Role of the G-Protein Coupled Receptor 3-Salt Inducible Kinase 2 Pathway in Human β Cell Proliferation

<jats:title>Abstract</jats:title><jats:p>Loss of pancreatic β cells is the hallmark of type 1 diabetes (T1D) <jats:sup>1</jats:sup>, for which provision of insulin is the standard of care. While regenerative and stem cell therapies hold the promise of generating single-source or host-matched tissue to obviate immune-mediated complications<jats:sup>2–4</jats:sup>, these will still require surgical intervention and immunosuppression. Thus, methods that harness the innate capacity of β-cells to proliferate to increase β cell mass in vivo are considered vital for future T1D treatment<jats:sup>5, 6</jats:sup>. However, early in life β cells enter what appears to be a permanent state of quiescence <jats:sup>7–10</jats:sup>, directed by an evolutionarily selected genetic program that establishes a β cell mass setpoint to guard against development of fatal endocrine tumours. Here we report the development of a high-throughput RNAi screening approach to identify upstream pathways that regulate adult human β cell quiescence and demonstrate in a screen of the GPCRome that silencing G-protein coupled receptor 3 (GPR3) leads to human pancreatic β cell proliferation. Loss of GPR3 leads to activation of Salt Inducible Kinase 2 (SIK2), which is necessary and sufficient to drive cell cycle entry, increase β cell mass, and enhance insulin secretion in mice. Taken together, targeting the GPR3-SIK2 pathway represents a novel avenue to stimulate the regeneration of β cells.</jats:p>