β cell mass is an important component of type 2 diabetes progression, lower β cell mass is associated with reduced insulinaemia, glucose intolerance and diabetes. β cell mass is highly heterogeneous among human individuals, and currently there are no methods for its clinical determination. Genetic information that predicts this, could become a cost-effective tool for diabetes diagnosis, treatment and prevention strategies; a great potential clinical asset in that could allow stratification of diabetes patients in the era of personalized medicine.
We study genetic variants associated with higher risk of diabetes, in both monogenic and polygenic types of diabetes. Animal models cannot recapitulate most of the phenotypes observed in human diabetes associated with these genetic alterations. Therefore, alternative models that allow the interrogation of human genetics are needed in order to advance our knowledge on the genetic components of human disease.
Our laboratory focuses on the modeling of human endocrine pancreas development, this can be achieved with the use of pluripotent stem cells, and differentiation protocols towards the endocrine lineage. This technique – in combination with the genome-editing capabilities of the CRISPR/Cas9 technology – and "omics" approaches, allows the molecular characterization of human genetics variants in this pancreas development.
Our goal is to uncover the role of these variants, which might be an invaluable tool in for the stratification of diabetes patients, but also for preemtive diagnosis. Besides, the molecular characterization of novel disease effectors of the disease might bring new therapies for both rare and common forms of diabetes.
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. We study type 2 diabetes risk loci and determine the effect of genes in the proliferation of pancreatic progenitors as well as the course of endocrine differentiation.
Genes are surveyed by gene "loss-of-function" approaches. After genetic perturbation in pluripotent stem cells, we subject these to differentiation protocols that “mimic” human development.
We aim to determine the molecular association between diabetes risk and single-nucleotide polymorphisms. By the integration of GWAS, eQTL databases and “omics” from differentiation protocols. The long-term objectives will be to translate these findings into the clinic. Linking genetic information to pathophysiological events will bring us closer to the era of personalized medicine.
Monogenic diabetes represents between 1-5% of all diabetes, they are considered underdiagnosed and poorly studied diseases. Known monogenic variants are predominantly associated with genes that are critical for endocrine pancreas development. Animal models cannot recapitulate most of the phenotypes observed in human diabetes associated with these genetic alterations. Therefore, alternative models that allow the interrogation of human genetics are needed in order to advance our knowledge on monogenic diabetes.
We study clinically-relevant genetic alterations that are putatively associated with monogenic diabetes. With the studies proposed in this project, we can determine if clinically observed phenotypes are derived from defective endocrine development and/or abnormal mature β cell function, as well as shed some light on the molecular mechanisms associated – key information that would allow better diagnosis and treatments for these patients.