Walter F. Boron • Emile L. Boulpaep
`
`MEDICAL
`PHYSIOLOGY
`
`Boehringer Ex. 2005
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`

`
`L
`
`y
`
`A Cellular and Molecular
`Approach
`
`Walter F. Boron, MD, PhD
`
`Professor
`Department of Cellular and Molecular Physiology
`Yale University School of Medicine
`New Haven, Connecticut
`
`•
`Emile L. Boulpaep, MD
`
`Professor
`Department of Cellular and Molecular Physiology
`Yale University School of Medicine
`New Haven, Connecticut
`
`SAUNDERS
`An lmprirn of ~!!sevier
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`
`SAUNDERS
`An lmprinl of Elsevier
`
`The Curus Center
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`Philadelphia, Pennsylvania 19106
`
`MEDICAL I'HYSIOLOGY
`Copyr ight II) 2003, Elsevier Scien ce (USA). All rlglus reserved.
`
`ISBN 0 · 7216-3256-4
`
`No parL of this publication may be rtproduc.ed or transmitt~d in any form or by any means. electronic or
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`Notice:
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`Medicine is an ever-changing field. Standard safety pr<cautions must be followed. but as n<w research and
`clinical experience broaden our knowledge, changes in treatment and drug therapy become necessary or
`appropriate. Readers are advised to check the most current product lnformallOn provided by the manufac(cid:173)
`turer or each drug to be admimstered to verify the recommended dose, the method and duration or
`admimstration, and contraindicauons. It is the responslbiuty or the treating physician, relying on experienct
`and knowledge of the patient, to d<termine dosages and the best treatment for each Individual patient. Nei(cid:173)
`ther th< Publisher nor the editor assumes any liability for any injury and/or damage to person< or propeny
`arising from this publication.
`
`The Publisher
`
`Library of Congress Cataloging-in-Publication Data
`
`Boron, Waller F.
`Medical phys•ology I Walter F. Boron, Emile L. Boulpaep-lst <d.
`p.
`em.
`ISBN 0-7216-3256-4
`1. Human physwlogy.
`I DNLM: I. Physiology.
`QP34.5 .865 2003
`612-dcll
`
`II. Tile
`Boulpaep, Emile L
`QT I 04 07356M 20031
`
`Acquislllons Editor; William R. Schmin
`Developnwllal Editor. Melissa Dudllck
`Publishing Servlcts Manager: Frank Polizzano
`
`00-051597
`
`PUDNP
`
`Printed in China
`
`Last digit Is the print number: 9 8 7 6 5 4
`
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`

`
`CHAPTER 50
`
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`
`The Endocrine
`Pancreas
`
`Eugene J. Barrell
`
`The Islets of Lange rhans Are Endocrine and Paracrine
`Tissues
`The pancreas contains two types L>l glands: {I) cx<1crinc gbnds, which
`secrete digestive enzymes and HCO, imo the Intestinal IL1nwn (sec Cl1apter
`12), and (2) endocrine glands, cal led the "islc.:ts of Langcrhans."
`The normal human pancreas conta ins buween 500.000 and several mil(cid:173)
`lion islc.:ts. Islets can be ov;il or spherical and lllL'asurc IJctween 50 :1nd 300
`/Lll1. Islets cort:lin HI least lou1 types L>f sn.Tctory cells- a cdb , {3 cells, 8
`cells, and F cells-plus variL>us vnsculat· and ncur:il elcmcms (Fig. '50-1
`f3 cells secrete insulin, lll"l>insullll, C pcptick. and a
`and Table 50- I)
`newly dcsuibcd protein. :1111)'1in. {3 cells arc the most numerous type of
`secrcwry cell within the islets; they ;1rc loC'ntcd throughout the islet hut are
`particularly ltl..ntcrous in the center. a Cells principally secrete glucngon, o
`cells secrete so111at.ostatin. ami F cells (a l~o called pancreatic polyp~ptide
`cells) secrete pancrcmic polypeptide.
