Oral Delivery of Glucagon Like Peptide-1 by a Recombinant Lactococcus lactis

• DOI: 10.1007/s11095-014-1430-3
• Publication Date: 2014-06-13T15:21:40Z
• Authors: Payal Agarwal; Pulkit Khatri; Blasé Billack; Woon-Kai Low; Jun Shao
• Keywords: Blood Glucose; Male; 0301 basic medicine; Mesocricetus; Madin Darby Canine Kidney Cells; Rats; Rats, Zucker; 3. Good health; Lactococcus lactis; 03 medical and health sciences; Dogs; Drug Delivery Systems; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Insulin-Secreting Cells; Animals; Insulin

To develop a live oral delivery system of Glucagon like peptide-1 (GLP-1), for the treatment of Type-2 Diabetes.LL-pUBGLP-1, a recombinant Lactococcus lactis (L. lactis)) transformed with a plasmid vector encoding GLP-1 cDNA was constructed and was used as a delivery system. Secretion of rGLP-1 from LL-pUBGLP-1 was characterized by ELISA. The bioactivity of the rGLP-1 was examined for its insulinotropic activity on HIT-T15 cells. Transport of rGLP-1 across MDCK cell monolayer when delivered by LL-pUBGLP-1 was studied. The therapeutic effect of LL-pUBGLP-1 after oral administration was investigated in ZDF rats.DNA sequencing and ELISA confirmed the successful construction of the LL-pUBGLP-1 and secretion of the active form of rGLP-1. In vitro insulinotropic studies demonstrated that LL-pUBGLP-1 could significantly (p < 0.05) stimulate HIT-T15 cells to secrete insulin as compared to the controls. When delivered by LL-pUBGLP-1, the GLP-1 transport rate across the MDCK cell monolayer was increased by eight times (p < 0.01) as compared to the free solution form. Oral administration of LL-pUBGLP-1 in ZDF rats resulted in a significant decrease (10-20%, p < 0.05) in blood glucose levels during 2-11 h post dosing and a significant increase in insulin AUC0-11h (2.5 times, p < 0.01) as compared to the free solution.The present study demonstrates that L. lactis when genetically modified with a recombinant plasmid can be used for the oral delivery of GLP-1.