Amylin: physiology and pharmacology

346 Pages·2005·5.276 MB·English

by  Andrew Young

SERIAL EDITORS
J. Thomas August Daryl Granner
Baltimore,Maryland Nashville,Tennessee
Ferid Murad
Houston,Texas
ADVISORY BOARD
R.Wayne Alexander Floyd E. Bloom
Boston,Massachusetts LaJolla,California
Thomas F.Burke Leroy Liu
Houston,Texas Piscataway,NewJersey
AnthonyR. Means G. Alan Robison
Durham,NorthCarolina Houston,Texas
JohnA. Thomas Thomas C.Westfall
SanAntonio,Texas St.Louis,Missouri
Contents
Foreword xi
Preface xiii
Historical Background
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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
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I. Summary 19
II. TissueExpression and Secretion 20
III. Patternsof Amylin Secretion 22
IV. Circulating Amylin Concentrations 24
V. Pharmacokinetic Studies 30
References 37
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Receptor Pharmacology
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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
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I. Summary 67
II. Overview of Reported Actions 68
III. Prior Theories of Pathogenicand Physiological Roles 70
References 73
Inhibition of Food Intake
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I. Summary 79
II. Food Intake 80
III. Localization ofEffect to Area Postrema 86
IV. Amylin Interaction atOtherAppetite Control Circuits 90
References 92
Inhibition of Gastric Emptying
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I. Summary 99
II. Background 100
III. Effects ofAmylin on Gastric Emptying 102
IV. Effects on Postprandial Nutrient Profiles 108
V. Hypoglycemic Override 111
References 116
Effects on Digestive Secretions
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I. Summary 123
II. GastricAcid Secretion 124
Contents vii
III. Pancreatic Enzyme Secretion 131
IV. Effects ofAmylin on GallbladderContraction 138
V. Effects ofAmylin on IntestinalGlucose Transport 141
References 143
Inhibition of Glucagon Secretion
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I. Summary 151
II. Glucagon Secretion in Insulinopenic Diabetes 154
III. Effects ofAmylin on Glucagon Releasefrom Isolated
Preparations 155
IV. Effects ofAmylin inWhole-AnimalPreparations 160
V. Pharmacology ofGlucagonostatic Effect 166
VI. Effect of Pramlintide inAnesthetized Rats 166
VII. Clinical Studies 167
References 167
Inhibition of Insulin Secretion
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I. Summary 173
II. Background 174
III. Effects ofAmylin on Insulin Secretion 175
IV. Pharmacology ofInsulinostaticEffect 182
V. Localization ofEffects on InsulinSecretion 185
References 186
Effects on Plasma Glucose and Lactate
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I. Summary 193
II. PlasmaLactate Concentration 194
III. PlasmaGlucose Concentration 200
IV. Timing ofChanges 202
V. Mechanisms Linking Changesin Glucose and Lactate 203
VI. The Hyperlactemic Clamp 203
VII. Postprandial Glucose 205
References 206
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Effects in Skeletal Muscle
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I. Summary 209
II. Glycogen Metabolism 210
III. MuscleGlycogen Synthase and Glycogen Content 216
IV. Glycogen Phosphorylase 216
V. CyclicAmp in Muscle 217
VI. Intracellular Glucose-6-Phosphate inMuscle 218
VII. LactateEffluxfrom Muscle 218
VIII. Glucose Efflux from Muscle 218
IX. Potenciesfor Amylin Effects in Muscle 219
X. Transport of Glucose,3-O-Methylglucose, and
2-Deoxyglucose 221
þ þ
XI. Na /K AtpaseinMuscle 223
References 223
Effects in Liver
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I. Summary 229
II. Effects ofAmylinomimetic Agents on Endogenous Glucose
Production 230
III. DirectEffects ofAmylin inHepatocytes 230
IV. Effects ofAmylin inIsolated Perfused Liver 231
V. Cori Cycle-Independent Effects on Endogenous Glucose
Production 231
References 233
Effects in Fat
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I. Summary 235
II. Effects ofAmylin inIsolated Adipocytes 235
References 238
Cardiovascular Effects
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I. Summary 239
