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Research groups

Linford Briant

PhD, MSci

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.

Simulating the electrical activity of cells in human islet

Simulations demonstrate that glucagon secretion is suppressed by delta-cells in high glucose. The left hand image shows electrical activity in beta-cells; these become electrically active in high glucose, activating delta-cells (middle image). These, by releasing somatostatin, inhibit alpha-cells (right hand image). Hence glucagon secretion in human islets is regulated by this pathway. Each cell is represented by a sphere; colour of each cell represents electrical activity, changing in time (time step = 10ms).

Opto-genetic silencing of alpha-cells

Alpha-cells were patch-clamped in islets, where the light-sensitive channel ChR2 was expressed in beta-cells. Opto-activation of beta-cells triggered a suppression of activity in alpha-cells, demonstrating the importance of "paracrine" regulation of alpha-cell activity glucagon secretion.