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

Abstract

Chronically deregulated blood-glucose concentrations in diabetes mellitus result from a loss of pancreatic insulin-producing β cells (type 1 diabetes, T1D) or from impaired insulin sensitivity of body cells and glucose-stimulated insulin release (type 2 diabetes, T2D). Here, we show that therapeutically applicable β-cell-mimetic designer cells can be established by minimal engineering of human cells. We achieved glucose responsiveness by a synthetic circuit that couples glycolysis-mediated calcium entry to an excitation-transcription system controlling therapeutic transgene expression. Implanted circuit-carrying cells corrected insulin deficiency and self-sufficiently abolished persistent hyperglycemia in T1D mice. Similarly, glucose-inducible glucagon-like peptide 1 transcription improved endogenous glucose-stimulated insulin release and glucose tolerance in T2D mice. These systems may enable a combination of diagnosis and treatment for diabetes mellitus therapy.

• Authors: Mingqi Xie, Haifeng Ye, Hui Wang, Ghislaine Charpin-El Hamri, Claude Lormeau, Pratik Saxena, Jörg Stelling, Martin Fussenegger
• Journal: Science (New York, N.Y.) (Science) Vol. 354 Issue 6317 Pg. 1296-1301 (12 09 2016) ISSN: 1095-9203 [Electronic] United States
• PMID: 27940875 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Blood Glucose
• Cacna1d protein, mouse
• Calcium Channels, L-Type
• Insulin
• Glucagon-Like Peptide 1
• Calcium

Topics

• Animals
• Biomimetics
• Blood Glucose (metabolism)
• Calcium (metabolism)
• Calcium Channels, L-Type (genetics, metabolism)
• Cell Engineering
• Diabetes Mellitus, Experimental (therapy)
• Diabetes Mellitus, Type 1 (therapy)
• Diabetes Mellitus, Type 2 (therapy)
• Glucagon-Like Peptide 1 (genetics)
• HEK293 Cells
• Humans
• Hyperglycemia (therapy)
• Insulin (metabolism)
• Insulin Secretion
• Insulin-Secreting Cells (metabolism, transplantation)
• Transcription, Genetic
• Transgenes