Induced Insulin Secretion and Glucose Regulation in Diabetic Mice
The iDimerize Inducible Reverse Dimerization technology is used to create a conditional export system for the controlled secretion of insulin through the endoplasmic reticulum (ER). Authors show rapid and reversible regulation of both insulin and glucose in hyperglycemic mice. Paper: Rollins et al. (2000) Proc. Natl. Acad. Sci. USA. 97(23):7096–101.
Advantages of inducible dimerization
- Fast (seconds) and reversible induction
- Plasma-stable ligand inducer
- Uses endogenous export machinery
- Eliminates the need for upstream stimuli
Engineered cells carrying a transgene for inducible insulin secretion were transplanted in hyperglycemic mice. Transgenes expressed human proinsulin fused to four copies of the DmrD domain (two copies shown in figure). A furin cleavage sequence was included to allow removal of fusion domains in the trans-Golgi, and release of biologically active protein. In the absence D/D Solubilizer ligand, the DmrD domain self-aggregates, resulting in cargo that is too large for ER export. Ligand treatment solubilizes the aggregates, enabling export.*
Cells treated with ligand showed insulin release in a dose-dependent manner.
Insulin secretion was observed 30 min following treatment, and was fully terminated an hour after ceasing treatment.
Hyperglycemic mice exhibited rapid regulation of both insulin and glucose levels, 15 min following ligand administration.
Studies are presented using iDimerize components. For complete experimental details please refer to the original publication. The optimal position and copy number of fusion domains varies per study and must be determined empirically.