`The cells within an islet receive information from the world outside the
`islet. These cells also can cumnntnicat.e with each othu and influence each
`other's secretion. We can group tltesc comntunkmion lin ks 1nt <>
`three
`categol'ics:
`
`I. Humoral communication. The blnod suppl)' of the islet courses out(cid:173)
`ward fmm the center of the islet toward the periphery , carrying glucose
`and other secrctagogues. In the mt- and less strikingly in huntans- {3
`cells arc 111orc abundant in tile cente r ol the islet, whereas a and I) cells
`arc more ~thunclnnt in the penphcry. Cells within :1 given 1slet can
`influence the scct·ction of other cells as the blood supply courses out(cid:173)
`ward thrnugh the islet carrying the secreted hormonal product nf each
`cell type with it. For exn111plc, glucagon is a potent insulin secretagogue,
`insuli n modestly inhibits glucng<1n release. and somatostatin potently
`inhibits the secretion of both insulin and !,;lLtcagon (as well as the
`sccr~ tiun of growth hormone and <>thcr nonislet h,lrmoncs).
`Cell-cell communication. Hot h gap and l.ight JUnctional structures con(cid:173)
`nect islet cdls with one another. Cells within ;111 islet can connuunicate
`via gap julll:tions, wh1ch may be impol'lalll l'or the regula1ion of both
`insulin and glucagon secretion.
`Neural communication . Another level ul regulation ol islet secretion
`occurs via innervation from both the sympathetic: and the pmasympa(cid:173)
`thetic divisions of the autonontic nervous system CANS). Cholinergic
`
`2.
`
`3.
`
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`The Endocrine Pancreas I 50
`
`1 067
`
`FIGURE 50 I. Islet of Langerhans.
`
`Common
`bile duct
`
`Pancreatic
`duct
`
`Duodenum _.......~
`
`insulin secretion . Adrenergic
`stimu lation augments
`stimulation can have either a stimulawry or inhibitory
`effect, depending on whether /3-adrenergic or a-adre(cid:173)
`nergic stimulation dominates (p. 1065).
`These three communication mechanisms allow for a
`tight control over the synthesis and secretion of islet hor(cid:173)
`mones.
`
`whelming acidosis. No effective therapy was available, and
`few prospects were on the horizon. It was known that the
`blood sugar was elevated in this disease, but beyond that,
`there was little understanding of its pathogenesis.
`In 1889, Minkowski and von Me.ring demonstrated that
`removing the pancreas from dogs caused hyperglycemia,
`
`INSULIN
`
`The discovery of msulin was among the most exciting
`and dramatic events in the history of endocrine physiol(cid:173)
`ogy and therapy. In the United States and Europe, insu(cid:173)
`lin-dependent diabetes mellitus (IDDM), or type 1 diabe(cid:173)
`tes, develops in about 1 in every 600 children in their
`Lifetime. However, the prevalence is only about 1 in
`10,000 in eastern Asia. Before 1922, all children with
`diabetes died within 1 or 2 years of diagnosis. It was an
`agonizing illness; the children lost weight despite eating
`well, became progressively weaker and cachectic, were
`soon plagued by infections, and eventually died of over-
`
`TABLE 50- 1
`
`PRODUCTS OF PANCREATIC ISLET CELLS
`
`CELL TYPE
`
`f3
`
`PRODUCT
`Glucagon
`
`Insulin
`Proinsulin
`C peptide
`Amylin
`Somatostatin
`
`Pancreatic polypeptide
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`1068
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`50 I The Endocrine Pancreas
`
`TABLE 50-2
`
`EFFECTS OF NUTRITIONAL STATES
`
`PARAMETER
`Plasma [glucose], mg/dl
`rnM
`
`Plasma [insulin], JJ.U/ml
`Plasma [glucagon!, pg/ml
`
`Liver
`
`AFTER A 24-HOUR FAST
`60- 80
`
`3.3-4.4
`
`3-8
`40- 80
`f Glycogenolysis
`j Gluconeogenesis
`
`Adipose lissue
`Muscle
`
`Lipids mobilized for fuel
`Lipids metabolized
`Protein degraded and amino acids exported
`
`2 HOURS AFTER A MIXED MEAL
`100- 140
`
`5.6- 7.8
`50-150
`80- 200
`~ Glycogenolysis
`~ Gluconeogenesis
`j Glycogen synthesis
`Lipids synthesized
`Glucose oxidized or stored as glycogen
`Protein preserved
`
`excess urination, thirst, weight loss, and death-in short,
`a syndrome closely resembhng type I diabetes. Following
`Lhis lead, a group of mvestigators in the Depanmem of
`Physiology at the University of Toronto prepared extracts
`of pancreas and tested the ability of these extracts to
`lower plasma [glucose! in pancreatectomized dogs. Despite
`months of failures, these investigators persisted in their
`belief that such extracts could be beneficial. Finally, by the
`lifil winter of 1921, Banting and Best were able to demonstrate
`that an aqueous extract of pancreas could lower blood
`glucose and prolong survival in a pancreatectomized dog.
