Amylin - Physiology and Pharmacology [Advances in Pharmacology, Vol 52] - A. Young (Elsevier, 2005) WW PDF
Preview Amylin - Physiology and Pharmacology [Advances in Pharmacology, Vol 52] - A. Young (Elsevier, 2005) WW
Contents Foreword xi Preface xiii Historical Background Andrew Young I. Discovery and Nomenclature 1 II. Molecular Biology 4 III. Amyloid and Association with Diabetes 6 IV. Properties of Human Amylin 7 References 9 Tissue Expression and Secretion of Amylin Andrew Young I. Summary 19 II. Tissue Expression and Secretion 20 III. Patterns of Amylin Secretion 22 IV. Circulating Amylin Concentrations 24 V. Pharmacokinetic Studies 30 References 37 v Receptor Pharmacology Andrew Young I. Summary 47 II. Amylin Receptors 48 III. Amylin Binding 54 IV. Identifying Amylinergic Responses 58 References 62 Amylin and the Integrated Control of Nutrient Influx Andrew Young I. Summary 67 II. Overview of Reported Actions 68 III. Prior Theories of Pathogenic and Physiological Roles 70 References 73 Inhibition of Food Intake Andrew Young I. Summary 79 II. Food Intake 80 III. Localization of Effect to Area Postrema 86 IV. Amylin Interaction at Other Appetite Control Circuits 90 References 92 Inhibition of Gastric Emptying Andrew Young I. Summary 99 II. Background 100 III. Effects of Amylin on Gastric Emptying 102 IV. Effects on Postprandial Nutrient Profiles 108 V. Hypoglycemic Override 111 References 116 Effects on Digestive Secretions Andrew Young I. Summary 123 II. Gastric Acid Secretion 124 vi Contents III. Pancreatic Enzyme Secretion 131 IV. Effects of Amylin on Gallbladder Contraction 138 V. Effects of Amylin on Intestinal Glucose Transport 141 References 143 Inhibition of Glucagon Secretion Andrew Young I. Summary 151 II. Glucagon Secretion in Insulinopenic Diabetes 154 III. Effects of Amylin on Glucagon Release from Isolated Preparations 155 IV. Effects of Amylin in Whole-Animal Preparations 160 V. Pharmacology of Glucagonostatic Effect 166 VI. Effect of Pramlintide in Anesthetized Rats 166 VII. Clinical Studies 167 References 167 Inhibition of Insulin Secretion Andrew Young I. Summary 173 II. Background 174 III. Effects of Amylin on Insulin Secretion 175 IV. Pharmacology of Insulinostatic Effect 182 V. Localization of Effects on Insulin Secretion 185 References 186 Effects on Plasma Glucose and Lactate Andrew Young I. Summary 193 II. Plasma Lactate Concentration 194 III. Plasma Glucose Concentration 200 IV. Timing of Changes 202 V. Mechanisms Linking Changes in Glucose and Lactate 203 VI. The Hyperlactemic Clamp 203 VII. Postprandial Glucose 205 References 206 Contents vii Effects in Skeletal Muscle Andrew Young I. Summary 209 II. Glycogen Metabolism 210 III. Muscle Glycogen Synthase and Glycogen Content 216 IV. Glycogen Phosphorylase 216 V. Cyclic Amp in Muscle 217 VI. Intracellular Glucose-6-Phosphate in Muscle 218 VII. Lactate Efflux from Muscle 218 VIII. Glucose Efflux from Muscle 218 IX. Potencies for Amylin Effects in Muscle 219 X. Transport of Glucose, 3-O-Methylglucose, and 2-Deoxyglucose 221 XI. Naþ/Kþ Atpase in Muscle 223 References 223 Effects in Liver Andrew Young I. Summary 229 II. Effects of Amylinomimetic Agents on Endogenous Glucose Production 230 III. Direct Effects of Amylin in Hepatocytes 230 IV. Effects of Amylin in Isolated Perfused Liver 231 V. Cori Cycle-Independent Effects on Endogenous Glucose Production 231 References 233 Effects in Fat Andrew Young I. Summary 235 II. Effects of Amylin in Isolated Adipocytes 235 References 238 Cardiovascular Effects Andrew Young I. Summary 239 II. Effects of Amylin on Blood Pressure 240 viii Contents III. Effects of Amylin in Specific Vascular Beds 243 IV. Pharmacology of Vascular Effect 245 V. Direct Inotropic Effects 246 References 248 Renal Effects Andrew Young I. Summary 251 II. Renovascular Effects 252 III. Amylin Binding in Kidney 252 IV. Effects on the Renin-Angiotensin-Aldosterone System 253 V. Effects on Kidney Fluid and Electrolyte Excretion 256 VI. Effects on Plasma Electrolyte Concentrations 258 VII. Effects in Isolated Kidney Preparations 261 VIII. Effects on Kidney Development and Endothelial Integrity 261 IX. Effects on Subfornical Organ and Drinking Behavior 262 References 263 Effects on Bone Andrew Young I. Summary 269 II. Effects at Calcitonin Receptors 269 III. Effects on Calcium Concentrations 271 IV. Effects on Osteoclasts 273 V. Effects on Osteoblasts 275 VI. Effects in Models of Diabetic Osteopenia 276 VII. Effects in Models of Osteoporosis 277 VIII. Effects on Bone in Humans 277 References 277 Central Nervous System and Other Effects Andrew Young I. Summary 281 II. Effects on Amino Acid Transport 282 III. Amylin Transport across the Blood–Brain Barrier 282 IV. Effects on Body Temperature 282 V. Effects on Memory 283 VI. Effects on Locomotor Activity, Grooming, and Stereotypy 284 Contents ix VII. Effects on Pain 284 VIII. Effects on Inflammation 287 References 287 Clinical Studies Andrew Young I. Summary 289 II. Pharmacokinetics 290 III. Tolerability 