LAUSR

&NA; The number of people suffering from insulin‐independent type 2 diabetes mellitus (T2DM) is ever increasing on a yearly basis. Current anti‐diabetic medications often result in adverse weight gain and hypoglycemic episodes. Hypoglycemia can be avoided with glucagon‐like peptide (GLP)‐1 receptor agonists, which are expensive and require daily injections that may result immune activation. This study demonstrates the use of non‐viral vector based oral delivery of GLP‐1 gene through enterohepatic recycling pathways of bile acids. Oral administration of the plasmid DNA (pDNA) encoding GLP‐1 decreased diabetic glucose levels to the normoglycemic range with significant weight reduction in a high‐fat diet (HFD) induced diabetic mouse model and a genetically engineered T2DM rat model. This novel oral GLP1 delivery system is an attractive alternative to treat late‐stage T2DM conditions that require repeated insulin injection and can potentially minimize the occurrence of hypoglycemic anomalies. Graphical abstract Figure. No caption available.