Perspectives on tissue-selective insulin derivatives
- 1Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences 1 , Prague, Czech Republic
- 2Department of Biochemistry, Faculty of Science, Charles University 2 , Prague, Czech Republic
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.
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BibTeX
@article{hejl2026perspectives,
title = {{Perspectives on tissue-selective insulin derivatives}},
author = {Maxmilián Hejl and Jiří Jiráček},
journal = {Open Biology},
year = {2026},
month = oct,
doi = {10.1098/rsob.260175},
url = {https://royalsocietypublishing.org/rsob/article/16/10/260175/483582/Perspectives-on-tissue-selective-insulin},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Perspectives on tissue-selective insulin derivatives
AU - Maxmilián Hejl
AU - Jiří Jiráček
PY - 2026
DA - 2026/10/07
JO - Open Biology
DO - 10.1098/rsob.260175
UR - https://royalsocietypublishing.org/rsob/article/16/10/260175/483582/Perspectives-on-tissue-selective-insulin
AB - 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.
SN - 2046-2441
ER -