Functional and computational analyses of the regulation of glucagon secretion in health and disease (360G-Wellcome-201325_Z_16_Z)

In type-2 diabetes mellitus (T2DM), pancreatic beta-cells fail to secrete insulin in response to high blood-glucose concentrations. However, in many diabetic patients, glucagon secretion from pancreatic alpha-cells is also impaired; glucagon secretion fails to be suppressed by high blood-glucose, and fails to increase even when blood-glucose falls to dangerously low levels. This impaired ‘counter-regulation’ in diabetes is a major cause of mortality in insulin-treated patients. The mechanisms underlying the glucose control of glucagon secretion from alpha-cells remain poorly understood, even under healthy conditions. There is conflicting evidence that at least four different ion channels contribute to the normal counter-regulation of glucagon secretion, as well as evidence for external paracrine influences. In this project, I will investigate the ion channels that contribute to the normal counter-regulation of glucagon secretion from alpha-cells by using pharmacological and electrophysiological techniques in KO strains of mice. I will combine this with computational modelling of alpha-cells; the models will help me to verify my experimental findings and understand which mechanism(s) could explain the impaired counter-regulation seen in T2DM. I will then investigate the findings of the model in an experimental (mouse) model of T2DM as well as by recording from human islets from T2DM donors.