499 Research Article Received: 24 June 2010 Revised: 18 November 2010 Accepted: 7 December 2010 Published online in Wiley Online Library: 14 April 2011 (wileyonlinelibrary.com) DOI 10.1002/psc.1352 Protective effect of recombinant human glucagon-like peptide-1 (rhGLP-1) pretreatment in STZ-induced diabetic mice Ye-Lin Wu, a‡ Jing Huang, a‡ Jian Liu, a Ming-Fei Jin, a Mei Gu, b Yiguo Hong c and Zi-Rong Wu a∗ Human glucagon-like peptide-1 (hGLP-1) and its mimetics have emerged as therapies for type 2 diabetes. However, clinical treatment of diabetes with hGLP-1 is ineffective because of rapid DPPIV-mediated hGLP-1 degradation in the circulation. In this study, we investigated the protective effect of recombinant human glucagon-like peptide-1 (rhGLP-1) treatment on STZ-induced diabetic mice. Mice were treated daily with rhGLP-1 (24 nmol/kg body weight) starting before or after STZ injection (40 mg/kg body weight) to induce diabetes. Mice pretreated with rhGLP-1 before but not after STZ showed significantly reduced blood glucose levels (P < 0.05), increased oral glucose tolerance (area under the curve, 1740 ± 71.18 vs 2416 ± 205.6, P < 0.05). Furthermore, the bioproduct of lipid peroxidation, MDA, was reduced and SOD and GSH-PX activities were enhanced globally and in pancreas of mice that received rhGLP-1 pretreatment before STZ, when comparing with STZ-treated mice. Finally, STZ-induced pancreatic islet damage was rescued by rhGLP-1 pretreatment. Taken together, the results of this study demonstrate that rhGLP-1 pretreatment has a protective effect against STZ-induced diabetes in mice. These findings suggest that the GLP-1 pretreatment may be a new therapeutic strategy in the preventive and protective treatment during diabetes initiation and progression. Copyright c  2011 European Peptide Society and John Wiley & Sons, Ltd. Supporting information may be found in the online version of this article Keywords: GLP-1; streptozotocin; lipid peroxidation; oxidative stress; diabetes mellitus; type 2 diabetes Introduction Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia [1]. Functional impairment of pancreas beta cells caused by reactive oxygen species (ROS) contributes to the increasing blood glucose in both type I and type II diabetes. ROS production is stimulated by growth factor withdrawal, human immunodeficiency virus infection, and cytokines including tumor necrosis factor α (TNF-α) and lipopolysaccharide [2,3]. ROS induce cellular damages including lipid peroxidation, protein oxidation, and DNA damage, all of which cause beta cell insufficiency and eventual death. In contrast, overexpression of antioxidant enzyme SOD or anti-apoptotic protein Bcl-2 can inhibit ROS-induced apoptosis [4,5]. These findings indicate ameliorating oxidative stress and beta cell damage may provide benefits to a broad subset of diabetic patients. Human glucagon-like peptide-1 (hGLP-1) has been shown to improve glucose-dependent insulin secretion, reduce plasma glucagon level, and inhibit gluconeogenesis [6]. However, hGLP-1 has a short half-life (less than 2 min) because of rapid DPPIV- mediated degradation in vivo. Therefore, once-daily hGLP-1 in the treatment of diabetic patients is ineffective. Recently, an increasing number of studies have uncovered additional functions for GLP-1 and its analogs. The evidence from our previous study demonstrated that a GLP-1 analog (mGLP-1) protected SH-SY5Y cells from apoptosis induced by amyloid-beta peptide [7]. Study from Hui’s [8] group showed GLP-1 treatment before the exposure to H 2 O 2 but not after had a protective effect on H 2 O 2 -induced apoptosis in insulinoma beta cells (MIN6) via a cAMP- and PI3K- dependent pathway. This study was undertaken to investigate whether recombinant hGLP-1 (rhGLP-1) has a protective effect on STZ-induced diabetic mice in vivo, independently from the amelioration of insulin secretion and the acquired glucose control that follow its administration. We treated mice with rhGLP-1 starting before or after STZ injection and then examined blood ∗ Correspondence to: Zi-Rong Wu, School of Life Science, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. E-mail: zrwu@bio.ecnu.edu.cn a School of Life Science, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China b Clinical Sciences Research Institute, University Hospital, University of Warwick, Coventry CV2 2DX, UK c Warwick HRI, University of Warwick, Wellesbourne, Warwick CV35 9EF, UK ‡ These authors contributed equally to this work. Abbreviations used: rhGLP-1, recombinant human glucagon-like peptide- 1; STZ, streptozotocin; SOD, superoxide dismutase; GSH-PX, glutathione peroxidase; CAT, catalase activity; KM mice, Kunming mice; H&E, hematoxylin and eosion; SE, standard error; OGTT, oral glucose tolerance test; MDA, malondialdehyde; DPPIV, dipeptidyl peptidase IV; T1D, type 1 diabetes; T2D, type 2 diabetes TNF-α, tumor necrosis factor α; ANOVA, analysis of variance. J. Pept. Sci. 2011; 17: 499–504 Copyright c  2011 European Peptide Society and John Wiley & Sons, Ltd.