`Within 2 months, a more purified extract was shown to
`lower blood sugar in a young man with diabetes. By the
`end of 1923, insulin (as the islet hormone was named)
`was being prepared from beef and pork pancreas on an
`mdustrial scale, and patients from around the world were
`recetving effective treatment of thetr diabetes.
`Since that time, the physiology of insulin synthesis,
`secretion, and action has been more extensively studied
`than that of any other hormone. Now, more than three
`quarters of a century later, much is known about the
`metabolic pathways through which insulin regulates car(cid:173)
`bohydrate, lipid, and protein metabolism in its major tar(cid:173)
`gets: the liver, muscle, and adipose tissue. However, the
`sequence of mtracellular signals that triggers insulin secre(cid:173)
`tion by pancreatic {3 cells, as well as the signal-Lransduc(cid:173)
`uon process triggered when insulin binds to a plasma
`membrane receptor on target tLSSues, and the process by
`wh.1ch the irnmum: system recogn.izes anti target~ {3 cells
`for destntction remain areas of mtense study.
`
`Insulin Replenishes Fuel Reserves in Muscle,
`Liver, and Adipose Tissue
`What does insulin do? Succinctly put, insulin efficiently
`integrates body fuel metabolism both dUJing periods of
`fasting and during feedmg (Table 50-2). When an indi(cid:173)
`vidual is fasting, the {3 cell secretes less insulin. When
`insulin levels decrease, lipids are mobilized from adtpose
`tissue and amino acids are mobilized from body protein
`stores wtthin muscle and other ussues. These lipids and
`amino acids provide fuel for oxidation and serve as pre·
`cursors for hepatic ketogenesis and gluconeogenesis, re(cid:173)
`spectively. With feeding, insulin secretion increases. Ele-
`
`the mobilization of
`levels of insulin dtminish
`vated
`endogenous fuel stores and sumulate carbohydrate, lipid,
`and amino acid uptake by specific, insulin-sensitive target
`tissues. In this manner, insulm rurects tissues to replenish
`the fuel reserves that were used during periods of fasung.
`As a result of its ability to carefully regulate the mobih(cid:173)
`zation and storage of fuels, insulin maintains the concen(cid:173)
`tration of glucose in the plasma within narrow limits.
`Such regulation provides the central nervous system
`(CNS) with a constant supply of glucose for fuel to main(cid:173)
`tain cortical function. In higher organisms, if the plasma
`glucose concentration declines below 2 to 3 mM (hypo(cid:173)
`glycemia) for even a brief period, confusion, seizures, and
`coma may result. Conversely, persistent elevations of
`plasma [glucose[ are characteristic of the diabetic state.
`Severe hyperglycemia (plasma glucose levels above 30 to
`40 mM) produces an osmotic diuresis (see box on p.
`782) and can lead to severe dehydration, hypertension,
`and vascular collapse.
`
`f3 Cells Synthesize and Secrete Insulin
`THE INSULIN GENE. Insulin ts made only in the {3 cells
`of the pancreatic islet. It is encoded by a single gene on
`
`CLINICAL MANIFESTATIONS OF
`HYPOGLYCEMIA AND
`HYPERGLYCEMIA
`
`Hypoglycemia: Early manifestations include palpita·
`tio ns, tachycardia, diaphoresis, anxiety, hypervenlila(cid:173)
`tion, shakiness, weakness, hunger, and nausea. For
`prolonged or severe hypoglycemia, manifestations in(cid:173)
`clude confusion, unusual behavior, hallucinations, sei(cid:173)
`zures, hypothermia, focal neurologic deficits, and
`coma.
`Hyperglycemia: Early manifestations include
`weakness, polyuria, polydipsia, altered vision, weight
`loss, and mild dehydration. For prolonged or severe
`hyperglycemia, manifestations include Kussmaul hyper(cid:173)
`ventilation (deep, rapid breathing), stupor, coma, hy(cid:173)
`potension, and cardiac arrhythmias.
