1. As the number of beta-cells decline with diabetes progression, decades of research have shown that significant changes occur in the function, numbers and types of pancreatic endocrine cells, as well as in key blood-circulating factors. In mice, these responses can, in some cases, promote remission and recovery from diabetes by fostering beta-cell regeneration or normalization of high blood glucose levels. Unfortunately, our knowledge of these convoluted processes is fragmented and incomplete, as previous studies only provide temporal snapshots or focus only on certain physiological aspects at a time. To address this, we developed a transgenic mouse model where we can destroy different amounts of beta-cells, modelling the progressive loss of beta-cells observed in diabetes.
We successfully carried out systematic multi-omics profiling of whole-body systemic responses and physiological adaptations to decremental beta-cell mass in mice, in comparison to whole-body insulin signaling blockade using a potent insulin receptor antagonist. Multi-omics included plasma lipidomics, metabolomics, proteomics and RNAseq of miRNAs in addition to bulk RNAseq of 10 organs, all at 10 days after either the ablation of the insulin-producing pancreatic beta-cells, or insulin receptor blockade. With this novel experimental approach, we identified phenotypes and circulating molecules that are beta-cell ablation-specific, including severe whitening (lipid accumulation) of brown adipose tissue (BAT) and a variety of plasma lipids, proteins, metabolites and miRNAs.
2. Concerning the studies with human pancreatic islets, we obtained preliminary results that have started to identify key metabolic differences between human alpha- and beta-cells.
3. Our work has advanced significantly in understanding endocrine cell plasticity in the pancreas. We discovered that Ppy-expressing islet gamma-cells can also produce insulin in the absence of beta-cells, as previously reported for alpha- and delta-cells (Nat Commun., 2021). We demonstrated that adult islet cells arise from embryonic hormone-expressing cells generated at different developmental stages, with no evidence of postnatal neogenesis (Cell Rep., 2022). We showed that murine islets in vivo and human pseudoislets composed exclusively of beta-cells can sustain regulated and adaptive insulin secretion in the absence of other endocrine cell types (Nat Metab., 2024). These projects have inspired new lines of investigation, including a promising project investigating the epigenetic mechanisms driving alpha-cell plasticity.
Results have been presented at major international meetings (EASD, ISG, SSED, SFD) and several papers in high impact journals have been published or are in preparation.
