Very happy that our latest research is out today https://www.nature.com/articles/s41467-020-20632-z. A massive effort by @DNikarus and the rest of the team @IMSR_UoB getting this over the line after almost 6 years of work. Also very thankful for the contributions of all our amazing collaborators!

Beta cell heterogeneity is complex, but it is generally accepted that cells co-exist in various states according to age, proliferative capacity, secretion etc. Cells with immature traits are thought to be proliferative, but poorly functional.

Such cells might be temporarily sheltering/recovering from the high demands of insulin production and associated ER stress. This however poses a conundrum- why would such cells (not an insignificant number) be allowed to exist, even temporarily, if they impaired organ function?

Since heterogeneity in most other tissues is seen as a sign of functional robustness/resilience, we wondered whether there may be more to immature cells than meets the eye. Using in situ imaging, we set out to observe what happens when we decrease the number of immature cells.

Unexpectedly, a decrease in the proportion of PDXlow/MAFAlow cells led to impaired ionic fluxes, cell-cell communication, metabolism and insulin secretion. Mechanistically, this involved changes in gene expression, gap junction expression and glucose-sensitivity.

We also confirmed our previous findings on hub cells, which are immature (PDX1low/MAFAlow). In three different models, loss of hubs was associated with more stochastic islet responses to glucose.

Lastly, we performed the opposite maneuver and reduced the number of PDX1high/MAFAhigh beta cells, which impaired islet function. We then re-established the balance between PDX1low/MAFAlow beta cells, leading to functional restoration.

In summary- 1) beta cell heterogeneity is required for robust islet responses; 2) cells with immature traits contribute to islet signaling even though they don't secrete much insulin; and 3) immature cells appear to be part of the normal islet functional phenotype.

The usual caveats apply- the studies were predominantly in vitro, selection of immature cells was based just upon a couple of markers, and whilst we update our knowledge of islet function, we do not promise that our studies-alone will change diabetes therapy.

Thanks to @LickertHeiko @PiemontiL @guy_rutter @LaiYuChiang @AimeeBastidas, people not on twitter (Joe Zhou, Mostafa). And of course, all the amazing HodSquad members! Lastly, the funders who make this work possible @ERC_Research @The_MRC @DUK_research

And of course the fantastic @IldemAkerman!