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`
`S' UTR "
`
`Ribosome
`
`B
`
`c
`
`A
`
`3 ' UTA
`/
`\. m ANA encoding
`preprolnsulin
`
`®
`
`Prolnsulin
`
`Golgi
`
`Converting
`enzymes
`
`-trans·Golgl
`
`Cleavage
`
`Secretory
`granule -......_
`
`J
`~ Cpeptlde
`~
`~~
`r
`
`s
`s
`
`s
`s
`
`Insulin
`
`FIGURE 50- 2. Synthesis and processing of the insulin molecule. The
`mature mRNA of the insulin gene product comams a 5' umranslated
`reg10n (UTR); nucleotide sequences that encode a 24-ammo actd leader
`sequence, as well as B. C, and A peptide domains; and a 3' UTR_
`Together, the lender plus the B. C, and A domatns consmme preprotn·
`sulin. During translation of the mRNA, the leader sequence is cleaved m
`the lumen of the rough endoplasmic rettculum. What rematns is proln(cid:173)
`sulin, which consists of the B, C, and A don1ains. Beginnmg In the
`tra11s-Golgi, proteases de.we the proinsulin at two sites, releasmg the C
`peptide as well as the mature insulin molecule, which consists o f the B
`and A •halns that are connected by two disulfide bonds. The secretory
`granule contains equtmolar amounts of lnsuhn and the C pepttde, as
`well as a small amount of promsuhn These components all are released
`mto the extracellular space durmg secretion ER. endoplasmtc reuculum;
`mRNA. messenger RN~
`
`The Endocrine Pancreas I 50
`
`1069
`
`the shon arm of chromosome 1 L. lnsulin synthesis, as
`well as the secretion of insulin, is stimulated when islets
`are exposed to glucose. These effects require that glucose
`be metabolized. However, the molecular mechanisms by
`which glucose metabolites regulate insulin synthesis are
`not known.
`
`INSULIN SYNTHESIS. Transcription of the insulin gene
`product and subsequent processing result in production
`of the rull-length mRNA that encodes preprolnsulin .
`Starting from its 5 ' end, this mRNA encodes a leader
`sequence and then peptide domains B, C, and A. Insulin
`is a secretory protein (p. 36). As the preprohormone is
`symhestzed, the leader sequence of approximately 24
`amino acids tS cleaved from the nascent peptide as tt
`enters the rough endoplasmic reticulum. The result is
`proinsulin (Fig. 50-2), which consists of domains B, C,
`and A. As the trans-Golgi packages the proinsulin and
`creates secretory granules, proteases begin to slowly
`cleave the proinsulin molecule at two spots and thus
`excise the 31-amino-acid C peptide. The resulting insulin
`molecule has two peptide chains, designated the A and B
`chains, that are joined by two disulfide linkages. The
`mature insulin molecule has a total of 51 amino acids, 2 1
`on the A chain and 30 on the B chain. In the secretory
`granule, the insulin associates with zinc. The secretory
`vesicle contains this insulin, as well as proinsulin and C
`peptide. All three are released into the ponal blood when
`glucose stimulates the f3 cell.
`
`SECRETION OF INSULIN, PROINSULIN, AND C PEPTIDE. C
`peptide has no established biologic action. However, be(cid:173)
`cause it is secreted in a l: l molar ratio with insulin, it is
`a useful marker for insulin secretion. Proinsulin does have
`modest insulin-like. activities; it IS approximately l/20th as
`potent as insulin on a molar basis. ln addition, the f3 cell
`secretes only about 5% as much proinsulin as 1nsuhn. As
`a result, prolnsulin does not play a major role in the
`regulation of blood glucose.
`Most of the insulin (approximately 60%) that is se(cid:173)
`creted into the portal blood is removed in a first pass
`through the liver. ln contrast, C peptide is not extracted
`by the liver at all. As a result, whereas measurements of
`the insulin concentration m systemic blood do not quan(cid:173)
`titatively mimic the secretion of insulin, measurements of
`C peptide do. C peptide is eventually excreted m the
`urine, and measuremen1s of the quantity of C peptide
`excreted in a 24-hour p eriod therefore reflect-on a mo(cid:173)
`lar basis-the amount of insulin made during that Lime.
`Measurements of urinary C peptide can be used clinically
`to assess a person's insulin secretory capability.
