Project description
Innovative treatment to prevent dysfunction of insulin-producing cells in diabetes
Currently, no drug treatment can prevent the progression of diabetes, which is characterised by insulin-producing β-cell dysfunction. The insulin inhibitory receptor (inceptor) was identified recently as a drug target for β-cell protection without insulin side effects. A combination of glucagon-like peptide-1 mediated delivery of oestrogen with insulin therapy might restore β-cell function. The ERC-funded BetaRegeneration project will explore novel approaches for targeted and combinatorial β-cell regeneration therapy. The inceptor will be probed as the target to enhance β-cell insulin sensitisation, secretion, and function. The project will also test monoclonal antibodies (both alone and as drug conjugates) for β-cell protection and regeneration. The goal is to find if combinatorial treatment can stop β-cell loss and dysfunction.
Objective
Glucagon-like peptide 1 (GLP-1) therapy was shown to regenerate β-cells in mice, but this did not translate to human. Early or intensive insulin therapy maintains residual β-cell function, but also causes weight gain and hypoglycaemia. Thus, currently no drug treatment can safely stop the progression of diabetes, a disease characterized by loss or dysfunction of insulin-producing β-cells.
In breakthrough discoveries we identified the insulin inhibitory receptor (inceptor) as a druggable target for β-cell insulin sensitization and protection without the side-effects of insulin. Moreover, we combined GLP-1-mediated safe β-cell delivery of estrogen together with 60% reduced insulin therapy to restore β-cell function for diabetes remission. The overarching goal of BetaRegeneration is to explore new avenues of targeted and combinatorial β-cell protection and regeneration therapy.
In Aim 1 we will reveal whether inceptor, beside desensitizing the insulin receptor, has also a function as insulin receptor in starvation/stress-induced insulin degradation and as scavenger receptor for insulin lysosomal degradation. This will reveal if inceptor can be targeted to enhance β-cell insulin sensitization, secretion and function.
In Aim 2 we will translate our basic findings to in vivo animal and human model systems to explore GLP-1-mediated β-cell delivery and targeting of WNT and β-cell insulin/IGF1 signaling to enhance specificity and target several pathways at once. Furthermore, we will genetically and pharmacologically target inceptor and test if monoclonal antibodies alone or as drug conjugates can promote β-cell protection and regeneration. Our approach will reveal if combinatorial targeting of survival and regenerative pathways can stop β-cell loss and dysfunction.
Taken together, the identification of clinically relevant targets and ways of combinatorial β-cell protection and regeneration therapy could open new avenues to stop and revert diabetes progression.
Fields of science
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-AG - HORIZON Action Grant Budget-BasedHost institution
85764 Neuherberg
Germany