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

Koshenov, Z.; Postic, S.; Schosiwohl, G.; van Amsterdam, S.; Hois-Zelinka, V.; Oflaz, F. E.; Rost, R.; Tiapko, O.; Gottschalk, B.; Hirtl, M.; Bachkoenig, O. G.; Koshenova, A.; Erdogan, Y. C.; Sagintayev, A.; Krnjic, A.; Pfabe, J.; Sarikas, S.; Hochreiter, B.; Gindlhuber, J.; Schittmayer, M.; Tadic, J.; Ehall, B.; Madeo, F.; Madl, T.; Malli, R.; Birner-Gruenberger, R.; Pieber, T.; Eisenberg, T.; Slak Rupnik, M.; Graier, W. F.

doi:10.1101/2025.09.05.674426

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bioRxiv · 10.1101/2025.09.05.674426

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

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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.

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Koshenov, Z., Postic, S., Schosiwohl, G., van Amsterdam, S., Hois-Zelinka, V., Oflaz, F. E., Rost, R., Tiapko, O., Gottschalk, B., Hirtl, M., Bachkoenig, O. G., Koshenova, A., Erdogan, Y. C., Sagintayev, A., Krnjic, A., Pfabe, J., Sarikas, S., Hochreiter, B., Gindlhuber, J., Schittmayer, M., Tadic, J., Ehall, B., Madeo, F., Madl, T., Malli, R., Birner-Gruenberger, R., Pieber, T., Eisenberg, T., Slak Rupnik, M., Graier, W. F.. 2025-09-05. Presenilin-1 controls glucose metabolism and identity of pancreatic beta cells. https://doi.org/10.1101/2025.09.05.674426

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