`
`Glucose is the M ajor Regulator of Insulin
`Secretion
`ln healthy individuals, plasma !glucose] remains within a
`remarkably narrow range. After an overnight fast, ll typi(cid:173)
`cally runs between 4 and 5 mM; the plasma !glucose]
`rises after a meal, but even with a very large meal It does
`not exceed 10 mM. Modest increases in plasma !glucose]
`provoke marked increases in insulin secretion and, thus,
`marked increases in the plasma !insulin] (Fig. 50-3A).
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`
`1070
`
`50 I The Endocrine Pancreas
`
`NONHUMAN AND MUTANT INSULIN
`
`Cloning of the insulin gene has led to an important
`therapeutic advance, namely, the use of recombinant
`human insulin for the treatment of diabetes. Human
`insulin was the first recombinant protein available for
`routine clinical use. Before the availability of human
`insulin, either pork or beef insulin was used to treat
`diabetes. Pork and beef insulin differ from human insu(cid:173)
`lin by one and three amino acids, respectively. The
`difference, although small, is sufficient to be recog(cid:173)
`nized by the immune system, and antibodies to the
`injected insulin develop in most patients treated with
`beef or pork insulin; occasionally, the reaction is severe
`enough to cause a frank allergy to the insulin. This
`problem is largely avoided by using human insulin.
`Sequencing of the insulin gene has not led to a
`major understanding of the genesis of the common
`forms of human diabetes. However, we have learned
`that rare diabetic individuals make a mutant insulin
`molecule. In these subjech, the abnormal insulin pos(cid:173)
`sesses a single amino-acid substitution in either the A
`or B chain. In each case that has been described,
`these changes lead to a less active insulin molecule
`(typically only about I% as potent as insulin on a
`molar basis). These patients have either glucose intol(cid:173)
`erance or frank diabetes, but very high concentrations
`of lrnmunoreaclivc insulin in their plasma. In these
`individuals, the immunoreactivity of insulin is not af.
`fected to the same extent as the bioactivity.
`In addition to Identifying these mutant types of
`insulin, sequencing of the insulin gene has allowed
`identification of a flanking polymorphic site upstream
`of the insulin gene that contains o ne of several com(cid:173)
`mon alleles. In some populations, one of these alleles
`is associated with an increased risk for the develop(cid:173)
`ment of type 1 diabetes m ellitus. The mechanism by
`which this increased risk is conferred is not known.
`
`Conversely, a decline in plasma [glucose] of only 20%
`markedly lowers plasma [insulin]. The change in the con(cid:173)
`cemralion of plasma glucose that occurs in response to
`feeding or fasting is the mam determinant of insuhn se(cid:173)
`creuon. In a patient with type 1 diabetes mellitus caused
`by destruction of pancreatic islets, an oral glucose chal(cid:173)
`lenge evokes either no response or a much smaller insulin
`response. but a much larger increment in plasma [glu(cid:173)
`cose] that lasts for a much longer time (see Fig. 50-3B).
`intravenously
`A glucose challenge given
`raises
`the
`plasma glucose concentration more rapidly than if given
`orally. Such a rapid rise in plasma glucose leads to two
`distinct phases of insulin secretion (see Fig. 50-3C). The
`acute- or first-phase insulin response lasts only 2 to 5
`mmutes; the duration of the second insulin response per(cid:173)
`SISts as long as the blood glucose level remains elevated.
`The insulin released during the acute-phase insulin re(cid:173)
`sponse to intravenous glucose arises from preformed insu(cid:173)
`lin that has been packaged in secretory vesicles in the
`cytosol of the f3 cell. The insulin released later comes
`from both preformed and newly symhesized insulin. One
`of the earliest detectable metaboltc defects that occurs in
`
`diabetes is loss of the first phase of insulin secreuon,
`which can be detected experimentally by an intravenous
`glucose tolerance test. If a subJeCt consumes glucose or a
`mixed meal, plasma [glucose] rises much more slowly(cid:173)
`as in Figure 50-3A -because the appearance of glucose
`depends on intestinal absorption. Because plasma [glu(cid:173)
`cose] rises so slowly, the acute-phase insulin response can
`no longer be distinguished from the chronic response,
`and only a single phase of insulin secretion is apparent.
