Restored UBE2C expression in islets promotes β-cell regeneration in mice by ubiquitinating PER1

Abstract Background The limited proliferation capacity of β-cells contributes to insulin insufficiency, which promotes the onset of diabetes. β-cells secrete multiple beneficial substances, except for insulin; therefore, the regeneration mechanism of β-cells requires further study. Previously, ubiquitin-binding enzyme 2C (UBE2C) was reported to be downstream of the key β-cell transcription factor NKX6.1, but the specific function and mechanism of UBE2C in pancreatic islets remain unknown. Methods We performed islet perfusion, immunofluorescence staining, and transmission electron microscopy (TEM) to examine the role of UBE2C in mice with a Cre-loxP-constructed β-cell-specific knockout (βUbe2cKO) or overexpression through lentivirus infusion within the pancreatic ducts. Single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq, tandem mass tag (TMT) quantification proteomics, immunoprecipitation, and immunoblotting were conducted to explore the mechanisms by which UBE2C regulates β-cell proliferation. Results We discovered that ubiquitin-conjugating enzyme E2C (UBE2C) was highly expressed in a β-cell subgroup, which exhibited active proliferation capacity. We confirmed that UBE2C promotes β-cell compensatory proliferation by activating cell cycle renewal during a high-fat diet (HFD) and weaning. Consequently, β-cell-specific Ube2c knockout (βUbe2cKO) mice developed typical type 2 diabetes owing to β-cell loss caused by insulin insufficiency. Mechanistically, UBE2C combines with CUL1 to regulate PER1 degradation through ubiquitination. Notably, restored Ube2c expression in islets activated β-cell regeneration in streptozotocin (STZ)-induced diabetic mice, and alleviated diabetic hyperglycaemia and glucose intolerance. Conclusion This study indicates that UBE2C positively regulates β-cell proliferation by promoting ubiquitination and degradation of the biological clock suppressor PER1. The UBE2C-mediated beneficial effects on β-cells suggest a promising application in the treatment of diabetic patients with β-cell deficiency.