Insulin receptor isoform B is required for efficient proinsulin processing in pancreatic β cells

Area of Science:

• Endocrinology
• Molecular Biology
• Metabolic Diseases

Background:

• The insulin receptor (INSR, IR) exists as two isoforms, IRA and IRB, generated by alternative splicing.
• The distinct in vivo functions of IRA and IRB remain largely uncharacterized, particularly in pancreatic beta cells.

Purpose of the Study:

• To investigate the specific in vivo role of insulin receptor isoform B (IRB) in pancreatic beta cells.
• To elucidate the molecular mechanisms underlying IRB's function in regulating insulin processing and beta cell health during obesity.

Main Methods:

• Generation of beta cell-specific IRB knockout (βIRBKO) mice.
• Assessment of metabolic parameters, including hyperinsulinemia and hyperproinsulinemia, in diet-induced obesity models.
• Analysis of molecular pathways involved in protein processing, translation, and signaling, including SREBP1 and ERK pathways.

Main Results:

• βIRBKO mice exhibited exacerbated hyperinsulinemia and hyperproinsulinemia in diet-induced obesity.
• Loss of IRB impaired proinsulin processing within beta cells.
• IRB deficiency led to suppressed eukaryotic translation initiation factor 4G1 (eIF4G1) via stabilization of sterol-regulatory element binding protein 1 (SREBP1).
• Excessive autocrine proinsulin in βIRBKO mice activated extracellular signal-regulated kinase (ERK) through IRA, further stabilizing nuclear SREBP1 in a feedback loop.

Conclusions:

• This study clarifies the isoform-specific functions of the insulin receptor in vivo.
• IRB plays a critical role in proper insulin processing within pancreatic beta cells.
• IRB is essential for protecting beta cells against lipotoxicity in the context of obesity and metabolic dysfunction.