synaptic contacts with several feeding-regulating peptide-containingneurons. The body weight in obese mice by intranasal GALPadministration was significantly decreased.

GALP and NPW may play neuromodulatory function in feedingand energy metabolism. Intranasal administration of GALP is aneffective route to exert its effect as anti-obese drug. This may help toestablish new therapies for obese people in near future.

doi:10.1016/j.regpep.2010.07.144

Incretin physiology and pathophysiologyJ.J. HolstDept of Biomedical Sciences, University of Copenhagen, Denmark

In healthy subjects, the incretin effect ensures that plasma glucoseconcentrations after oral carbohydrates remain low regardless of theamount of glucose taken in. It is due to proportional increases in GLP-1and GIP secretion and corresponding insulin responses We studied thisphenomenon in obese subjects with T2DM and matched controls andfound that incretin release was unimpaired and proportional to theglucose load, but in T2DM the effect on insulinwas dramatically reducedregardless of load.We also identified reduced gastric emptying of glucoseto contribute to both the release of incretin hormones and to regulation ofpostprandial glycaemia. The incretin effect was also reduced in diabetessecondary to chronic pancreatitis suggesting that the loss is secondary todiabetes. In further studies we were able to identify that obesity andglucose intolerance are associated with the loss, and a similar loss couldbe brought about in perfectly healthy subjects during glucocorticoidinduced insulin resistance andglucose intolerance. InpatientswithT2DMpostprandial GLP-1 secretion is generally impaired, and several factorsincluding BMI, insulin resistance and poor metabolic control areassociated with this. The actions insulinotropic actions of physiologicalamounts ofGLP-1 andGIPare lost, but pharmacological amountsofGLP-1can still normalize glucose induced insulin secretion and glucagonsuppression. As a result, pharmacological doses of GLP-1 may greatlyimprove diabetic metabolism. It can be demonstrated that insulinotropicand glucagonostatic effects of GLP-1 contribute equally to its glucoselowering action. The suppression of glucagon may be one of the mostimportant actions of GLP-1 as indicated from studies of the effects of theantagonist exendin 9–39. Recent studies of GLP-1 secretion in patientswith RYGB suggest that hypersecretion of GLP-1 plays a prominent role inthe antidiabetic actions of this operation. Convincing clinical results withGLP-1 agonist support this view.

doi:10.1016/j.regpep.2010.07.145

Pituitary adenylate cyclase-activating polypeptide (PACAP) andislet functionBo AhrénDepartment of Clinical Sciences, Division of Medicine, Lund University,Lund, Sweden

The neuropeptide pituitary adenylate cyclase-activating polypeptide(PACAP) is expressed in autonomic nerve terminals in the pancreaticislets. The majority of these nerve terminals are parasympathetic nerves.There are three types of PACAP receptors; all of these are G-protein-coupled receptors. They are namedVPAC1 receptors, VPAC2 receptors andPAC1 receptors; vasoactive intestinal polypeptide (VIP) is also a ligand forthe first two receptor subtypes. All PACAP receptor types are expressed inpancreatic islets and upon activation of the islets, PACAP stimulatesinsulin and glucagon secretion. These actions are mainly achievedthrough increased formationof cAMPafter activation of adenylate cyclaseand through increase in cytosolic calcium. Insulin secretion is impairedafter deletionof PAC1 receptors orVPAC2 receptors, andmicewith genetic

deletionof these receptorshaveglucose intolerance. Furthermore, studiesin PAC1 receptor gene deletedmice have suggested that PACAPmay be ofphysiological importance inmediating prandial insulin secretion. Animalstudies have also suggested that activation of the receptors, in particularVPAC2 receptors,may be a therapeutic approach for the treatment of type2 diabetes. Hence, PACAP is an islet neuropeptide with potential role inislet physiology and as a basis for development of islet promoting therapyin type 2 diabetes. Nevertheless, much remains to be established, such asthedetailed signallingof islet PACAP receptoractivation, thepotential roleof PACAP in the regulation of islet cell mass, the potential involvement ofPACAP in diabetes pathophysiology and as a target for treatment.

doi:10.1016/j.regpep.2010.07.146

REG PEP 2010PLENARY

PEPTIDE RELATED DRUG DISCOVERY

Mike ConlonChris ShawSteven Bloom

Strategies for transformation of antimicrobial peptides from frogskin into therapeutically valuable anti-infective agentsJ.M. ConlonDepartment of Biochemistry, Faculty of Medicine and Health Sciences,United Arab Emirates University, 17666 Al-Ain, United Arab Emirates

Cationic, amphipathic alpha-helical peptides that are synthesized inthe skins of several frog species, particularly those belonging to theHylidae and Ranidae families, show broad-spectrum antimicrobialproperties and are active against pathogens that have developedresistance to conventional antibiotics. Their therapeutic potential is oftenlimited by low potency against microorganisms, high toxicity againsteukaryotic cells, and short half-life in the circulation. The cytolytic activityof a peptide is determined by a complex interaction between cationicity,helicity, hydrophobicity and amphipathicity. The growth inhibitorypotency of a particular peptide against bacteria and fungi may beenhanced by appropriate amino acid substitutions that produce selectiveincreases in cationicity while maintaining amphipathicity. Its cytolyticactivity against human cells may be reduced by selective decreases inhydrophobicity and helicity and increase in the polar angle. Approachesto preparing long-acting, protease-resistant analogs of naturally occur-ring peptides include incorporation of D-amino acids and/or unnaturalamino acids such as alpha-aminoisobutyric acid, coupling to fatty acids,and replacing cystine residues in cyclic peptides by a hydrocarbon bridge.Analogs of the naturally occurring frog skin peptides alyteserin-1c,ascaphin-8, brevinin-1BYa, peptide XT-7, and temporin-DRa have shownpotential for treatment of infections caused by microorganisms such asmethicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant strains of Acinetobacter baumannii.

doi:10.1016/j.regpep.2010.07.147

Helokinestatins: A novel family of bioactive peptides with drug-leadpotential fromthe venomof theGilaMonster (Heloderma suspectum)Chris Shaw, T. ChenMolecular Therapeutics Research, School of Pharmacy,Queens University, Belfast, United Kingdom

Venomof theGilaMonster (Heloderma suspectum) has proven to bean unlikely source of lead compounds (exendins) for the development

Abstracts / Regulatory Peptides 164 (2010) 19–25 23