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

Abstract

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 β-cell function and glucose homeostasis by genetically ablating eIF4G1 specifically in β-cells in vivo (βeIF4G1 knockout [KO]). 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 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.

Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice

“…Glucose and insulin tolerance tests were performed by intraperitoneal delivery of 2 g/kg glucose or 0.75 U/kg insulin (Novolin, Novo Nordisk Inc) to mice after 12 or 6 hours of fasting as previously described ( 57 ). The HOMA-IR index was calculated as (fasting insulin [ng/mL] × fasting glucose [mmol/L])/22.5 to assess insulin resistance.…”

“…Glucose and insulin tolerance tests were performed by intraperitoneal delivery of 2 g/kg glucose or 0.75 Unit/kg insulin (Novolin, Novo Nordisk Inc.) to mice after 12 or 6 hours of fasting as previously described (57).…”

Advances in the study of RNA-binding proteins in diabetic complications

“…found that the mammalian rapamycin complex 1 (mTORC1) trophic sensing pathway is dysregulated in diabetes [ 110 ], while Seokwon Jo et al. demonstrated that the translation factor EIF-4G1 and EIF-4E protein damaged insulin secretion, glucose homeostasis and β-cell function in EIF-4G1 knockout [ 111 ]. This suggests the potential of EIF-4E and EIF-4G1 targeting therapies in reducing the risk of type 2.…”

Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo

“…In βOGAKO islets, pro-insulin levels and pro-insulin to insulin ratio was reduced, and this is associated with increased expression of prohormone processing enzyme carboxypeptidase E (CPE), suggesting increased pro-insulin processing with possible reduction in pro-insulin transcription or translation. In our previous work in βOGTKO islets, a model of hypo-O-GlcNAcylation, we found that reduced insulin content occurred in part due to disruption in insulin transcription (decrease Ins1/2 mRNA and Pdx1 protein) as well as proinsulin processing, through dysregulation of CPE via O-GlcNAcylation of eIF4G1 ( 26 ). These data suggest that insulin processing in part through CPE and eIF4G1 is dependent on the presence of O-GlcNAcylation, where absence leads to reduced processing, while an increase in this PTM leads to enhanced proinsulin processing.…”