Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2015 Amylin: Pharmacology, Physiology, and Clinical Potential Hay, Debbie L ; Chen, Steve ; Lutz, Thomas A ; Parkes, David G ; Roth, Jonathan D Abstract: Amylin is a pancreatic ฀-cell hormone that produces effects in several different organ systems. Here, we review the literature in rodents and in humans on amylin research since its discovery as a hormone about 25 years ago. Amylin is a 37-amino-acid peptide that activates its specific receptors, which are multisubunit G protein-coupled receptors resulting from the coexpression of a core receptor protein with receptor activity-modifying proteins, resulting in multiple receptor subtypes. Amylin’s major role is as a glucoregulatory hormone, and it is an important regulator of energy metabolism in health and disease. Other amylin actions have also been reported, such as on the cardiovascular system or on bone. Amylin acts principally in the circumventricular organs of the central nervous system and functionally interacts with other metabolically active hormones such as cholecystokinin, leptin, and estradiol. The amylin-based peptide, pramlintide, is used clinically to treat type 1 and type 2 diabetes. Clinical studies in obesity have shown that amylin agonists could also be useful for weight loss, especially in combination with other agents. DOI: https://doi.org/10.1124/pr.115.010629 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-112571 Journal Article Published Version Originally published at: Hay, Debbie L; Chen, Steve; Lutz, Thomas A; Parkes, David G; Roth, Jonathan D (2015). Amylin: Pharmacology, Physiology, and Clinical Potential. Pharmacological Reviews, 67(3):564-600. DOI: https://doi.org/10.1124/pr.115.010629 1521-0081/67/3/564–600$25.00 http://dx.doi.org/10.1124/pr.115.010629 PHARMACOLOGICAL REVIEWS Pharmacol Rev 67:564–600, July 2015 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: PAUL A. INSEL Amylin: Pharmacology, Physiology, and Clinical Potential Debbie L. Hay, Steve Chen, Thomas A. Lutz, David G. Parkes, and Jonathan D. Roth School of Biological Sciences, Maurice Wilkins Centre for Molecular Biodiscovery and Centre for Brain Research, University of Auckland, Auckland, New Zealand (D.L.H.); Amylin Pharmaceuticals LLC, San Diego, California (S.C., D.G.P.); Institute of Veterinary Physiology, Institute of Laboratory Animal Sciences and Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (T.A.L.); and Intercept Pharmaceuticals, Inc., San Diego, California (J.D.R.) Abstract ...................................................................................565 Downloaded from I. Introduction . ..............................................................................566 II. Amylin ....................................................................................566 A. Amylin and Related Peptides...........................................................566 B. Amylin Expression, Secretion, and Metabolism .........................................568 III. Amylin Receptors . ........................................................................568 pharmrev.aspetjournals.org A. Molecular Composition .................................................................568 B. Pharmacology . ........................................................................569 C. Signaling ..............................................................................571 D. Regulation .............................................................................571 E. Expression and Physiologic Relevance of Amylin Receptor Subtypes . ...................572 IV. Genetic Models ............................................................................573 A. Genetic Models of Amylin Deficiency or Overexpression . ...............................573 B. Genetic Models of Amylin Receptors ....................................................574 at Universitaet Zuerich on September 3, 2015 V. Physiology of Amylin’s Effect on Eating ....................................................575 A. Amylin as a Satiation Signal ...........................................................575 B. Amylin as an Adiposity Signal..........................................................576 C. Amylin and Energy Expenditure . ......................................................576 VI. Mechanisms Underlying Amylin Actions . ................................................577 A. Amylin Action in the Brainstem . ......................................................577 B. Brainstem Mechanisms Mediating Amylin Signaling ....................................577 C. Amylin-Sensitive Area Postrema Neurons Are Sensitive to Nutrients. ...................578 D. Neuroaxis Activation by Amylin . ......................................................578 E. Amylin Action in Other Brain Areas....................................................578 F. Summarizing Remarks .................................................................579 VII. Other Actions of Amylin and Potential Therapeutic Areas . ...............................579 A. Amylin in the Cardiovascular System . ................................................579 B. Amylin and Lipolysis. ..................................................................580 C. Amylin and Maternal Behaviors . ......................................................580 D. Amylin and Stress-Induced Eating .....................................................581 This research was supported by the Health Research Council of New Zealand, the Maurice Wilkins Centre for Molecular Biodiscovery, the Auckland Medical Research Foundation, the Maurice and Phyllis Paykel Trust, and the New Zealand Lotteries Commission (to D.L.H.). Continued financial support from the Swiss National Science Foundation, as well as support from the Zurich Center of Integrative Human Physiology, the Novartis Foundation, the Ciba-Geigy Foundation, the Olga Mayenfisch Foundation, and the Vontobel Foundation are gratefully acknowledged (to T.A.L.). D.L.H. has been a speaker for Amylin Pharmaceuticals and received in-kind support from Amylin Pharmaceuticals in the form of peptides. S.C., D.G.P., and J.D.R. have been employed by and have held equity in Amylin Pharmaceuticals, Inc. T.A.L. has received in-kind support from Amylin Pharmaceuticals in the form of peptides. Address correspondence to: Debbie L. Hay, School of Biological Sciences, Maurice Wilkins Centre for Molecular Biodiscovery and Centre for Brain Research, University of Auckland, Thomas Building, 3A Symonds Street, Auckland 1142, New Zealand. E-mail: dl.hay@ auckland.ac.nz dx.doi.org/10.1124/pr.115.010629. 564 Amylin 565 E. Antipsychotic-Like Actions of Amylin . ................................................581 F. Amylin and Alzheimer’s Disease. ......................................................581 G. Amylin in Renal Physiology ............................................................581 VIII. Amylin Therapeutic Applications: Overview/Rationale . .....................................581 A. Diabetes . ..............................................................................582 1. Amylin Secretion in Diabetes. ......................................................582 2. Postprandial Hyperglucagonemia and Diabetes. .....................................582 3. Gastric Emptying and Diabetes......................................................583 B. Obesity . ..............................................................................583 1. Amylin Secretion in the Obese State.................................................583 2. Amylin Sensitivity in the Obese State. ..............................................584 3. Food Intake and Body Weight: Preclinical Studies in Diet-Induced Obese Rat Models.. ........................................................................585 C. Identifying Amylin Agonist-Responsive Populations in Preclinical Models . .............585 D. Next-Generation Drugs for the Amylin System..........................................586 1. Davalintide. ........................................................................586 2. PEGylated or Glycosylated Amylin. ................................................587 3. Oral Amylin Agonists. ............................................................587 4. Inhibition of Amylin Degradation. ................................................587 IX. Amylin Interactions: Physiology and Pharmacology .........................................587 A. Amylin and Leptin . ..................................................................587 B. Amylin and PYY(3-36) .................................................................589 C. Amylin and Cholecystokinin............................................................589 D. Amylin and Melanocortins . ............................................................589 E. Amylin and Glucagon-Like Peptide 1 . ................................................589 F. Amylin and Small Molecule Anorectics . ................................................589 X. Amylin in Clinical Studies .................................................................590 A. Pharmacology of Amylin Agonists ......................................................590 B. Clinical Studies Relating to Diabetes . ................................................590 C. Clinical Studies Relating to Food