The transcription factor E2F1 controls the GLP-1 receptor pathway in pancreatic β cells

Cell Rep. 2022 Aug 9;40(6):111170. doi: 10.1016/j.celrep.2022.111170.

Abstract

The glucagon-like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential in type 2 diabetes (T2D) treatment, notably by improving β cell functions. The cell-cycle regulator and transcription factor E2f1 is involved in glucose homeostasis by modulating β cell mass and function. Here, we report that β cell-specific genetic ablation of E2f1 (E2f1β-/-) impairs glucose homeostasis associated with decreased expression of the Glp-1 receptor (Glp1r) in E2f1β-/- pancreatic islets. Pharmacological inhibition of E2F1 transcriptional activity in nondiabetic human islets decreases GLP1R levels and blunts the incretin effect of GLP1R agonist exendin-4 (ex-4) on insulin secretion. Overexpressing E2f1 in pancreatic β cells increases Glp1r expression associated with enhanced insulin secretion mediated by ex-4. Interestingly, ex-4 induces retinoblastoma protein (pRb) phosphorylation and E2f1 transcriptional activity. Our findings reveal critical roles for E2f1 in β cell function and suggest molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways.

Keywords: CP: Metabolism; E2F1; beta cells; glucagon-like peptide 1; insulin secretion; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diabetes Mellitus, Type 2* / metabolism
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism
  • Exenatide / pharmacology
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells* / metabolism

Substances

  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Exenatide
  • Glucose