β cell mass plays a pivotal role in type 2 diabetes progression, with decreased mass linked to reduced insulinaemia, glucose intolerance, and diabetes onset. Notably, β cell mass exhibits considerable heterogeneity across individuals, but current clinical tools fall short of effectively measuring it. Predictive genetic information could serve as a valuable tool for efficient diabetes diagnosis, treatment, and prevention, and aid in patient stratification in this era of personalized medicine.

In our quest to understand diabetes better, we probe genetic variants that escalate diabetes risk in both its monogenic and polygenic forms. Given that animal models often fail to faithfully represent human diabetes phenotypes linked with these genetic modifications, we rely on the use of alternative models to explore human genetics further.

Our lab specializes in modeling human endocrine pancreas development through the use of pluripotent stem cells and differentiation protocols steered towards the endocrine lineage. By merging this approach with the genome-editing power of CRISPR/Cas9 technology and comprehensive "omics" methodologies, we can decode the molecular characteristics of human genetic variants in pancreatic development.

Our ultimate goal is to unveil the influence of these variants, a step that could significantly aid in patient stratification and preemptive diagnosis. Furthermore, understanding novel disease effectors may open doors to innovative therapies for both rare and common forms of diabetes.

Current projects

Unraveling the genetic basis of human β cell mass by the study of diabetes risk loci

Study of novel genes and mutations putatively associated with monogenic diabetes

Adult beta cell mass is determined by the size and proliferation of the pancreas progenitor pool. Our focus lies in examining type 2 diabetes risk loci and discerning the influence of specific genes on the proliferation of pancreatic progenitors and the trajectory of endocrine differentiation.

Utilizing "loss-of-function" approaches, we investigate these genes. After genetic perturbation in pluripotent stem cells, we apply differentiation protocols that emulate human development.

Our primary aim is to elucidate the molecular link between diabetes risk and single-nucleotide polymorphisms by integrating GWAS, eQTL databases, and “omics” data from differentiation protocols. The ultimate objective is clinical translation of our findings, connecting genetic data to pathophysiological events and accelerating the advent of personalized medicine.<

Monogenic diabetes, accounting for 1-5% of all diabetes cases, is often underdiagnosed and under-researched. Recognized monogenic variants are predominantly linked with genes vital for endocrine pancreas development. Given that animal models fall short of replicating most human diabetes phenotypes linked with these genetic modifications, we need alternative models for probing human genetics and deepening our understanding of monogenic diabetes.

We study clinically relevant genetic alterations putatively linked with monogenic diabetes. Our proposed studies can help determine if observed clinical phenotypes arise from defective endocrine development or abnormal mature β cell function. Furthermore, they shed light on associated molecular mechanisms – invaluable insights for improving diagnosis and treatment modalities for these patients.