β-cell-mimetic designer cells provide closed-loop glycemic control.

Area of Science:

• Biotechnology
• Endocrinology
• Synthetic Biology

Background:

• Diabetes mellitus involves chronically deregulated blood glucose due to beta cell loss (T1D) or impaired insulin sensitivity and release (T2D).
• Current treatments often struggle with long-term glucose control and complications.

Purpose of the Study:

• To develop therapeutically applicable, glucose-responsive "designer cells" using minimal human cell engineering.
• To establish synthetic biological systems for treating type 1 and type 2 diabetes.

Main Methods:

• Engineered human cells with a synthetic circuit coupling glycolysis-mediated calcium entry to an excitation-transcription system.
• Controlled therapeutic transgene expression in response to glucose levels.
• Implanted engineered cells in mouse models of type 1 and type 2 diabetes.

Main Results:

• Implanted designer cells corrected insulin deficiency and normalized hyperglycemia in type 1 diabetes mice.
• Engineered cells expressing glucagon-like peptide 1 improved glucose tolerance and insulin release in type 2 diabetes mice.
• Demonstrated self-sufficient glucose regulation and therapeutic transgene expression.

Conclusions:

• Minimal engineering of human cells can create functional beta-cell-mimetic designer cells.
• Synthetic biological circuits offer a viable strategy for diabetes mellitus therapy.
• These systems hold potential for combined diagnosis and treatment of diabetes.