Redox homeostasis and the regulation of glucagon secretion from pancreatic alpha cells

Diabetes is a major health concern worldwide with a steadily increasing prevalence. Both insulin and glucagon regulation are disrupted in diabetes resulting in dysregulated blood glucose levels. In healthy individuals, insulin is secreted in response to high blood glucose, while glucagon is a counter-regulatory hormone preventing life-threatening hypoglycaemia. The role of insulin in diabetes is well described, including the pathophysiology of beta cell loss or dysfunction in diabetes type 1 and 2, respectively. Diabetic alpha cells have been shown to over-secrete glucagon at higher blood glucose levels, but fail to respond to hypoglycaemia. The underlying cause of glucagon dysregulation in diabetes is however unknown. This drastically impairs diabetes therapy due to the constant risk of therapy-induced hypoglycaemia.
The glucagon output of alpha cells is regulated by paracrine signalling, as well as an intrinsic mechanism of glucose sensing. However, the latter remains controversial as different pathways have been suggested to serve as alpha cell glucose sensor. One mechanism suggests that alpha cells rely on fatty acid oxidation in low glucose, which is inhibited once glucose levels increase. Alpha cells oxidise low amounts of glucose for energy production, which suggests a metabolic specialisation for a cell that needs to function in unfavourable conditions of low glucose availability.
The aim of this PhD project was to explore whether glucose is used in alternative metabolic pathways not to provide energy, but redox equivalents. This thesis shows that glucose increases the cytosolic glutathione redox pool in alpha cells, which increases the secretory potential in subsequent hypoglycaemia. Glucose is metabolised via the pentose phosphate pathway in alpha cells, which is essential for adequate glucagon secretion. Redox charging also has implications for glucagon secretion in vivo in mice. Further, redox amplification of glucagon secretion acts via the protein kinase A axis, activating calcium oscillations in isolated islets.
In summary, the here presented findings show that glucose charges the alpha cellular redox pool which is essential for adequate glucagon responses to glucose changes. This provides a new perspective for redox imbalance as the potential root of glucagon dysregulation in diabetes.