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

Abstract

Insulin deficiency may be due to the reduced proliferation capacity of islet β-cell, contributing to the onset of diabetes. It is therefore imperative to investigate the mechanism of the β-cell regeneration in the islets. NKX6.1, one of the critical β-cell transcription factors, is a pivotal element in β-cell proliferation. The ubiquitin-binding enzyme 2C (UBE2C) was previously reported as one of the downstream molecules of NKX6.1 though the exact function and mechanism of UBE2C in β-cell remain to be elucidated. Here, we determined a subpopulation of islet β-cells highly expressing UBE2C, which proliferate actively. We also discovered that β-cell compensatory proliferation was induced by UBE2C via the cell cycle renewal pathway in weaning and high-fat diet (HFD)-fed mice. Moreover, the reduction of β-cell proliferation led to insulin deficiency in βUbe2cKO mice and, therefore, developed type 2 diabetes. UBE2C was found to regulate PER1 degradation through the ubiquitin-proteasome pathway via its association with a ubiquitin ligase, CUL1. PER1 inhibition rescues UBE2C knockout-induced β-cell growth inhibition both in vivo and in vitro. Notably, overexpression of UBE2C via lentiviral transduction in pancreatic islets was able to relaunch β-cell proliferation in STZ-induced diabetic mice and therefore partially alleviated hyperglycaemia and glucose intolerance. This study indicates that UBE2C positively regulates β-cell proliferation by promoting ubiquitination and degradation of the biological clock suppressor PER1. The beneficial effect of UBE2C on islet β-cell regeneration suggests a promising application in treating diabetic patients with β-cell deficiency.