Perspectives on tissue-selective insulin derivatives

AI Summary

Systemic insulin therapy fails to reproduce physiological tissue distribution, causing non-physiological exposure and metabolic limitations.
Emerging strategies include engineered insulin analogues, insulin receptor isoform targeting and organ-directed delivery for liver, muscle, brain and adipose.
Proof of principle exists, but balancing tissue selectivity with whole-body metabolic control remains challenging; advances in protein design and delivery required.

TL;DR (AI Generated)

Despite major advances in insulin formulations, current therapies rely on systemic delivery and do not reproduce the physiological distribution of endogenous insulin, resulting in non-physiological tissue exposure and associated metabolic limitations.

In this perspective, we discuss emerging strategies aimed at achieving tissue-selective insulin action, including molecular engineering of insulin analogues, modulation of insulin receptor isoform specificity and targeted delivery approaches.

Advances in protein design and delivery technologies may ultimately enable the development of next-generation insulin therapies that better mimic physiological insulin action and improve clinical outcomes in metabolic and neurodegenerative diseases.

Basic summary

Open Biol. 2026 Oct 14;16(10):260175. doi: 10.1098/rsob.260175.

ABSTRACT

Insulin is a central regulator of metabolic homoeostasis with diverse, tissue-specific actions across multiple organs. Despite major advances in insulin formulations, current therapies rely on systemic delivery and do not reproduce the physiological distribution of endogenous insulin, resulting in non-physiological tissue exposure and associated metabolic limitations. In this perspective, we discuss emerging strategies aimed at achieving tissue-selective insulin action, including molecular engineering of insulin analogues, modulation of insulin receptor isoform specificity and targeted delivery approaches. Attention is given to hepato-preferential, muscle-directed, brain-targeted and adipose-modulating strategies, highlighting their mechanistic basis, therapeutic potential and inherent limitations. While proof of principle has been established for several approaches, challenges remain in balancing tissue selectivity with whole-body metabolic control. Advances in protein design and delivery technologies may ultimately enable the development of next-generation insulin therapies that better mimic physiological insulin action and improve clinical outcomes in metabolic and neurodegenerative diseases.

PMID:42869456 | DOI:10.1098/rsob.260175

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