original article Diabetes, Obesity and Metabolism 13: 434 – 438, 2011.  2011 Blackwell Publishing Ltd original article LY2189265, a long-acting glucagon-like peptide-1 analogue, showed a dose-dependent effect on insulin secretion in healthy subjects P. Barrington 1 , J. Y. Chien 2 , F. Tibaldi 3 , H. D. H. Showalter 2 , K. Schneck 2 & B. Ellis 2 1 Eli Lilly and Company, Erl Wood Manor, Surrey, UK 2 Eli Lilly and Company, Indianapolis, IN, USA 3 GSK Biologicals, Rixensart, Belgium Aim: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics and potential immunogenicity of single, escalating subcutaneous injections of a once-weekly glucagon-like peptide-1 analogue in healthy subjects. Methods: This phase 1, three-period, crossover, double-blind, placebo-controlled study investigated single, escalating subcutaneous doses of LY2189265 (LY) ranging from 0.1 to 12 mg; approximately six subjects were randomized to each dose. Parameters of safety, including adverse events, were assessed. The pharmacokinetic profile was assessed over 14 days. Pharmacodynamic parameters (glucose and insulin concentrations) were measured following a step-glucose infusion (day 3) and as part of an oral glucose tolerance test (OGTT) (day 5). Results: LY was generally well tolerated with some increase in gastrointestinal symptoms with escalating doses. There were small dose- dependent increases in pulse rate with doses ≥1.0 mg and diastolic blood pressure with doses ≥3.0 mg. The half-life of LY was approximately 90 h, with C max occurring between 24 and 48 h in most subjects. Evidence of increase in glucose-dependent insulin secretion and suppression of serum glucose excursions were observed during an OGTT at all doses compared to placebo; no episodes of hypoglycaemia occurred. No subjects developed antibodies to LY2189265. Conclusions: LY showed an acceptable safety profile and exhibited the expected glucagon-like peptide-1 pharmacological effects on glucose suppression and insulin secretion with a half-life that supports once-weekly dosing. Keywords: antidiabetic drug, clinical trial, diabetes mellitus, GLP-1 analogue, pharmacodynamics, type 2 diabetes Date submitted 31 March 2010; date of first decision 5 May 2010; date of final acceptance 4 January 2011 Introduction Current therapeutic options for type 2 diabetes have limita- tions decreasing their effectiveness. Although conventional therapies that raise insulin levels or lower glucose production can provide adequate glycaemic control, factors such as patient compliance and disease progression can limit the realized effectiveness of these therapies in achieving stable glycaemic control [1]. In addition, differences in patient response and the multiple factors that contribute to diabetes necessitate the development of novel therapies to provide greater efficacy in treating diabetes mellitus. Incretin mimetics, including analogues of the incretin hormone glucagon- like peptide 1 (GLP-1), are a growing class of therapeutic agents for diabetes [exenatide, approved by Food and Drug Administration (FDA) in 2005; liraglutide, approved by the European Medicines Agency in 2009 and US FDA in 2010] that provide enhanced glucose-dependent insulin secretion [2] and glycaemic control [3 – 5]. Correspondence to: Philip Barrington, Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK. E-mail: barringtonph@lilly.com GLP-1 is an incretin hormone shown in humans and animals to enhance glucose-dependent insulin secretion [6,7], suppress inappropriate glucagon secretion [8] and slow gastric emptying rate [9]. These biological activities have made GLP-1 an attractive potential therapeutic agent for the treatment of type 2 diabetes. Despite the beneficial effects observed for native GLP-1 in patients with type 2 diabetes, its rapid inactivation by the protease dipeptidyl peptidase-IV (DPP-IV) limits its pharmaceutical utility. Endogenous GLP-1 is secreted by intestinal L-cells in response to meals [5] and affects carbohydrate metabolism. GLP-1 is a potent stimulator of insulin secretion in the setting of hyperglycaemia [2], with a low probability of caus- ing hypoglycaemia [3]. GLP-1 also suppresses inappropriate glucagon secretion frequently observed in individuals with type 2 diabetes [8,10]. GLP-1 delays gastric emptying [11], thereby slowing the absorption of nutrients and reducing post- prandial glucose excursions. GLP-1 has also been shown to suppress appetite and promote weight loss [12], which may impact glycaemic control over a longer time frame. Although early GLP-1 analogue therapies require once (liraglutide) or twice (exenatide) daily injections, newer, longer lasting GLP-1 analogues are being developed to provide the phar- macodynamic (PD) benefits of GLP-1 analogue treatment