Associated organisationsLeibniz-Forschungsinstitut fuer Molekulare Pharmakologie · University of Birmingham · University of OxfordEurope PMC affiliations are not treated as award recipients or mapped locations.
Funding£2.5M
PeriodMar 2024 — Feb 2029
In plain English
AI plain-English summary
People with type 1 diabetes who receive transplanted beta cells often see those cells fail or die within months. The problem is that replacement cells lack the molecular tools to survive immune attack and function long-term. This project aims to solve that by using two well-known cell-surface receptors—GLP1R and GIPR—as molecular addresses to deliver protective therapies directly to beta cells. GLP1R is a marker of healthy beta cells and is still present on 10–20% of stem-cell-derived beta cells, as well as on beta cells in early type 1 diabetes models. GIPR, meanwhile, is abundant on alpha cells, which survive even in advanced disease, offering a route to coax them into becoming new beta cells. If successful, this work could transform beta cell replacement from a niche, short-lived intervention into a durable therapy for the majority of people with type 1 diabetes. It would allow precise delivery of gene therapies or immune inhibitors to beta cells without affecting other tissues, and could also enable regeneration of beta cells from the body’s own alpha cells. The research is applied and translational, with a clear path toward improving transplantation outcomes and reducing reliance on immunosuppression.
View original technical description
One of the greatest challenges in type 1 diabetes (T1D) is ensuring function and survival of replacement beta cells. Rolling beta cell replacement out as an option for the majority of people living with T1D remains the major goal. Glucagon-like peptide-1 (GLP1R) and gastric inhibitory polypeptide (GIPR) receptors are 7-transmembrane receptors widely involved in beta cell function. Drugs targeting GLP1R and GIPR are the mainstay of type 2 diabetes and obesity therapy, since they influence insulin secretion and food intake. However, GLP1R and GIPR also constitute potentially powerful targets for T1D treatment, since: 1) GLP1R is a beta cell marker critical for proper function/survival; 2) GLP1R is expressed in a subpopulation (10-20%) of stem-cell derived beta cells (SBCs); 3) GLP1R is still present in beta cells in preclinical models of early T1D onset; 4) GLP1R provides a molecular address for precision delivery of drugs (e.g. gene therapy, immune inhibitors) directly to beta cells; and 5) GIPR (but not GLP1R) is highly expressed in alpha cells, which persist even during T1D, allowing interrogation of alpha cell to beta cell transdifferentiation. Over the past decade, our interdisciplinary team has made major contributions to GLP1R/GIPR biology and beta cell replacement. We will now leverage GLP1R and GIPR as mature cell markers and molecular addresses for improved beta cell replacement and regeneration during T1D. Our ultimate goal is to pioneer precision approaches to generate better functioning/longer-lasting SBCs for transplantation, protect transplanted beta cells during immune attack, and replenish beta cells from other sources.
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