`
`Metabolism of Glucose by the fJ Cell Triggers
`Insulin Secretion
`The pancreauc {3 cells take up and metabolize glucose,
`galactose, and mannose, and each can provoke insulin
`secretion by the 1slet. Other hexoses (for example, 3-0-
`methylglucose or 2-deoxyglucose) that are transported
`into the f3 cell but that cannot be metabolized do not
`stimulate insulin secrelion. Although glucose itself is the
`best secretagogue, some amino acids (especially arginine
`and leucine) and small keto acids (a-ketoisocaproate), as
`well as ketohexoses (fructose), can also weakly stimulate
`insulin secretion. The amino acids and keto acids do not
`share any metabohc pathway with hexoses other than
`terminal oxidation via the citric acid cycle (p. l220). These
`observations have led to the suggestion that the adenosine
`triphosphate (ATP) generated from the metabolism of
`these varied substances may be involved in insulin secre(cid:173)
`tion. In the laboratory, depolarizing the islet-cell mem(cid:173)
`brane by raising extracellular IK•] provokes insulin secre(cid:173)
`tion. In addition, glucagon has long been known LO be a
`strong insulin secretagogue.
`From these data has emerged a relatively unified pic(cid:173)
`ture of how various secretagogues trigger insulin secre(cid:173)
`uon. Key to this picture is the presence in the islet of an
`ATP-sensitive K+ channel and a voltage-gated Ca2+ chan(cid:173)
`nel in the plasma membrane (Fig. 50-4). Glucose triggers
`insulin release in a seven-step process:
`
`l. Glucose enters the {3 ceU via the GLUT2 glucose trans(cid:173)
`porter by facilitated diffusion (p. 60). Amino acids
`enter via a different set of transporters.
`2. In the presence of glucokinase (the rate-limiting en(cid:173)
`zyme in glycolysis), the entering glucose undergoes
`glycolysis and raises [ATPI, by phosphorylaung adeno(cid:173)
`sine diphosphate (ADP). Some amino acids also enter
`the citric acid cycle and produce similar changes in
`[ATP], and IADPk
`3. Either the increased [ATP]; or the increased [ATPI/
`]ADP] 1 ratio causes KArp-type K+ channels (p. 198) to
`close.
`4. Reducing the K+ conductance of the cell membrane
`causes the f3 cell to depolarize (i.e., the membrane
`potential is less negative).
`5. This depolarization activates voltage-gated CaH chan(cid:173)
`nels (p. 189).
`increased
`6. The increased CaH permeability leads LO
`Ca2+ influx and increased intracellular free Ca2+. This
`rise in [Ca2+j1 additionally triggers Ca2+-induced Cal+
`release (p. 242).
`7. The increased [Ca2+];, perhaps by activation of a Cal+_
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`
`A NORMAL SUBJECT RECEIVING ORAL GLUCOSE
`
`B DIABETIC SUBJECT RECEIVING ORAL GLUCOSE
`
`The Endocrine Pancreas I SO
`
`1071
`
`300
`
`200
`
`100
`
`Glucose
`(mg/dl)
`
`150
`
`100
`
`50
`
`Insulin
`(~Uiml)
`
`Glucose
`(mg/dl)
`
`300
`
`200
`
`100
`
`Glucose
`\
`
`0
`
`0
`
`3
`2
`n me(hr)
`
`4
`
`5
`
`6
`
`0
`
`0
`
`3
`2
`Tlme(hr)
`
`4
`
`5
`
`6
`
`FIGURE 50- 3 Glucose tolerance test A, When a human con(cid:173)
`sumes a load or glucose (75 g), plasma !glucose! rises slowly,
`refiecting the Intestinal up1ake of the glucose. In response, the
`pancrealic f3 celts secrete insuhn and plasma !insu lin] nses
`sharply. ll, In a pauem with type I dtabetes, the same glucose
`load as that m A causes plasma lglucosel to rise to a higher
`level and to remnln there for a longer Lime. The reason 1s that
`plasma lin5ulinl rises very lmle m respon5e to the glucost
`challenge so that the tissues fail to dispose of the glucost lo:td
`as raptdly as normal The d iagnosiS of diabetes Is made If the
`plasma glucose is above 200 mgldl at the second hour. C, If
`the glucose challenge (0.5 g glucose/kg body weight given as a
`25% glucose solution) Is given lnlrovenously, then the plnsma
`Jglucosel nses much more r.~pidly than it does with an oral
`glucose load Sensing a rapid nse In lglucosel. the {3 cells first
`secrete thctr stores of presynthestzed tn5uhn Followmg thiS
`•acute-phase." the cells begin to secrete newly manufactured
`msulin in the •chronic phase." which lasts as long as the
`glucose challenge. IV, intravenous.
