Stronger together: understanding pancreatic beta-cell connectivity in health and disease
Persistently elevated levels of glucose and fatty acids are known to contribute to failed insulin secretion during the development of Type 2 diabetes. We have shown that glucolipotoxic conditions impair cell-cell communication (“connectivity”) to impair insulin secretion (Hodson et al, 2013). Recently (Johnston et al, 2016) we have combined optogenetics and rapid Ca2+ imaging across the islet syncytium to demonstrate that a subset (~5%) of beta cells (“hubs”) coordinate the activity of “follower” cells. Photo-painting using a light sensitive-RFP revealed that hub cells are enriched for glucokinase, but show low levels of Nkx6.1 and insulin gene expression. These cells also display enhanced mitochondrial membrane potential in response to high glucose. Interrogation of single β cell RNASeq data (Xin et al PNAS, 2016) confirms the existence of a subset of cells with a similar transcriptomic configuration. Hub cells are unusually susceptible to metabolic stresses including high fatty acid/glucose levels, and cytotoxic cytokines, suggesting that they may be targeted in diabetes. Since deletion of GWAS genes for diabetes including ADCY5 and TCF7L2 affect cell-cell communication, future work will explore the possibility that genes at other loci, including STARD10 (Carrat et al, 2017) also act in part by altering hub cell-led β cell connectivity. Recent findings exploring the existence of β cell sub-populations in islets in the living animal, including zebra fish and after engraftment into the anterior chamber of the mouse eye, will also be discussed.
Date:
9 November 2018, 13:00 (Friday, 5th week, Michaelmas 2018)
Venue:
Sherrington Building, off Parks Road OX1 3PT
Venue Details:
Large Lecture Theatre
Speaker:
Professor Guy Rutter (Imperial College London)
Organising department:
Department of Physiology, Anatomy and Genetics (DPAG)
Host:
Dr James Cantley (Department of Physiology, Anatomy and Genetics)
Part of:
DPAG Head of Department Seminar Series
Booking required?:
Not required
Audience:
Members of the University only
Editors:
Victoria Bullett,
Isabella Renehan