Unravelling the mechanisms regulating GLP1 receptor internalization and recycling in insulin secreting pancreatic Beta-cells.
Lead Research Organisation:
University of Cambridge
Department Name: Pharmacology
Abstract
Therapies targeting insulin secreting beta-cells for the treatment of type 2 diabetes (T2D) remain an unmet medical need because there are no approved therapies that reverses loss of functional beta-cell mass, the primary defect leading to disease progression in T2D. Biologics offer great promise as regenerative treatments, for example antisense oligonucleotides [ASO] can knockdown currently undruggable genetic targets or transcription factors linked to beta-cell loss in T2D. However, pancreatic beta-cells are resistant to uptake of ASOs from systemic circulation. Thus, inability to selectively deliver ASO therapies to beta-cells is a substantial barrier to their development as safe treatments for T2D.
Recently AZ has shown, in vitro and in vivo, that conjugation of ASOs to a peptide agonist based upon GLP-1 (an insulinotropic gut hormone) is an unexpected and remarkably effective approach to specifically deliver ASO-cargo to pancreatic beta-cells. While novel, exciting and therapeutically important, as yet, we do not understand the underlying biology related to GLP-1 receptor endo/exocytosis in beta-cells although accessory proteins such as beta-arrestin proteins are expected to play a role. Finally, nothing is known about these processes in T2D.
Recently AZ has shown, in vitro and in vivo, that conjugation of ASOs to a peptide agonist based upon GLP-1 (an insulinotropic gut hormone) is an unexpected and remarkably effective approach to specifically deliver ASO-cargo to pancreatic beta-cells. While novel, exciting and therapeutically important, as yet, we do not understand the underlying biology related to GLP-1 receptor endo/exocytosis in beta-cells although accessory proteins such as beta-arrestin proteins are expected to play a role. Finally, nothing is known about these processes in T2D.
Organisations
People |
ORCID iD |
| Graham Ladds (Primary Supervisor) | |
| Abigail Pearce (Student) |
Publications
Carvalho S
(2021)
Novel mathematical and computational models of G protein-coupled receptor signalling
in Current Opinion in Endocrine and Metabolic Research
Marti-Solano M
(2020)
Combinatorial expression of GPCR isoforms affects signalling and drug responses.
Marti-Solano M
(2020)
Combinatorial expression of GPCR isoforms affects signalling and drug responses
in Nature
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M011194/1 | 30/09/2015 | 31/03/2024 | |||
| 2120024 | Studentship | BB/M011194/1 | 30/09/2018 | 29/09/2022 | Abigail Pearce |
| Description | We have been looking at other cellular proteins that might interact with my receptor of choice, and whether these proteins have any effect on the internalisation of the receptor. A previously unknown interaction has been identified and characterised, with its role on receptor signalling and internalisation elucidated. I have then looked at the role of this interaction on insulin secretion; the protein interaction enhances secretion. This has then opened up the question of whether this interaction can be strengthened in order to become therapeutically exploitable. |
| Exploitation Route | The interacting partners of this receptor must now be considered when designing and improving therapeutic strategies targeting this receptor. This will have an impact on drug design, and how drugs progress through the different stages of R&D; the expression of the interacting protein must be considered when targeting the receptor. |
| Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |