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

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.

It is becoming increasingly apparent that pancreatic beta-cells can be grouped into subpopulations according to their transcriptomic, protein and functional signatures. A unifying feature is that immature and mature beta-cell subpopulations co-exist within the islet. Plasticity in these subpopulations occurs during ageing and metabolic stress, and is generally associated with reductions in insulin release. In particular, maturity might be traded for proliferation at the expense of insulin secretion. However, this questions the role of immature beta-cells in the adult islet given the low levels of beta-cell proliferation and the requirement to maintain function. Moreover, most studies to date have either used isolated beta-cells, devoid of paracrine, juxtacrine and electrical communications known to shape beta-cell function, or alternatively have averaged measures across the population. Our preliminary data show that loss of immature beta-cells from the islet leads to insulin secretory failure due to impaired cell-cell communication, metabolism and amplifying signals. As such, we hypothesise that immature beta-cells are an underappreciated player in the regulation of insulin release when viewed directly within the islet setting. By melding cutting-edge imaging, recombinant genetics, light-activated transcription factors and photopharmacology, we now aim to functionally interrogate a role for immature beta-cells in islet operation and insulin release. Specifically, we will:

1) produce and test a loss-of-immaturity beta-cell model using viral approaches and mouse genetics;

2) deploy next-generation optogenes and photoactivatable doxycycline to reversibly control beta-cell maturity with pinpoint precision in multiple systems;

3) understand how inducible loss of immature beta-cells in vivo might influence glucose tolerance;

4) investigate whether loss of immature beta-cells leads to islet failure and diabetes during metabolic stress.

Pharmaceutical industry: The proposed research will provide new mechanistic insights into how beta-cell heterogeneity within the islet contributes to insulin release. This may lead to the identification of drug targets achieving glucose homeostasis in humans. Indeed, current treatment regimens are based on single cell characteristics, yet increasing evidence suggests that we should be aiming to reverse "networkopathies" (i.e. defects in the functional pattern of cell gene expression/activation). Moreover, islets engineered from stem cells (iPSC) are currently in phase 1 trials for transplantation during diabetes, but their in vitro performance does not match that of native islets. The present studies will therefore be important for informing how we can engineer better performing and more robust iPSC-derived islets for transplantation.

UK economy: Since the diabetes drugs market is worth billions per year, and the stem cell market predicted to be similarly large, the licensing or spin-off of any molecules/novel targets may contribute to UK economic competitiveness.

Life Sciences suppliers: We will generate a number of novel tools to precisely induce gene expression in single cells within a tissue using light. This will impact many different research fields (cancer, cardiovascular, neuroscience) that currently rely on less specific methodology to control gene expression levels.

Patients living with diabetes: The characterization of novel mechanisms governing insulin secretion from islets may eventually lead to therapies which allow better or ancillary control of blood glucose levels (e.g. by preserving the balance between immature and mature beta-cells). Moreover, by applying this information to the production of islets from iPSC cells, transplants may be more robust and perform better.

Staff: The postdoctoral researcher and technician will be recruited into the IMSR (~ 80 researchers), providing excellent opportunities for multi-disciplinary training. The present project proposal seeks to apply cutting-edge technologies to functionally dissect the contribution of immature beta-cells to insulin secretion. This would equip the postdoctoral researcher with a broad and interdisciplinary skills-set, which would open up the possibility to work in a number of other academic fields, thus increasing their future career prospects. In addition, such a background is desirable for the private sector. For example, PhD candidates with strong interdisciplinary skills are attractive not only to the pharmaceutical industry, but also to the financial sector.

General engagement: Societal impact will be assisted through engagement activities. These include formal and informal presentations (e.g. Pint of Science, Life Sciences in Six), press releases and social media (e.g. Twitter). The lab has an extensive track record in public engagement, including production of bitesize YouTube videos and appearances on BBC Radio.