A new gene therapy approach may overcome the problem of cleavage of proinsulin into active insulin for treatment of autoimmune type I diabetes. Researchers from Korea and Canada have engineered a liver-targeting recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analog (SIA), which does not require enzymatic conversion to act as biologically active insulin (Nature 408, 483–488, 2000). Because insulin secretion from the pancreas is induced mainly by glucose, the SIA gene was placed under the control of the glucose-responsive L-type pyruvate kinase (LPK) promoter. One week after injecting diabetic rats and mice with rAAV-LPK-SIA, blood glucose levels became normal and remained so throughout the entire eight-month study period. According to corresponding author Hyun Chul Lee, the researchers are currently working to solve lower post-digestion glucose levels of SIA “through protein engineering techniques.” In another approach, genetically engineered K cells from the gut, which are naturally responsive to glucose, have been engineered to express glucose-dependent polypeptide, successfully protecting mice from developing diabetes after destruction of beta cells (Science 290, 1959–1962, 2000).