Author's personal copy GHTD-amide: A naturally occurring beta cell-derived peptide with hypoglycemic activity S.G. Paule a,1 , B. Nikolovski a,1 , R.E. Gray a , J.P. Ludeman a , A. Freemantle a , R.A. Spark a , J.B. Kerr b , F.M. Ng a , P.Z. Zimmet a,c , M.A. Myers a,2, * a Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia b Department of Anatomy and Cell Biology, Monash University, Clayton, Victoria 3800, Australia c Baker IDI Heart and Diabetes Institute, Caulfield, Victoria 3162, Australia 1. Introduction Regulation of blood glucose primarily revolves around control of insulin secretion and action. In addition to insulin, beta cells produce a variety of bioactive peptides including amylin, pancreastatin, preptin, and kisspeptins. Amylin contributes to metabolic regulation through its actions on insulin secretion and insulin sensitivity [6,13], and feedback signals to the brain that reduce food intake [25]. Pancreastatin, the product of a proteolytic cleavage of chromogranin-A unique to beta cells [26,29], and kisspeptins [21], both reduce glucose stimulated insulin release [11,21], whereas preptin, a cleavage product of proinsulin-like growth factor II, appears to amplify glucose stimulated insulin secretion [4]. Pancreatic peptides that originate from other cells types but also influence insulin secretion include Ghrelin, which is predominantly expressed in the gut mucosa but also found in islet alpha cells [8] and galanin, which is expressed in nerve endings surrounding the islets [28]. Both of these peptides inhibit insulin secretion [10,28,1,27]. Comprehensive knowledge of all factors controlling insulin secretion and action is required to complete our understanding of glucose homeostasis and its disturbance in disease states. In the early 1970s a peptide containing preparation with insulin potentiating activity was isolated from human urine [19,32] but the active constituent remained chemically unidentified. Based on chromatographic properties and activity the urinary peptide was originally thought to be a fragment of growth hormone called acceleratory fragment of growth hormone or AcG that derived from pituitary extracts [19,20]. Improvements in liquid chromatography and mass spectrometry have now allowed the purification to near homogeneity of this peptide from the original semi-pure prepara- * Corresponding author. Tel.: +61 3 53279291; fax: +61 3 53279240. E-mail address: m.myers@ballarat.edu.au (M.A. Myers). 1 They contributed equally to the manuscript. 2 Current address: School of Science and Engineering, University of Ballarat, Ballarat, Victoria 3353, Australia. Abbreviations: BLAST, basic local alignment and search tool; ES, electrospray; FBG, fasting blood glucose; GHTD-amide, alpha amidated tetrapeptide with the sequence Gly-His-Thr-Asp; MALDI, matrix assisted laser desorption ionization; PDA, photodiode array; PMF, peptide mass fingerprint; TFA, trifluoroacetic acid; TOF, time of flight.