Sorting receptor SORCS2 facilitates a protective stress response in pancreatic islets

Objective: SORCS2 is an intracellular sorting receptor genetically associated with body mass index (BMI) in humans, yet its mode of action remains unknown. Elucidating the receptor function that defines its role in metabolic health is the objective of this work. Methods: Combining in vivo metabolic studies in SORCS2-deficient mouse models with ex vivo structural and functional analyses as well as single-cell transcriptomics of murine pancreatic tissues, we studied the pathophysiological consequences of receptor dysfunction for metabolism. Results: Our studies identified an important role for SORCS2 in islet stress response essential to sustain glucose-stimulated insulin release. In detail, we show that SORCS2 is predominantly expressed in islet alpha cells. Loss of expression impairs the ability of these cells to produce osteopontin, a secreted factor that facilitates insulin release from beta cells under stress. In line with diminished osteopontin levels, beta cells in SORCS2-deficient islets show changes in gene expression related to aggravated stress, protein misfolding, as well as mitochondrial dysfunction; and they exhibit defects in insulin granule maturation and a blunted response to glucose stimulation in vivo and ex vivo. Impaired glucose tolerance in receptor mutant mice coincides with alterations in body weight and composition. Conclusion: Our data identified a novel concept in protective islet stress response involving the alpha cell receptor SORCS2, and they provide experimental support for association of SORCS2 with metabolic control in humans. Overall design: Pancreatic islets from 3 animals per genotype (Sorcs2+/+ and Sorcs2-/- ; ~ 400-600 islets per sample )