Loss of EGR-1 uncouples compensatory responses of pancreatic ? cells.
Ontology highlight
ABSTRACT: Rationale: Subjects unable to sustain ?-cell compensation develop type 2 diabetes. Early growth response-1 protein (EGR-1), implicated in the regulation of cell differentiation, proliferation, and apoptosis, is induced by diverse metabolic challenges, such as glucose or other nutrients. Therefore, we hypothesized that deficiency of EGR-1 might influence ?-cell compensation in response to metabolic overload. Methods: Mice deficient in EGR-1 (Egr1 -/-) were used to investigate the in vivo roles of EGR-1 in regulation of glucose homeostasis and beta-cell compensatory responses. Results: In response to a high-fat diet, Egr1 -/- mice failed to secrete sufficient insulin to clear glucose, which was associated with lower insulin content and attenuated hypertrophic response of islets. High-fat feeding caused a dramatic impairment in glucose-stimulated insulin secretion and downregulated the expression of genes encoding glucose sensing proteins. The cells co-expressing both insulin and glucagon were dramatically upregulated in islets of high-fat-fed Egr1 -/- mice. EGR-1-deficient islets failed to maintain the transcriptional network for ?-cell compensatory response. In human pancreatic tissues, EGR1 expression correlated with the expression of ?-cell compensatory genes in the non-diabetic group, but not in the diabetic group. Conclusion: These results suggest that EGR-1 couples the transcriptional network to compensation for the loss of ?-cell function and identity. Thus, our study highlights the early stress coupler EGR-1 as a critical factor in the development of pancreatic islet failure.
SUBMITTER: Leu SY
PROVIDER: S-EPMC7086362 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
ACCESS DATA