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

Area of Science:

• Cell Biology
• Metabolism
• Endocrinology

Background:

• Protein translation is vital for cellular function, and its dysregulation is linked to aging-related diseases like type 2 diabetes.
• Reduced levels of the initiation factor eIF4G1 are associated with diabetes in humans and mice.

Purpose of the Study:

• To investigate the critical role of eIF4G1 in pancreatic beta-cell function and glucose homeostasis.
• To test the hypothesis that eIF4G1 is essential for maintaining normal beta-cell physiology and glucose metabolism in vivo.

Main Methods:

• Generation of a specific beta-cell eIF4G1 knockout (βeIF4G1KO) mouse model.
• Assessment of glucose tolerance, insulin sensitivity, beta-cell mass, proliferation, and apoptosis.
• Analysis of insulin secretion, mitochondrial function, calcium flux, and eIF4E levels.

Main Results:

• βeIF4G1KO mice exhibited glucose intolerance but normal insulin sensitivity.
• Beta-cell mass remained normal, but proliferation and apoptosis increased.
• Deficits in insulin secretion were linked to reduced mitochondrial respiration, impaired Ca2+ flux, and decreased insulin content due to eIF4E loss.
• Restoring eIF4E in βeIF4G1KO mice recovered insulin content.

Conclusions:

• The translational factor eIF4G1 plays an essential role in glucose homeostasis and beta-cell function.
• eIF4G1/eIF4E interaction is critical for insulin biosynthesis and secretion.
• These findings reveal an unexplored role for eIF4G1 in regulating beta-cell function and metabolism.