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Séminaire

Genetic and nutritional control of beta cell connectivity

Pr Guy RUTTER
Imperial College London, Royaume-Uni

vendredi 15 décembre 2017 - 11h00 - Auditorium, IGBMC
Invité(e) par Biologie du développement et cellules souches, Gérard GRADWOHL

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.

 

References

Carrat G et al Am J Hum Gen  100(2):238-256 (2017)

http://www.sciencedirect.com/science/article/pii/S0002929717300113

Johnston N et al Cell Metabolism 24(3):389-401 (2016)

http://www.sciencedirect.com/science/article/pii/S1550413116303060

Hodson DJ et al Diabetes 63(9):3009-21 (2014)

http://diabetes.diabetesjournals.org/content/63/9/3009.long

Xin, Y et al Proc Nat Acad Sci 113(12):3293-8 (2016)

http://www.pnas.org/content/113/12/3293.long

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