Sir Henry Wellcome Postdoctoral Fellow & Junior Research Fellow at Trinity College
- Mathematical modeller
- Patch-clamp electrophysiologist
- Dynamic imaging
- Time-series analysis
Computational and experimental investigation of islet cells
Blood glucose concentrations are tightly controlled in the body. This is via the action of two hormones secreted from the pancreas; insulin (which lowers glucose) and glucagon (which increases glucose). Type 2 Diabetes (which costs the NHS a whopping £1m/hour) is typically characterised by a loss of control of blood glucose. Now, everybody knows about the role of insulin in this disease; insulin therapy has been around as a treatment for over 90 years. Yet the disease remains poorly treated! This is because diabetes is a bi-hormonal disease; part of the increased blood glucose in diabetes is actually due to excess glucagon.
It is therefore very surprising that we don’t know which mechanisms regulate glucagon secretion from pancreatic alpha-cells. We don’t know whether glucagon secretion is regulated by the cells themselves (“intrinsic regulation”), or by their neighbouring cells (“paracrine regulation”). Fundamentally, we don’t even know a very basic fact about alpha-cells; whether glucose increases or decreases activity! Paracrine or intrinsic; the mechanisms are poorly understood and hotly debated. Glucagon is therefore a very important area of diabetes research that is insufficiently investigated.
Perhaps intrinsic and paracrine mechanisms are important for regulating glucagon secretion. Given the complexity of this system, I will take an interdisciplinary approach – combining electrophysiological and computational techniques. Of course, much research has been in the rodent – studies into human alpha-cells are very rare. But I am not interested in treating rodent diabetes! In Oxford, I will have the opportunity to record from and build models of human alpha-cells, integrating experimental and computational techniques with the support of my key international sponsors.
Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet.
Kellard JA. et al, (2020), Mol Metab, 40
Vitamin D-binding protein contributes to the maintenance of α-cell function 2 and glucagon secretion
VILORIA K. et al, (2020), Cell Reports
The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis
Carrat GR. et al, (2020), Molecular Metabolism, 101015 - 101015
Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta-cells.
Vergari E. et al, (2020), Nat Metab, 2, 32 - 40
Leader β-cells coordinate Ca2+ dynamics across pancreatic islets in vivo
Salem V. et al, (2019), Nature Metabolism
Opto-genetic silencing of alpha-cells