`
`C NORMAL SUBJECT RECEIVING IV GLUCOSE
`
`300
`
`200
`
`100
`
`Glucose
`(mg/dl)
`
`Glucoso
`
`150
`
`100
`
`- 50
`
`Insulin
`(J.LU/ml)
`
`0 L-- - - - :2- - :3- -4----:-- '
`
`Time(hr)
`
`calmodulin phosphorylation cascade, ultimately leads
`to insulin release.
`
`In addition to the pathway just outlined, other secreta(cid:173)
`gogues can also modulate insulin secretion via the phos(cid:173)
`pholipase C pathway (p. 100) or via the adenylyl cyclase
`pathway (p. 97). For example, glucagon, which stimulates
`insuliu release, may bypass part ur all uf tht: glucost:!
`(Ca2+]1 pathway by stimulating the adenylyl cyclase, rais(cid:173)
`ing cyclic adenosine monophosphate (cAMP) levels, and
`activitating protein kinase A (PKA). Conversely, somato(cid:173)
`statin, which inhibits insulin release, may act by inhtbit(cid:173)
`ing adenylyl cyclase.
`
`Neural and Humoral Factors Modulate Insulin
`Secretion
`The islet ts richly innervated by both the sympathetic and
`the parasympathetic divisions of the ANS. Neural signals
`appear to play an important role in the {3-cell response in
`several settings. P -adrenergic stimulation augments islet
`insulin secretion, whereas a -adrenergic stimulation inhib-
`
`its it (see Fig. 50-4). Isoproterenol, a synthetic catechol(cid:173)
`amine that is a specific agonist for the {3-adrenergic recep(cid:173)
`tor, potently stimulates
`insulin release.
`In contrast,
`norepinephrine and synthetic a-adrenergic agonists sup(cid:173)
`press insulin release both basally and in response to hy(cid:173)
`perglycemia. Because the postsynaptic sympathettc neu(cid:173)
`rons of the pancreas release norepinephrine, which
`stimulates a more than f3 adrenoceptors, sympathetic
`stimulation via the celiac nerves inhibits insulin secretion.
`In contrast to a -adrenergic stimulation, p arasympathetic
`stimulation vta the vagus nerve, which releases acetyltho(cid:173)
`line, causes an increase in insulin release.
`
`EXERCISE. The effect of the sympathetic division on in(cid:173)
`sulin secretion may be particularly important during exer(cid:173)
`cise, when adrenergic stimulauon of the islet increases.
`The major role for a-adrenergic inhibition of insulin secre(cid:173)
`tion during exercise is to prevent hypoglycemia. Exercis(cid:173)
`ing muscle tissue uses glucose even when plasma [insu(cid:173)
`lin! is low. Lf Insulin levels were to rise, glucose use by
`the muscle would increase even further and promote hy(cid:173)
`poglycemia. Furthermore, an increase in [insulin] would
`
`Boehringer Ex. 2005
`Mylan v. Boehringer Ingelheim
`IPR2016-01565
`Page 9
`
`

`
`1072
`
`50 I The Endocrine Pancreas
`
`Extracellular
`space
`
`CCK
`acotylcholln~
`
`..-Phospholipase C
`
`- PIP2 LG . .):;>~~A f # ... '
`
`Protein~ ~\
`C C
`., f ![Ca2•],
`.. #
`Secretory
`/granules
`
`2
`I[Ca
`
`•] 1\•
`
`\
`
`2
`Ca
`'
`Voltage-gated
`Ca2 • channel
`
`I
`~
`PKC
`
`_.......-kinase C
`
`St..•<Tction net viil the
`~dcnylyl cycl~sc•-cAMI'­
`protcin kin~sc A palhw~y
`~nd the phospholipase
`C- phosphoinositide
`pathway.
`
`.. ... ••
`• .. . • • • Insulin
`
`The elevate-d IC~hl; lcatb h1
`t>xocytusis i\nd rclcC\sc into the
`blood uf insulin contained
`within the secretory granukos .
