Translational Factor eIF4G1 Regulates Glucose Homeostasis and Pancreatic beta-Cell Function

Protein translation is essential for cell physiology, and dysregulation of this process has been linked to aging-related diseases such as type 2 diabetes. Reduced protein level of a requisite scaffolding protein of the initiation complex, eIF4G1, downstream of nutrients and insulin signaling is associated with diabetes in humans and mice. In the current study, we tested the hypothesis that eIF4G1 is critical for beta-cell function and glucose homeostasis by genetically ablating eIF4G1 specifically in beta-cells in vivo (beta eIF4G1 knockout [KO]). Adult male and female beta eIF4G1KO mice displayed glucose intolerance but normal insulin sensitivity. beta-Cell mass was normal under steady state and under metabolic stress by diet-induced obesity, but we observed increases in proliferation and apoptosis in beta-cells of beta eIF4G1KO. We uncovered deficits in insulin secretion, partly due to reduced mitochondrial oxygen consumption rate, glucose-stimulated Ca2+ flux, and reduced insulin content associated with loss of eIF4E, the mRNA 5 ' cap-binding protein of the initiation complex and binding partner of eIF4G1. Genetic reconstitution of eIF4E in single beta-cells or intact islets of beta eIF4G1KO mice recovers insulin content, implicating an unexplored role for eIF4G1/eIF4E in insulin biosynthesis. Altogether these data demonstrate an essential role for the translational factor eIF4G1 on glucose homeostasis and beta-cell function.

Automated summary

The translational factor eIF4G1 is crucial for glucose homeostasis and beta-cell function, as evidenced by its impact on insulin secretion, mitochondrial oxygen consumption rate, and insulin content maintenance in beta-cells.