Therapeutic Potential of Lentivirus-Mediated Glucagon-Like Peptide-1 Gene Therapy for Diabetes Hale M. Tasyurek, 1 Hasan Ali Altunbas, 2 Mustafa Kemal Balci, 2 Thomas S. Griffith, 3 and Salih Sanlioglu 1, * 1 Human Gene and Cell Therapy Center of Akdeniz University Hospitals, Antalya, Turkey; 2 Department of Internal Medicine, Division of Endocrinology and Metabolism, Akdeniz University Faculty of Medicine, Antalya, Turkey; and 3 Department of Urology, University of Minnesota, School of Medicine, Minneapolis, Minnesota. Postprandial glucose-induced insulin secretion from the islets of Langerhans is facilitated by glucagon- like peptide-1 (GLP-1)—a metabolic hormone with insulinotropic properties. Among the variety of effects it mediates, GLP-1 induces delta cell secretion of somatostatin, inhibits alpha cell release of glucagon, reduces gastric emptying, and slows food intake. These events collectively contribute to weight loss over time. During type 2 diabetes (T2DM), however, the incretin response to glucose is reduced and accom- panied by a moderate reduction in GLP-1 secretion. To compensate for the reduced incretin effect, a human immunodeficiency virus–based lentiviral vector was generated to deliver DNA encoding human GLP-1 (LentiGLP-1), and the anti-diabetic efficacy of LentiGLP-1 was tested in a high-fat diet/ streptozotocin-induced model of T2DM. Therapeutic administration of LentiGLP-1 reduced blood glucose levels in obese diabetic Sprague Dawley rats, along with improving insulin sensitivity and glucose tol- erance. Normoglycemia was correlated with increased blood GLP-1 and pancreatic beta cell regeneration in LentiGLP-1-treated rats. Plasma triglyceride levels were also normalized after LentiGLP-1 injection. Collectively, these data suggest the clinical potential of GLP-1 gene transfer therapy for the treatment of T2DM. Keywords: type 2 diabetes, glucagon-like peptide-1, lentiviral gene therapy INTRODUCTION TYPE 2 DIABETES (T2DM) is characterized by insulin resistance, glucose intolerance, and pancreatic beta cell loss leading to hyperglycemia. 1 Obesity contributes to T2DM progression by causing in- sulin resistance. Diabetes may not appear in insulin-resistant prediabetic patients because of a compensation mechanism resulting from an increase in beta cell mass and insulin secretion. Moreover, impaired glucose tolerance may ap- pear long before hyperglycemia. Despite these clinical situations, the combination of beta cell malfunction and insulin resistance eventually leads to T2DM. 2 Unfortunately, no effective treatment strategies apart from dietary changes and life-style modification protect pancreatic beta cells in the long term. Diabetic patients eventually become insulin dependent due to the loss of pancreatic beta cells. 3 Glycemic control is ultimately lost in all T2DM patients because blood glucose–lowering drugs do not interfere with the disease progression, 4 as evidenced by the fact that an intensive insulin regimen only delays the functional deterioration of pancreatic beta cells in newly diagnosed diabetic patients. 5 Pancreatic beta cell mass is mainly determined by islet cell replication, apoptosis, and new islet formation from exocrine pancreatic ducts, and agents that interfere with beta cell formation or new islet generation can decrease beta cell mass. 6 Unfortunately, disease progression in obese dia- betic individuals cannot be reversed by medica- tions that only induce insulin sensitivity and/or weight loss. Because of the diabetes pandemic seen in recent years, new therapeutic strategies are needed to prevent or reverse disease progression. 7 *Correspondence: Prof. Dr. Salih Sanlioglu, Human Gene and Cell Therapy Center, Akdeniz University Hospitals and Clinics, B Block, 1st floor, Campus, Antalya, 07058, Turkey. E-mail: ssanlioglu@icloud.com 802 j HUMAN GENE THERAPY, VOLUME 29 NUMBER 7 DOI: 10.1089/hum.2017.180 ª 2018 by Mary Ann Liebert, Inc. Downloaded by Harvard University FRANCIS A COUNTWAY from www.liebertpub.com at 08/03/18. For personal use only.