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Monomeric insulins and their experimental and clinical implications
Diabetes Care
|September 1, 1990
Summary
Developing new human insulin analogues with reduced self-association improves subcutaneous absorption for better meal-related therapy in diabetes. Monomeric insulins are absorbed three times faster than human insulin, enhancing glycemic control.
Area of Science:
- Pharmacology and Endocrinology
- Biotechnology and Drug Development
Background:
- Current insulin formulations face limitations in achieving normoglycemia without impacting patient quality of life due to pharmacokinetic properties.
- The self-association state of insulin (hexameric) in pharmaceutical preparations influences subcutaneous absorption rates.
Purpose of the Study:
- To describe the development of human insulin analogues with reduced self-association for improved meal-related therapy.
- To investigate the relationship between insulin analogue structure, absorption kinetics, and in vivo activity.
Main Methods:
- Utilized DNA technology to create human insulin analogues with altered self-association properties (dimeric or monomeric).
- Characterized analogues for receptor binding, in vitro potency, and subcutaneous absorption in preclinical (pigs) and clinical studies.
- Employed clamp studies to correlate receptor binding, clearance, and circulating insulin concentrations.
Main Results:
- Insulin analogues with reduced self-association demonstrated significantly faster subcutaneous absorption rates compared to human insulin.
- Monomeric insulin analogues were absorbed up to three times faster, exhibiting no lag phase and a monoexponential absorption profile.
- A strong inverse correlation was observed between the rate of subcutaneous absorption and the mean association state of insulin analogues (r = 0.96).
- In vivo activity was largely consistent across analogues, explained by receptor-mediated clearance balancing in vitro potency differences.
Conclusions:
- Reduced insulin self-association leads to more rapid subcutaneous absorption, making analogues suitable for meal-related glucose control.
- The associated state of insulin in formulations explains the absorption lag phase and progressive dissociation observed with native insulin.
- Understanding these absorption mechanisms allows for optimization of factors like concentration, volume, temperature, and massage to enhance insulin delivery.