Table Of ContentContents
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
