Deciphering cellular and molecular mechanisms of β-cell regeneration

Projektinformationen

BetaRegeneration

ID Finanzhilfevereinbarung: 101054564

DOI

10.3030/101054564

EK-Unterschriftsdatum 26 Juli 2022

Startdatum 1 November 2022

Enddatum 31 Oktober 2027

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 2 446 645,00

EU-Beitrag

€ 2 446 645,00

Koordiniert durch

HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Germany

Periodic Reporting for period 1 - BetaRegeneration (Deciphering cellular and molecular mechanisms of β-cell regeneration)

Berichtszeitraum: 2022-11-01 bis 2025-04-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Diabetes mellitus is a complex and multifactorial disease characterized by progressive loss or dysfunction of the insulin-producing β-cells in the pancreas, leading to chronic hyperglycemia, systemic metabolic complications and, in the long-term, to multi-organ damage and premature death.
Currently, all pharmacotherapies, including insulin supplementation, focus on managing high blood sugar levels and avoiding the secondary complications rather than addressing the underlying cause of diabetes: pancreatic beta cell failure or loss. Research into beta cell protection and regeneration is crucial and holds promises for addressing the root cause of diabetes, offering potential avenues for causal treatment. Glucagon-like peptide 1 (GLP-1) therapy was shown to regenerate beta cells in mice, but this did not translate to human. Early or intensive insulin therapy maintains residual beta cell function, but also causes weight gain and is associated with an increased risk for severe hypoglycaemic episodes. In breakthrough discoveries we identified the insulin inhibitory receptor (inceptor) as a druggable target for beta cell insulin sensitization and protection without the side-effects of insulin. Moreover, we combined GLP-1-mediated safe beta cell delivery of estrogen with a 60% reduced insulin demand to restore beta cell function for diabetes remission.
With our ERC grant “BetaRegeneration”, we aim to decipher cellular and molecular mechanisms of beta cell protection and regeneration. Based on the previous identification and validation of known and novel therapeutic targets, we want to explore new avenues of targeted and combinatorial beta cell protection and regeneration therapies that could stop and revert diabetes progression.
If successful, BetaRegeneration will initiate a paradigm shift from symptomatic to causal diabetes therapy.

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

Within BetaRegeneration we showed that inceptor binds and directs proinsulin and insulin towards lysosomal degradation in beta cells. This knowledge about inceptor’s function gives us a deeper understanding of how beta cells regulate their insulin homeostasis and might be an target intervention point to replenish insulin stores in stressed and diabetic beta cells. The increased presence of inceptor in diabetic beta cells suggests that the receptor plays a role in insulin resistance and blunding of first-phase insulin secretion, hallmarks of diabetes manifestation. Thus blocking inceptor function, may refill beta cells' insulin stores, enhance insulin release and sensitivity, and prevent beta cell failure and death.

Moreover, in a second study, we explored the effects of inceptor knock-out in diet-induced obese mice. We demonstrated that inhibiting inceptor function also enhanced glucose tolerance in diet-induced obesity and insulin resistance, both critical pre-clinical stages in the progression towards clinical diabetes, hence corroborating the idea that blocking inceptor to enhance beta cell function offers promise in alleviating the detrimental effects of beta cell failure/loss on blood sugar and metabolism. This approach avoids the associated risks of severe hypoglycemic episodes in hypoglycemia-unaware patients and unwanted weight gain typically observed with intensive insulin therapy. Currently, we are actively testing the potential of several inceptor-blocking drug classes to enhance beta cell health in pre-diabetic and diabetic mice for clinical translation.

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)

The findings from BetaRegeneration suggest that specifically targeting inceptor could be a promising strategy for improving the survival and function of insulin-producing beta cells in people with early manifestation of diabetes to slow disease progression and to reduce the risk of complications.

Inceptor proteins moving from within a cell to its surface in a rat insulinoma cell, tagged with a f