Investigating the role of immature beta cells in insulin release from the intact islet

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Type 2 diabetes mellitus (T2DM) occurs when pancreatic beta-cells are unable to release enough insulin to combat resistance to the hormone. The resulting increase in blood glucose levels drives a range of severe complications including cardiovascular disease, renal and liver failure, retinal degeneration and cancer. As such T2DM is considered an immediate healthcare crisis, affecting 1 in 10 adults in the UK and consuming 9% of the NHS annual budget. Despite intensive research efforts, T2DM incidence continues to rise and NHS spend is projected to double by 2035. To have any hope of halting this trend, we urgently need to open up new research avenues to identify mechanisms and therapeutic targets. Research from us and others over the past few years has shown that not all beta-cells are equal. Much like society, beta-cells possess different ages, abilities and capacities. When the proportions between these different beta-cells become imbalanced, for example during obesity, ageing or diabetes, then insulin release declines. In particular, predominance of younger or immature beta-cells is associated with generation of more beta-cells, but at the expense of insulin release. Despite this, practically nothing is known about the immature beta-cells that are normally resident in the healthy adult pancreas. Our most recent studies have shown that, contrary to expectation, immature beta-cells might in fact play a central role in regulating insulin release. We now aim to: 1) investigate how loss of immature cells influences behaviour of the other, more mature beta-cells;2) control the maturity status of individual beta-cells using light to directly explore their contribution to insulin release; 3) develop a mouse model where immature beta-cells can be made to be more mature using drugs in the food; 4) determine whether loss of immature beta-cells predisposes to T2DM. It is anticipated that these studies will provide an updated blueprint for insulin release, with relevance for T2DM treatment as well as the generation of islets from stem cells for transplantation.