SORCS2 activity in pancreatic α-cells safeguards insulin granule formation and release from glucose-stressed β-cells

TY - JOUR

T1 - SORCS2 activity in pancreatic α-cells safeguards insulin granule formation and release from glucose-stressed β-cells

AU - Kalnytska, Oleksandra

AU - Qvist, Per

AU - Kunz, Séverine

AU - Conrad, Thomas

AU - Willnow, Thomas E

AU - Schmidt, Vanessa

N1 - © 2023 The Author(s).

PY - 2024/1

Y1 - 2024/1

N2 - 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.

AB - 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.

KW - Biological sciences

KW - Endocrinology

KW - Natural sciences

KW - Physiology

UR - http://www.scopus.com/inward/record.url?scp=85180305606&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2023.108725

DO - 10.1016/j.isci.2023.108725

M3 - Journal article

C2 - 38226160

SN - 2589-0042

VL - 27

SP - 108725

JO - iScience

JF - iScience

IS - 1

M1 - 108725

ER -