Characterizing and modulating the insulin-producing beta-cell fate in monogenic diabetes by using novel genetic setups

The goal of this project was to study and control the cellular and molecular changes characterizing diabetes development. To achieve this objective, we designed a combination of top-notch genetic tools, which were deployed in the context of the most common monogenic diabetes condition, MODY3 (Maturity Onset Diabetes of the Young) a disorder caused by mutations in the HNF1A gene. As part of this effort, we generated two novel mouse MODY3 disease models allowing the specific and timed induction of the Hnf1a mutation in the organ, tissue, or cell type of choice. When the Hnf1a mutation was restricted to the insulin-producing cells, the mice were mildly hyperglycemic and exhibited glucose regulation problems. Moreover, the pancreatic islet architecture was changed with fewer than normal insulin-producing cells, while certain other neighboring cell types displayed an increased fraction. These effects only occur when the Hnf1a mutation is induced during development, not adulthood. Notably, when the Hnf1a mutation is extended to the entire pancreatic islet, these mice are severely hyperglycemic, reduction of the islet endocrine cell numbers and cell fate conversion phenomena. At molecular level, these models presented a profound and dynamic deregulation of specific signatures at both transcriptome and proteome levels. Targeting complex metabolic networks as well as specific genetic manipulation improved the diabetes phenotype. Our data indicate that Hnf1a is a master regulator of cell identity in the mammalian pancreas and its deregulation leads to changes in islet architecture and key molecular networks, which can be tuned to improve the diabetes condition.

We generated a timeline of the cellular and molecular changes underlying MODY3 development and identified ways to significantly ameliorate the condition. Based on the genetic models, pipelines, and tools that were developed while performing this research, we established a strong network of novel local, national and international collaborations. The identification of strategies able to improve the diabetes state prompted new collaborations with relevant local clinicians. If our research proves clinically translatable, this project paved the ground for better diabetes management. By abroad research stages and collaborations, we transferred to Bergen materials and expertise (transgenic mouse lines, cell lines, analysis pipelines, circadian rhythms setups, islet isolation). One PhD student and one MSc student used the generated data for their theses, while 3 newly recruited PhD students are now working on distinct research aspects uncovered in this work.

Diabetes is characterized by hyperglycaemia resulted from the impaired ability of the body to produce or respond to insulin. This group of energy metabolism diseases is showing an alarming increase in the incidence rate, the worldwide prevalence being estimated to rise from 2.8% in 2000 to 4.4% in 2030. The two prevailing forms of diabetes are exceedingly difficult to study due to their complex aetiology caused by an intricate genetic/environmental interaction (polygenic and multifactorial). Consequently, their exact causational factors and underlying mechanisms have not yet been defined. Using novel setups, we plan to comprehensively characterize and modulate the systemic cellular processes and molecular mechanisms defining the insulin-producing beta-cell fate in a maturity-onset monogenic diabetes disorder (MODY3 due to HNF1alpha mutation). Specifically, this proposal addresses the following key questions: (1) What are the systemic cellular and molecular mechanisms characterizing beta-cell dysfunction and diabetes onset? (2) Could they be delayed or reversed? To address these issues, we propose an innovative strategy combining the reliability of genetic cell-tracing analysis and the precision of three complementary murine MODY3 models. This systemic approach will provide unprecedented insights into the mechanisms and dynamics underlying diabetes as well as age-related monogenic disorders. Concretely, by analyzing the beta-cell decay in a niche context, we shall generate the first dynamic cellular and molecular timeline of a slowly progressive MODY disorder and attempt its modulation.