Translational factor eIF4G1 regulates glucose homeostasis and pancreatic β-cell function
figureposted on 2020-10-27, 21:39 authored by Ada AdminAda Admin, Seokwon Jo, Amber Lockridge, Ramkumar Mohan, Nicholas Esch, Regina Schlichting, Neha Panigrahy, Ahmad Essawy, Eric Gustafson, Emilyn U. Alejandro
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 both humans and mice. In the present study, we tested the hypothesis that eIF4G1 is critical for β-cell function and glucose homeostasis by genetically ablating eIF4G1 specifically in β-cells in vivo (βeIF4G1KO). Adult male and female βeIF4G1KO mice displayed glucose intolerance but normal insulin sensitivity. β-cell mass was normal under steady state and under metabolic stress by diet-induced obesity, but we observed increases in both proliferation and apoptosis in β-cells of βeIF4G1KO. 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 β-cells or intact islets of βeIF4G1KO 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 β-cell function.