ISF402
Source ISF402 at Peptiology
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Summary
ISF402 (VHTD‑amide) is a synthetic tetrapeptide derived from the urinary peptide GHTD‑amide. In pre‑clinical work it has been investigated as an adjunct to insulin therapy, aiming to improve insulin’s glucose‑lowering effect by altering insulin’s zinc‑dependent aggregation state.
Mechanism of Action
ISF402 binds zinc ions in a 1:1 stoichiometry, forming a peptide‑zinc complex that destabilises zinc‑stabilised insulin hexamers. By chelating Zn²⁺, the peptide promotes disassembly of hexameric insulin into dimers and monomers, which can more readily engage the insulin receptor. The resulting increase in bioavailable monomeric insulin is thought to enhance downstream signalling and glucose uptake.
What the Research Shows
Evidence for ISF402 comes from a single 2009 study. In vitro assays showed that ISF402, like its parent GHTD‑amide, bound Zn²⁺ and converted hexameric insulin to smaller oligomers. In insulin‑resistant Zucker rats, co‑administration of ISF402 with conventional zinc‑insulin produced larger reductions in blood glucose and C‑peptide levels than insulin alone, and altered serum insulin kinetics suggestive of reduced clearance or improved dispersion. The potentiating effect was attenuated when the rapid‑acting, non‑zinc‑binding lispro insulin was used, supporting a zinc‑chelation mechanism. No human data or clinical trials have been reported.
Reported Benefits
In the animal model, ISF402 enhanced the hypoglycaemic action of zinc‑containing insulin, leading to greater glucose lowering and higher circulating C‑peptide compared with insulin alone. The peptide’s ability to disperse insulin oligomers could theoretically improve the efficiency of insulin therapy, particularly in insulin‑resistant states.
Limitations of the Evidence
Findings are limited to in vitro experiments and a single rodent study; no human pharmacology, safety, or efficacy data exist. The peptide’s effect appears dependent on zinc‑stabilised insulin formulations, limiting its relevance to modern rapid‑acting analogues. Without clinical trials, the magnitude and durability of benefit remain uncertain.
Safety Considerations
The abstract does not report adverse events in the rat study, and no safety data are available for humans. As a zinc‑chelating agent, ISF402 could theoretically disturb systemic zinc homeostasis or interact with other zinc‑dependent proteins, warranting caution pending formal toxicology assessments.
How It Is Administered
In the reported study ISF402 was administered by injection together with insulin in rats. No formulation details or alternative routes have been described, and the peptide has not been evaluated for oral or other delivery methods.
Routes of Administration
No administration routes recorded yet.
Goals & Uses
No goal associations recorded yet.
Contraindications
No contraindications recorded yet.
Adverse Effects
No adverse effects recorded yet.
Drug Interactions
No drug interactions recorded yet.
Population Constraints
No population constraints recorded yet.
Regulatory Status
No regulatory status recorded yet.
Evidence & Sources
- Journal ArticleLowPaule SG, et al.2009-01-01T00:00:00.000000Z
Frequently Asked Questions
What is the intended use of ISF402?
ISF402 is being explored as an adjunct to injectable insulin, with the goal of enhancing insulin’s glucose‑lowering effect by breaking down zinc‑stabilised insulin hexamers into more active monomers.
Has ISF402 been tested in humans?
No. The only published data are in vitro experiments and a study in insulin‑resistant rats. Human pharmacokinetic, safety, or efficacy studies have not been reported.
Does ISF402 work with all insulin types?
The peptide potentiated conventional zinc‑containing insulin but showed reduced effect with lispro, a rapid‑acting insulin that does not form zinc‑stabilised hexamers, indicating its activity depends on the presence of zinc‑bound insulin aggregates.
Are there any known side effects?
The animal study did not report adverse effects, but no systematic safety evaluation has been performed. Potential concerns include unintended zinc chelation that could affect other physiological processes.
How would ISF402 be given?
In the pre‑clinical work ISF402 was co‑administered by injection with insulin. No other routes or commercial formulations have been described.