Receptor-isoform-selective insulin analogues give tissue-preferential effects

Area of Science:

• Endocrinology
• Molecular Biology
• Pharmacology

Background:

• Insulin receptor (IR) isoforms, IR-A and IR-B, exhibit distinct tissue expression patterns.
• Understanding these differential expression patterns is crucial for targeted therapeutic development.

Purpose of the Study:

• To develop insulin analogues with varying binding affinities for IR-A and IR-B.
• To investigate if these analogues can achieve tissue-preferential biological effects.

Main Methods:

• Creation of insulin analogues (INS-A and INS-B) with differential affinities for human IR-A and IR-B.
• In vitro assays measuring glycogen synthesis and lipogenesis in rat tissues (muscle, liver, fat).
• In vivo studies in mice assessing blood-glucose-lowering effects and IR phosphorylation in the liver.

Main Results:

• INS-A showed higher potency for glycogen synthesis in muscle (IR-A dominant) compared to liver and fat (IR-B dominant).
• INS-B demonstrated greater potency for glycogen accumulation in hepatocytes and lipogenesis in adipocytes (IR-B dominant) versus muscle effects.
• INS-B induced significantly higher IR phosphorylation in the liver than human insulin (HI) for equivalent glucose-lowering effects.

Conclusions:

• Insulin analogues designed for preferential binding to specific IR isoforms can elicit tissue-selective biological responses.
• These findings support the potential of isoform-selective insulin analogues for targeted diabetes therapy based on IR expression profiles.