291 IV. Safety 293 V. Effects on Glycemic Indices 296 VI. Effects on Body Weight 303 VII. Effects on Specific Actions 306 References 311 Index 321 Contents of Previous Volume 329 x Contents SERIAL EDITORS J. Thomas August Baltimore, Maryland Daryl Granner Nashville, Tennessee Ferid Murad Houston, Texas ADVISORY BOARD R. Wayne Alexander Boston, Massachusetts Floyd E. Bloom La Jolla, California Thomas F. Burke Houston, Texas Leroy Liu Piscataway, New Jersey Anthony R. Means Durham, North Carolina G. Alan Robison Houston, Texas John A. Thomas San Antonio, Texas Thomas C. Westfall St. Louis, Missouri Preface It is rare that so much of the burden of discovery of the physiology of a new hormone has been the domain of a corporate entity—in this case, one that has acquired the name of the hormone. Several factors have conspired to delay full publication of much of amylin’s unique biology. The impetus to write this book was not only to review what has been fully published, but also to summarize much of what has not. One purpose of this book is to present the totality of what I believe to be true about the physiology of the hormone amylin. I have appraised the peer- reviewed literature. But I have also unashamedly cited lesser publications, particularly the meeting abstracts of learned societies. These often represent the only public record of an amylin-related biology. I have occasionally drawn from the patent literature where this too is the only record. In rare instances, I have included unpublished data, where I have considered them to be necessary. I apologize in advance if in places I appear to have over-reported the work of my own laboratory. This comes from an intent to inform via a familiar knowledge base and not from a desire to diminish the work of others. This book is the quintessence of the efforts of so many individuals, that I would offend most to name a few. I have estimated that Amylin Pharma- ceuticals, Inc., has expended 300 person-years in exploring amylin’s biolo- gy, and the effort outside the company must have well exceeded that figure. The fruits of this effort have included not only an understanding of the ac- tions of a single hormone, but the revelation of entirely new physiologies and new modes of therapy, especially in regards to metabolic control. I am privileged to represent here that collective effort. Andrew Young October 2005 xiii Foreword Amylin is a peptide hormone secreted by the pancreatic beta cell along with insulin in response to meal/glucose stimuli. An analog of amylin (pramlin- tide) is now a pharmaceutical product for treating diabetes. The story of amylin’s discovery 20 years ago and the battle to show its therapeutic utility is a fascinating one, and Andrew Young has been in it from the beginning. It begins with the unexpected finding that a strange and probably noxious de- posit in the beta cell turned out to be a precipitate of a natural hormone, amylin. This was followed by the steady uncovering of its physiological role. Evolution seems often to derive new functions from old, and amylin, too, is derived from an ancient family of hormones, which includes calcito- nin and the powerful neurotransmitter calcitonin-gene related peptide. Although amylin is an islet hormone co-released with insulin, it is also found elsewhere—for example in the central nervous system. Amylin’s receptor is a member of a larger family, but here specificity is partly provided by a receptor activity modifying protein (RAMP) that turns the calcitonin receptor into the amylin receptor. This illustrates an important principle: a receptor greatly alters its characteristics according to its envi- ronment. The old pharmacological certainty about the specificity of recep- tors was thus challenged by amylin—specificity in reality depends on the cell environment and can differ from tissue to tissue in major or minor ways even with a completely identical receptor sequence. The range of amylin’s actions is considerable. It is an anorexigen, it has multiple effects on the gastrointestinal tract and digestive processes, it inter- acts with the actions of other islet hormones, and it affects other peripheral tissues. Its analog, pramlintide, is useful in correcting various metabolic abnormalities in diabetes, where endogenous amylin release is deficient as a consequence of the reduction in beta cell numbers. All of amylin’s actions xi are described within and add up to an enthralling picture of the intricacy of mammalian control systems. This extraordinarily readable book takes us through the whole fascinating story with amazing insights into biology and functional control systems. It is a comprehensive treasure of information from a scientist who has been personally involved in every aspect of the amylin world. Steve R. Bloom Department of Metabolic Medicine Division of Investigative Science Hammersmith Hospital Imperial College London London, United Kingdom xii Foreword
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