Investigating beta cell heterogeneity in the context of type 2 diabetes
Lead Research Organisation:
University of Birmingham
Department Name: Inst of Metabolism & Systems Research
Abstract
Type 2 diabetes (T2D) currently affects ~10% of the UK adult population and is one of the foremost health challenges currently facing society. This syndrome can be described as a failure of the pancreatic beta cell mass to secrete sufficient insulin to counteract elevated blood glucose levels. It is largely believed that all beta cells are the same. However, recent studies by us and others have shown that beta cells in fact comprise discrete subpopulations, some of which contribute more to T2D than others. The aim of the present project is to identify these beta cells, with the hope of developing new, more targeted therapies to restore insulin release during T2D. To allow this, state-of-the-art imaging approaches, including multiphoton microscopy, will be combined with mouse genetics and optogenetics to explore how subtle variations in the beta cell 'barcode' may predispose to T2D both in vitro and in vivo. The present project presents an excellent opportunity to perform research at the cutting edge of endocrinology in a supportive and nurturing environment. The PhD student will join a vibrant, dynamic and internationally-recognised team, with close collaborators in France, Germany and the USA.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013913/1 | 01/10/2016 | 30/09/2025 | |||
| 1854365 | Studentship | MR/N013913/1 | 01/10/2017 | 30/09/2019 | Lewis Everett |
| Title | Artist in residence |
| Description | We are currently working with an artist in residence who will design a creative media piece to show how diversity across beta cells impacts insulin release. |
| Type Of Art | Artwork |
| Year Produced | 2020 |
| Impact | The artwork is still in progress. |
| Description | Design, synthesis and testing of SNAP labels for visualizing surface proteins |
| Organisation | Cornell University |
| Department | Weill Cornell Medicine |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | We helped to develop and generate a number of cell-impermeable fluorophores for interrogating surface proteins. We performed trafficking studies using the SNAP_GLP1R. |
| Collaborator Contribution | Our partners performed SIMPull experiments, as well as synthesised compounds. |
| Impact | The is an inter-disciplinary collaboration. The collaboration has only just started, so outputs are pending. |
| Start Year | 2019 |
| Description | Design, synthesis and testing of SNAP labels for visualizing surface proteins |
| Organisation | Max Planck Society |
| Department | Max Planck Institute for Medical Research |
| Country | Germany |
| Sector | Charity/Non Profit |
| PI Contribution | We helped to develop and generate a number of cell-impermeable fluorophores for interrogating surface proteins. We performed trafficking studies using the SNAP_GLP1R. |
| Collaborator Contribution | Our partners performed SIMPull experiments, as well as synthesised compounds. |
| Impact | The is an inter-disciplinary collaboration. The collaboration has only just started, so outputs are pending. |
| Start Year | 2019 |
| Description | Design, synthesis and testing of orthosteric peptide labels for visualizing GLP1R |
| Organisation | Max Planck Society |
| Country | Germany |
| Sector | Charity/Non Profit |
| PI Contribution | We performed all the pharmacological and biological testing of next generation antagonist far red GLP1R peptide labels. To test specificity of the probes, we also generated GLP1R-/- mice using CRISPR technology. |
| Collaborator Contribution | Kai Johnsson's and Johannes Broichhagen's group at the MPI for Medical Research designed and synthesised next generation antagonist far red peptide labels for detecting endogenous GLP1R. They also performed super-resolution microscopy (STED) using Stefan Hell's nanoscopy platform, located in Heidelberg, Germany. |
| Impact | We have had numerous requests for probes and animals based upon conference presentations. So far, we have disseminated probes to muliple labs in UK, EU and North American. We have also distributed GLP1R-/- mice under MTA to Imperial College London and Helmholtz Munich. We are finalizing a licensing agreement with Spirochrome for supply of compound. We are also using these compounds in a number of other projects. The collaboration is highly multi-disciplinary spanning chemistry, chemical biology, structural biology, physiology and pharmacology. |
| Start Year | 2018 |
| Description | Purifying mature hESC-derived beta cells using GLP1R probes |
| Organisation | University of British Columbia |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | We developed and validated GLP1R probes, allowing its visualization. |
| Collaborator Contribution | The partner generated beta-like cells from hESC, before staining with GLP1R probes and FACS-sorting for assessment of maturity. |
| Impact | We have shown that GLP1R can be used to purify the most mature beta-like cells derived from hESC. This is important, since transplants of such cells are in clinical trials, yet performance is still lacking versus native islets. |
| Start Year | 2019 |