Project description
Insight into metabolic reprogramming in diabetes
Emerging evidence indicates that human islet non-beta cells in the pancreas display plasticity and can naturally switch to insulin production upon loss of beta cells. The EU-funded Merlin project will investigate islet cell dynamics and circulating molecules in diabetes aiming to understand the metabolic adaptations that occur in the pancreas and in peripheral organs in response to insulin deficiency. Scientists will experimentally trigger and molecularly characterise the metabolic reprogramming after hyperglycaemia and determine if it suffices to control glucose levels in the blood. The project's results will pave the way for novel ways to regulate hyperglycemia and contribute to diabetes recovery.
Objective
My group aims at fostering the regeneration of insulin-producing -cells in the diabetic pancreas by promoting the reprogramming of other islet endocrine non- cells. I will use mice and human islets to trigger the metabolic reprogramming of: i) peripheral organs, in order to reduce hyperglycemia, and ii) human islet non--cells, to induce their acquisition of insulin secretion.
I developed transgenics to elicit total (>99%) or graded (5-90%) -cell loss. These mice revealed that non--cells, which produce other hormones, can naturally switch to insulin production upon -cell loss, and lead to diabetes recovery. My group recently showed that human non--cells, from healthy or diabetic donors, also display plasticity and can engage in regulated insulin secretion.
What metabolic adaptations occur in peripheral organs in response to insulin deficiency, but without complications? Can metabolic reprogramming of peripheral organs, based on these adaptations, suffice to control glycemia? Can metabolic reprogramming change the identity of a cell?
Natural recovery of euglycemia after -cell loss is documented in mice. To know the mechanisms driving relief, my lab will characterize islet cell dynamics and circulating molecules (metabolites, RNA, peptides) after various degrees of -cell loss. We will perform a full analysis of blood and peripheral organs in recovered mice, and an array of genetic and pharmacological experiments modulating BAT mass and function to test its role in taming hyperglycemia.
We will explore and define the metabolic differences between human - and non--cells. Using monotypic pseudoislets we will do RNAseq, proteomics and metabolomics after exposure to glucose. We will quantify oxygen consumption, extracellular acidification and ATP production in response to nutrients and metabolic toxins. From this, we will genetically (CRIPR-Cas9) and chemically reprogram the metabolism of human non--cells to boost the expression of -like genes.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesclinical medicineendocrinologydiabetes
- natural sciencesbiological sciencesgeneticsRNA
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
1211 Geneve
Switzerland