Project description
Insight into the role of glucagon in diabetes
Emerging evidence indicates that apart from reduced insulin, diabetes is also influenced by the hormone glucagon. The latter is produced by the alpha cells of the pancreas and counteracts the effect of insulin, maintaining blood glucose levels. Diabetes patients present with increased glucagon levels and concomitantly high production of glucose from the liver. Funded by the European Research Council, the ParaALPHA project aims to investigate the effect of intrinsic and paracrine signalling pathways that regulate glucagon secretion. The working hypothesis is that paracrine signalling affects the metabolism of alpha cells and deregulates glucagon secretion. Given the high prevalence of diabetes globally, results have important clinical consequences.
Objective
Diabetes is a common disease affecting millions of patients world-vide. The disease is characterised by hyperglycaemia, caused by reduced insulin signalling and release. Recent findings suggest that the hormone glucagon also plays a critical role. Glucagon is a counteregulatory hormone released form alpha cells in pancreatic islets, to increase hepatic glucose production. Diabetic and obese patients suffer from hyperglucagonaemia, which leads to inappropriate hepatic glucose production. Glucagon secretion is regulated by intrinsic and paracrine mechanisms. The intrinsic regulation rely on the effect of glucose on metabolism and the paracrine on secretion of hormones from neighbouring beta and delta cells. Paracrine signalling form insulin and somatostatin inhibits glucagon secretion through activation of Protein kinase B and inhibition of protein kinase A leading to lower electrical and exocytotic activity. Both kinases regulate transcription and metabolism in other tissues. I suggest that paracrine signalling also affect alpha cell metabolism to regulate glucagon secretion. My recent work show that alpha cells rely on fatty acids for ATP production and that the mechanism by which glucose inhibits glucagon secretion requires glucose to lower fatty acid oxidation. In this project, I will 1) investigate whether insulin and somatostatin signalling regulate metabolism and ATP production in alpha cells, 2) identify the underlying kinase signalling, and 3) explore the role of hyperglucagonaemia in diabetes. To understand the effect of insulin and somatostatin on alpha cell function and glucagon secretion, I will use dynamic measurements of kinase signalling, ATP levels, membrane potential and calcium in mouse and human islets. Combining this with genetically modified animal models, we will have the unique opportunity to study if dysfunction of both paracrine and intrinsic regulation of glucagon secretion is required for the development of hyperglucagonaemia in diabetes.
Fields of science
- natural scienceschemical sciencesinorganic chemistryalkaline earth metals
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biologycell metabolism
- medical and health sciencesclinical medicineendocrinologydiabetes
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
ERC - Support for frontier research (ERC)Host institution
1165 Kobenhavn
Denmark