Paracrine signalling in alpha cells and the integration of mechanisms that control glucagon secretion

Projektinformationen

ParaALPHA

ID Finanzhilfevereinbarung: 101078420

DOI

10.3030/101078420

EK-Unterschriftsdatum 16 Dezember 2022

Startdatum 1 April 2023

Enddatum 31 Juli 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 659 836,00

EU-Beitrag

€ 1 659 836,00

Koordiniert durch

KOBENHAVNS UNIVERSITET
Denmark

Periodic Reporting for period 1 - ParaALPHA (Paracrine signalling in alpha cells and the integration of mechanisms that control glucagon secretion)

Berichtszeitraum: 2023-04-01 bis 2025-09-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

More than 500 million people live with diabetes. It is a disease characterized by elevated blood glucose levels. The main culprit is thought to be the hormone insulin, which, under normal physiological conditions, acts to lower blood glucose. In diabetes, peripheral tissues become insulin resistant and eventually insulin secretion is lost, leading to hyperglycaemia. Recent research has revealed that another hormone, called glucagon, also contributes to the development of hyperglycaemia. Glucagon is a counterregulatory hormone that acts on the liver to restore blood glucose levels when they become too low. In diabetic patients glucagon levels are elevated at normal blood glucose levels, but release hampered at low glucose, contributing to the development of hyperglycaemia. While treatment of hyperglucagoneamia hold promise lowering hyperglycaemia in diabetes, there is currently no drugs targeting hyperglucagoneamia in diabetes. One reason is that we know very little about the mechanisms that control glucagon secretion from pancreatic alpha cells. There is currently no consensus mechanism of how glucose acts to suppress glucagon secretion. One thing that is consensus about is that there are two main mechanisms in play, intrinsic glucose sensing, driven by metabolic regulation, and paracrine control, driven by kinase signalling. The relative importance of both mechanisms is debated, but there seems to be no clear answer. Here I propose that this is in reality one integrated mechanism, where intrinsic and paracrine mechanisms work synergistically to drive changes in glucagon secretion. The results from this project will close a clear knowledge gap in our basic understanding of the regulation of glucagon secretion, the development of hyperglucagoneamia and the importance of normal alpha cell function for the development of diabetes.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The team has spent the initial two years of the project, establishing the tools required to answer the main hypothesis. We have been successful in establishing a range of Kinase sensors and a novel mouse model. This has allowed us to collect preliminary data in several work packages, and we are beginning to se the emergence of initial indication on the role of kinase signaling in alpha cells.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

We have established the first alpha cell specific range of Kinase sensors and have developed a novel mouse model. This will allow us to pursue larger goals such as the improved understanding of the effects of paracrine signaling in alpha cells.