Presenilin-1 controls glucose metabolism and identity of pancreatic beta cells

Zhanat Koshenov; Sandra Postić; Gabriela Schosiwohl; Savina van Amsterdam; Victoria Hois; Furkan Enes Oflaz; René Rost; Oleksandra Tiapko; Benjamin Gottschalk; Martin Hirtl; Olaf A. Bachkoenig; Aigerim Koshenova; Yusuf Ceyhun Erdogan; Adlet Sagintayev; Anita Krnjic; Johannes U. Pfabe; Srdjan Sarikas; Bernhard Hochreiter; Juergen Gindlhuber; Matthias Schittmayer; Jelena Tadić; Barbara Ehall; Frank Madeo; Tobias Madl; Roland Malli; Ruth Birner‐Gruenberger; Thomas Rudolf Pieber; Tobias Eisenberg; Marjan Slak Rupnik; Wolfgang F. Graier

doi:10.1101/2025.09.05.674426

Cell BiologybioRxivSep 5, 2025

Preprint

Presenilin-1 controls glucose metabolism and identity of pancreatic beta cells

Zhanat Koshenov iD, Sandra Postić iD, Gabriela Schosiwohl, Savina van Amsterdam, Victoria Hois, Furkan Enes Oflaz iD, René Rost iD, Oleksandra Tiapko iD, Benjamin Gottschalk iD, Martin Hirtl iD, Olaf A. Bachkoenig, Aigerim Koshenova, Yusuf Ceyhun Erdogan iD, Adlet Sagintayev iD, Anita Krnjic, Johannes U. Pfabe iD, Srdjan Sarikas iD, Bernhard Hochreiter iD, Juergen Gindlhuber iD, Matthias Schittmayer iD, Jelena Tadić iD, Barbara Ehall iD, Frank Madeo iD, Tobias Madl iD, Roland Malli iD, , Wolfgang F. Graier iD

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Abstract

AbstractPresenilin 1 is an endoplasmic reticulum protein, most known for its role in pathogenesis of familial Alzheimers Disease (AD). Presenilin 1 has been attributed roles in intracellular calcium homeostasis in the brain, as well as in the pancreatic beta cells, where it has been shown to be fundamental for glucose-induced insulin secretion. Functional similarity of presenilin 1 in regulation of intracellular calcium homeostasis in the brain and pancreas prompted us to investigate a prevalent assumption that associates AD and diabetes mellitus. By examining pancreatic islets from AD model mice, we have found deficits in initial phase of glucose-induced calcium signaling and insulin secretion. Furthermore, these transgenic mice showed a tendency towards reduced expression of mature beta cell markers, which was even more pronounced in islets and beta cell lines with a transient knock down of presenilin 1. We demonstrate here that presenilin 1 controls beta cell glycolysis by regulating sub-cellular calcium homeostasis and, in doing so, contributes to preservation of beta cell identity.