-cells and hypothalamic organoids will be used to investigate functional impairment as well as organ communication, namely hypothalamus-pancreas interplay, and shed light on the full spectrum of diabetes pathomechanisms. Here, a microfluidic co-culture set-up will capture mutant islets' insulin secretion kinetics, combined with hypothalamic organoids for comprehensive metabolic and endocrine analysis. In conclusion, SEROTONIN seeks to provide insights into how genetic variations and tissue interactions contribute to diabetes pathology, potentially unveiling new therapeutic targets and enhancing treatment strategies for T2D and related metabolic disorders.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Sandra Heller