Potential proliferative and differantiative effects of lentivirus mediated glp-1 gene therapy on pancreatic beta cells

Objective: Glucagon-like peptide-1 (GLP-1), which has been evaluated as a therapeutic agent for Type 2 Diabetes, stimulates glucose-induced insülin secretion (GSIS), and suspected to increase beta-cell mass through proliferation, neogenesis, and trans-differentiation. Additionally, reduced gastric emptying and food intake result in weight loss in the long run. Inhibition of glucagon release from the pancreatic alpha cells is another beneficial effect of GLP-1 relevant to diabetes therapy. Unfortunately, the incretin response to glucose is reduced in type 2 diabetes which is accompanied by a moderate degree of GLP-1 hypo-secretion. Method: In order to produce stable GLP-1 synthesis and secretion, a GLP-1 encoding lentiviral vector (LentiGLP-1) was generated and its therapeutic efficacy was tested in experimental animal models of Type 2 Diabetes. Immunohistochemical analyses were performed on pancreatic sections dissected from LentiGLP-1 administrated rats to reveal the mechanism of beta cell expansion. Results: Intraperitoneal injection of LentiGLP-1 into obese diabetic rats broke-down insülin resistance, improved glucose tolerance, and reduced plasma glucose levels without altering plasma lipid profile. Reduced plasma glucose level was correlated with increased pancreatic beta cell mass. In addition to appearance of small insülin positive cell clusters on pancreatic sections, Ki67 (+) cells were also observed in the acinar regions of pancreatic tissue. Conclusion: Based on these findings, it is safe to claim that LentiGLP-1 vector should be assessed as a novel gene therapy modality for the treatment of patients with T2DM. Our findings also suggest that GLP-1 gene delivery promotes cellular proliferation and differentiation of pancreatic cells. Key words: gene therapy, glucagon like peptide-1, type 2 diabetes, beta cells