Leveraging GLP1R and GIPR as molecular addresses for precision beta cell therapy/replacement during type 1 diabetes

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.