`
`FIGURE 50- 4. Mechanism of insulin secretion by the poncreatic (3 cell. lncreosed levels of extracellular glucose tngger the (3 cell to secrete msulin in
`the seven steps outlined in this figure. Metabolizable sugars (e.g., galoctose nnd mannose) and certain amino acids (e.g., arg~ninc and leucine) can also
`stimulate the fusion of vesicles that contain previously synthesized insulin. In addition to these fuel sources. certain hormones (e.g .. glucagon,
`somatostatin, CCI<) can also modulate insulin secretion. ADP, adenos1 ne thphosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine mono(cid:173)
`phosphate; CCK, cholecystokinin; DAG, diacylglycerol; ER, endoplasmic reticulum; IP,, Inositol 1,4,5-ttiphosphate; PIP,, phosphatidylinosltol 4,5-
`blphosphate; PKA, protein kinase A; PLC, phospholipase C.
`
`Boehringer Ex. 2005
`Mylan v. Boehringer Ingelheim
`IPR2016-01565
`Page 10
`
`

`
`SULFONYLUREAS
`
`An entire class of drugs known as the sulfonylurea
`agents are used in the treatment of patients with
`adult-onset diabetes-also called type 2 or non-insu(cid:173)
`lin-dependent diabetes mellitus (NIDDM). Patients
`with type 2 diabetes have two defects: (1) although
`their {J cells are capable of making insulin, they do not
`respond normally to increased blood glucose leveh,
`and (2) the target tissues are less sensitive to Insulin.
`The sulfonylurea agents were discovered acciden(cid:173)
`tally. During the development of sulfonamide antibiot(cid:173)
`ics after the Second World War, investigators noticed
`that the chemically related sulfonylure~ agenl5 pro(cid:173)
`duced hypoglycemia. These drugs turned out to have
`no value as antibiotics, but they did prove effective in
`treating the hyperglycemia of NIDDM. These drugs
`appeared to work in two ways: ('I) the sul fonylurea~
`enhance insulin secretion by /3 cells by binding to and
`inhibiting adenosine triphosphate- sensitive K' chan(cid:173)
`nels, thereby decreasing the likelihood that these
`channels will be open. This action enhances glucose(cid:173)
`stimulated insulin secretion, a process in which this
`same channel is responsible lor cell depolarization (see
`Fig ure S0- 4). (2) By increasing Insulin secretion and
`decreasing blood glucose, the sulfonylureas decrease
`the insulin resistance that is seen in these patients.
`Unlike insulin, which must be injected, sullonylureas
`can be taken orally and are therefore preferred by
`many patients. However, they hdve a therapeutic role
`only in type 2 diabetes (i.e., NIDDM); the {3 cells in
`patients with type 1 or juvenile-onset diabetes (i.e.,
`insulin-dependent diabetes) are nearly all destroyed,
`and these patients must be treated with insulin re(cid:173)
`placement therapy.
`
`inhibit lipolysis and fatty acid release from adipocytes and
`thus diminish the availability of fatty acids, which the
`muscle can use as an alternative fuel to glucose (p. 1246).
`Finally, a rise in !insulin! would decrease glucose produc(cid:173)
`tion by the hver. Suppression of insulin secretion during
`exercise may thus serve to prevent excessive glucose up(cid:173)
`take by muscle, which if it were to exceed the abihty of
`the liver to produce glucose, would lead to severe hypo(cid:173)
`glycemia, compromise the brain, and abruptly end any
`exercise!
`
`FEEDING. Another important setting in which neural
`and humoral factors regulate insulin secretion lS during
`feeding periods. Food ingestion triggers a complex series
`of neural, endocrine, and nutritional signals to many
`body tissues. The "cephalic phase" (see Chapters 41, 42,
`and 44) of eating, which occurs before food is ingested,
`results ln stimulation of gastric-acid secretion and a small
`rise in plasma insulin. This response appears to be medi(cid:173)
`ated by the vagus nerve in both cases. H no food is
`forthcoming, blood !glucose! declines slightly and msulin
`secretion is again suppressed. If food ingestion does oc(cid:173)
`cur, the acetylcholine released by postganglionic vagal fi(cid:173)
`bers in the islet augments the insulin response or the {3
`cell to glucose.
`
`The Endocrine Pancreas I 50
`
`1073
`
`Phosphorylation
`sites
`
`FIGURE 50-5. The insuhn receptor The msulin receptor is a heterotel(cid:173)
`rnmer that consists of two extrncellular a chains and two membrane(cid:173)
`spanning {3 chams. Insulin bindmg lakes place on the cystelne-ri~h
`regio