II. Effects ofAmylin on Blood Pressure 240
Contents ix
III. Effects ofAmylin inSpecificVascularBeds 243
IV. Pharmacology ofVascularEffect 245
V. DirectInotropic Effects 246
References 248
Renal Effects
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I. Summary 251
II. RenovascularEffects 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 inIsolated KidneyPreparations 261
VIII. Effects on Kidney Development and Endothelial Integrity 261
IX. Effects on Subfornical Organ and Drinking Behavior 262
References 263
Effects on Bone
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I. Summary 269
II. Effects atCalcitonin Receptors 269
III. Effects on CalciumConcentrations 271
IV. Effects on Osteoclasts 273
V. Effects on Osteoblasts 275
VI. Effects inModels ofDiabetic Osteopenia 276
VII. Effects inModels ofOsteoporosis 277
VIII. Effects on Bone in Humans 277
References 277
Central Nervous System and Other Effects
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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
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VII. Effects on Pain 284
VIII. Effects on Inflammation 287
References 287
Clinical Studies
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I. Summary 289
II. Pharmacokinetics 290
III. Tolerability 291
IV. Safety 293
V. Effects on GlycemicIndices 296
VI. Effects on Body Weight 303
VII. Effects on SpecificActions 306
References 311
Index 321
ContentsofPreviousVolume 329
Foreword
Amylinisapeptidehormonesecretedbythepancreaticbetacellalongwith
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’sdiscovery20yearsagoandthebattletoshowitstherapeuticutility
isafascinatingone,andAndrewYounghasbeeninitfromthebeginning.It
beginswiththeunexpectedfindingthatastrangeandprobablynoxiousde-
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,isderivedfromanancientfamilyofhormones,whichincludescalcito-
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 witha completely identicalreceptorsequence.
Therangeofamylin’sactionsisconsiderable.Itisananorexigen,ithas
multipleeffectsonthegastrointestinaltractanddigestiveprocesses,itinter-
actswiththeactionsofotherislethormones,anditaffectsotherperipheral
tissues. Its analog, pramlintide, is useful in correcting various metabolic
abnormalities in diabetes, where endogenous amylin release is deficient as
aconsequenceofthereductioninbetacellnumbers.Allofamylin’sactions
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xii Foreword
aredescribedwithinandadduptoanenthrallingpictureoftheintricacyof
mammalian control systems.
This extraordinarily readable book takes us through the whole
fascinating storywithamazinginsightsinto biologyandfunctional control
systems.Itisacomprehensivetreasureofinformationfromascientistwho
hasbeen personallyinvolvedin every aspect ofthe amylin world.
Steve R. Bloom
Department ofMetabolic Medicine
Division ofInvestigative Science
Hammersmith Hospital
Imperial College London
London,United Kingdom
Preface
Itisrarethatsomuchoftheburdenofdiscoveryofthephysiologyofa
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
reviewwhathasbeenfullypublished,butalsotosummarizemuchofwhat
hasnot.
OnepurposeofthisbookistopresentthetotalityofwhatIbelievetobe
trueaboutthephysiologyofthehormoneamylin.Ihaveappraisedthepeer-
reviewed literature. But I have also unashamedly cited lesser publications,
particularlythemeetingabstractsoflearnedsocieties.Theseoftenrepresent
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
tobe necessary.
IapologizeinadvanceifinplacesIappeartohaveover-reportedthework
of my own laboratory. This comes from an intent to inform via a familiar
knowledgebaseandnotfromadesiretodiminishtheworkofothers.
Thisbookisthequintessenceoftheeffortsofsomanyindividuals,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,andtheeffortoutsidethecompanymusthavewellexceededthatfigure.
The fruits of this effort haveincluded notonly an understanding ofthe ac-
tions of a single hormone, but the revelation of entirely new physiologies
and new modes of therapy, especially in regards to metabolic control.
Iamprivileged torepresent here that collective effort.
AndrewYoung
October2005
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