University Research Lecturer
- Diabetes UK RD Lawrence Research Fellow
In body, glucose concentration is tightly regulated within a narrow range. Pancreatic islets play a central role in maintaining such homoeostasis. They do so by secreting two glucose regulating hormones; insulin from the beta cells and glucagon from the alpha cells. Diabetes, a disease characterised by unregulated systemic glucose, is caused not only by lacking of glucose-lowering insulin, but also by lack of proper control of glucose-elevating glucagon. The importance of glucagon in diabetes is underpinned by the observation that mice lacking of glucagon signalling do not develop diabetes even when their insulin secretion was abolished.
Normally glucagon secretion is stimulated at low glucose levels and inhibited at high glucose levels. How glucagon secretion is regulated remains poorly understood. Currently mechanisms proposed include paracrine (that controlled by factors secreted from neighbouring cells) and intrinsic (that within the alpha cell itself) regulations. Intrinsic glucose regulation of glucagon secretion involves an ATP-regulated potassium channel (KATP-channel). Glucose metabolism produces ATP to restrict KATP-channel activity to modulate alpha cell activity and inhibit secretion. Dysregulation of glucagon secretion seen in diabetes can be corrected by application of low dose KATP-channel blocker highlights the causal role of the channel in diabetes.
However, there are cases that glucagon secretion can be regulated by mechanisms independent to the KATP channels. For example, amino acids and adrenaline have similar effect in alpha cell activity as glucose but opposite effect in secretion. Intra-islet hormones like insulin and somatostatin also regulate glucagon secretion. Their secretion is stimulated by glucose. Therefore their function becomes more important when blood glucose level is higher.
Using electrophysiology, hormone secretion and imaging techniques, we aim to address how different mechanisms operate in alpha cells to maintain a timely and precise control of glucagon release - in a way that prevents the body from hypoglycaemia without causing prolonged hyperglycaemia. Such study will also lead to understanding of how glucagon regulation becomes impaired in diabetes and provide possible means to correct the defect seen in disease.
Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ release.
Denwood G. et al, (2019), J Gen Physiol, 151, 1094 - 1115
Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production.
Knudsen JG. et al, (2019), Cell Metab, 29, 430 - 442.e4
Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion.
Vergari E. et al, (2019), Nat Commun, 10
α-cell glucokinase suppresses glucose-regulated glucagon secretion.
Basco D. et al, (2018), Nat Commun, 9
Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy.
Babinsky VN. et al, (2017), Endocrinology, 158, 2486 - 2502