SORCS2 activity in pancreatic α-cells safeguards insulin granule formation and release from glucose-stressed β-cells
Oleksandra Kalnytska,
Per Qvist,
Séverine Kunz,
Thomas Conrad,
Thomas E. Willnow,
Vanessa Schmidt
Affiliations
Oleksandra Kalnytska
Molecular Cardiovascular Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Charité – Universitätsmedizin Berlin, 10117 Berlin, Germany
Per Qvist
Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
Séverine Kunz
Technology Platform for Electron Microscopy, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Thomas Conrad
Genomics Technology Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 10115 Berlin, Germany
Thomas E. Willnow
Molecular Cardiovascular Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Charité – Universitätsmedizin Berlin, 10117 Berlin, Germany; Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; Corresponding author
Vanessa Schmidt
Molecular Cardiovascular Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Corresponding author
Summary: Sorting receptor SORCS2 is a stress-response factor protecting neurons from acute insults, such as during epilepsy. SORCS2 is also expressed in the pancreas, yet its action in this tissue remains unknown. Combining metabolic studies in SORCS2-deficient mice with ex vivo functional analyses and single-cell transcriptomics of pancreatic tissues, we identified a role for SORCS2 in protective stress response in pancreatic islets, essential to sustain insulin release. We show that SORCS2 is predominantly expressed in islet alpha cells. Loss of expression coincides with inability of these cells to produce osteopontin, a secreted factor that facilitates insulin release from stressed beta cells. In line with diminished osteopontin levels, beta cells in SORCS2-deficient islets show gene expression patterns indicative of aggravated cell stress, and exhibit defects in insulin granule maturation and a blunted glucose response. These findings corroborate a function for SORCS2 in protective stress response that extends to metabolism.
