Ultrastable Insulin-Glucagon Fusion Protein Exploits an Endogenous Hepatic Switch to Mitigate Hypoglycemic Risk

Area of Science:

• Biotechnology
• Endocrinology
• Protein Engineering

Background:

• Insulin therapy for diabetes mellitus is limited by hypoglycemia risk.
• Existing glucose-responsive technologies include closed-loop systems and smart insulins.
• There is a need for simpler, more accessible glucose-responsive therapies.

Purpose of the Study:

• To develop a stable glucagon-insulin fusion protein that exploits endogenous glucose-dependent signaling.
• To create a basal glucose-responsive insulin biotechnology with enhanced stability and accessibility.

Main Methods:

• Engineered a fusion protein with stabilized glucagon and insulin moieties.
• Assessed in vitro stability against fibrillation and dual hormonal activity.
• Evaluated glucodynamic responses in rats using continuous intravenous infusion.

Main Results:

• The fusion protein demonstrated resistance to fibrillation and balanced dual hormonal signaling.
• In vivo studies showed maintained efficacy in reducing hyperglycemia.
• The fusion protein enhanced endogenous glucose production during hypoglycemia.

Conclusions:

• The developed glucagon-insulin fusion protein provides a proof of principle for basal glucose-responsive insulin therapy.
• Augmented stability of the fusion protein may overcome cold chain limitations, improving global access.
• This approach offers a simple yet effective strategy for diabetes management.