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Related Experiment Video

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Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion

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Single-chain insulins as receptor agonists.

Gautam Rajpal¹, Ming Liu, Yi Zhang

¹Cell and Molecular Biology Program, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.

Molecular Endocrinology (Baltimore, Md.)

|February 21, 2009

Summary

Bioengineers created single-chain insulins (SCIs) that effectively bind insulin receptors and stimulate glucose uptake. Optimized linker peptides enhance SCI bioactivity for potential diabetes therapies.

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Measuring Relative Insulin Secretion using a Co-Secreted Luciferase Surrogate

Measuring Relative Insulin Secretion using a Co-Secreted Luciferase Surrogate

Published on: June 25, 2019

Area of Science:

Biochemistry
Molecular Biology
Endocrinology

Background:

Single-chain insulins (SCIs) link insulin A- and B-chains via a connecting peptide.
Standard SCIs show limited insulin receptor binding; bioengineering linkers is key to improving activity.
Understanding linker characteristics is crucial for developing functional SCIs.

Purpose of the Study:

Investigate the impact of linker length, cleavability, and specific residues on SCI bioactivity.
Determine how linker modifications affect insulin receptor binding and activation.
Explore the potential therapeutic applications of engineered SCIs.

Main Methods:

Constructed and analyzed a series of cDNAs encoding modified SCIs.
Utilized radioimmunoassay (RIA) to measure SCI concentration.
Assessed SCI binding affinity to insulin receptors and downstream signaling in adipocytes and hepatocytes.

Main Results:

SCIs with specific linker sequences (e.g., -Gln-Arg-) resisted cleavage, maintaining single-chain integrity.
Optimal bioactivity was observed with linkers containing an Arg residue preceding the A-chain.
Increased linker length diminished receptor interaction, approaching proinsulin levels.
SCIs effectively stimulated glucose uptake and suppressed gluconeogenesis with minimal IGF-I receptor cross-reactivity.

Conclusions:

Engineered SCIs with optimized linkers demonstrate potent insulin receptor activation and metabolic effects.
Specific linker design, including residue type and length, is critical for SCI function.
SCIs hold theoretical promise for immunotherapy or gene therapy in diabetes treatment.