`
`17th Edition
`
`RRI 50N's
`INTERNAL
`MEDICI N
`
`E!
`
`i
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`r+
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`
`EDITORS
`
`AnthonY S. tauci, MD
`Chipf' Laboratory of lmmunoregulation; Director'
`Natiônal Institott áf elt'gy und Infectious Diseases'
`Ñ"ii""J tui'*ts of Health' Bethesda
`Oennis [. KasPet, MD
`William Ellery Channing Professor of Medicine'
`Prgféssor of fufit''oUlofogy ãnd-Molecular Genetics'
`uuruur['í'rtaical School; pirectotlChaqning Laborator¡
`ütaiti""' otiglttl" and Womert'$ HosPital' Boston
`o.n"rrr** "i
`Dan L. longo, MD
`Scientific Director' National Institute on Aging'
`Nutio"ul t"'titotts of Health' Bethesda and Baltimore
`tosePh Loscalzo, MD' Ph9..
`Hersey Påfes'or of the Theory and Practice of Medicine'
`Harvard Medical School; Cïui'rnu"' Department of Medicine;
`stigl'u* and womeris Hospital' Boston
`ïËä;--*Jr,
`
`Euoene Braunwald, MD
`-oiit*"on.U
`Hersey Professor of Medicine'
`ätr"ffi*i"il.tt"a' chairman' TIMI studv Group'
`nìigh"* and Womeris Hospital' Boston
`stephen l' Huj:.:-ti,*30 n-**- and chairman,
`Robert A. Fishman Disttn¡
`universitv of calirornia'
`;#;"Ï;tÑ.lt"l"tt'
`San Francisco, San Franctsco
`t. tanY tameson, MD, PhD
`Professor of Medicine;
`Vice-President for Medical Affails and Lewis Landsberg Dean'
`Northwestern urri,r.*ityî.nterg school of Medicine, chicago
`
`'
`
`,/\d
`¿-
`
`"'
`
`i
`
`ffi Medical
`
`I
`NewYork Chicago Sän
`New Delhi San
`
`lon Madrid Mexico CitY
`Francisco ' Lisbon Lonc
`loä- s.o.rr 'Si"gupo" Sydney Toronto
`
`MPI EXHIBIT 1136 PAGE 1
`
`
`
`íãillFllttænmna¡n¡
`Fauci's and Dr Longo's works AS editors and authors were performed outside the scope of their
`Note: Dr.
`personal and professional vlews
`employment as U.s. government employees. These works represent their
`of the
`U. S. government.
`and not necessarily those
`
`Harrison's
`PRINCIPLES OF INTERNAL MEDICINE
`Seventeenth Edition
`Copyright@2008,2005,2001, lg98,Igg4,IggI,|g87,1983,1980,1977,1g74,|g70,t966,|962,|i58byThe
`McGraw-Hill Co*porlrr, irr. eff ri'tr" r.r"r*d. Printed in the United States of America' Except as permit-
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`permission of the publisher'
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`Two Volume Set ISBN 978-0-07-L47691-1; MHID 0-07-L47691-I
`Volume 1 ISBN 978-0-07-147692-8; MHID 0-07-147692-X
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`rector was phil Galea and production manager was Catherine Saggese. The index was prepared by Barbara
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`Library of Congress Cataloging-in-Publication Data
`Harrison's principles of internal medicine. -- lTthed. / editors, Anthony S' Fauci "' [et al']'
`P'; cm'
`Includes bibliographical references and index'
`ISBN-13: 978-0-07-146633-2 (hardcover : v' 2 : alk' paper)
`ISBN- 10: 0-07 -146633-9 (hardcover : v.2 : alk' paper)
`ISBN-13: 978-0-07-147691-1 (hardcover : set: v' 2 : alk' paper)
`ISBN-IO: 0-07-147691-1 (hardcover : set : v. 2 : alk' paper) 1. Internal medicine' I' Fauci' Anthony S''
`II. Title: Principles of internal medicine.
`IDNLM: l.Internal Medicine. WB i15 H32220081
`RC46.H333 2008
`61.6--dc22
`
`20070LZtBl
`
`- i)--l
`
`.
`
`':J^ç)-'-ì'
`j*,.-
`
`MPI EXHIBIT 1136 PAGE 2
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`fURTHTR READINGS
`BAUSCH B et al: Clinical and genetic character-
`istics of patients with neurofibromatosis
`tlpe I and pheochromocytoma. N Engl I
`Med 354:2729,2006
`et al: Germline NFI mutational spec-
`tra and loss-of-heterozygq$ity analyses in
`patients with pheochromocþoma and neu-
`rofibromatosis tfpe 1. J Clin Endbcrinol
`Metab 92:2784,2007
`LENDERS JW et al: Phaeochromocytoma. Lan-
`cet 366:665,2005
`NEUMANN HP et al: Distinct clinical features
`of paraganglioma syndromes associated
`with SDHB and SDHD gene mutations.
`IANIA292:943,2004
`et al: Evidence of MEN-2 in the origi-
`nal description of classic pheochromocy-
`toma. N Engl ] Med 357:1311,2007
`et al: Gerrrlrline mutations in nonsyn-
`dromic pheochromocytoma. N Engl J Med
`346:1459,2002
`ScHoLZ T et al Clinical review: Current teatment of malignant pheo-
`chromocytoma. J Clin Endocrinol Metab 92:1217, 2007
`WÁ.LZ MK et al: Laparoscopic and retroperitoneoscopic treatment of
`pheochromocytomas and retroperitoneal paragangliomas: Results
`of 161 tumors in 126 patients. World J Surg 30:899, 2006
`
`0-10 11-20 21-30
`
`31-40 41-50
`Age/years
`
`51-60 61-70
`
`71-81
`
`317.6 Mutation distribution ¡n the RET, VHL, NFI , 5,PHB, SDHC, and SDHD
`The bars depict the frequency of sporadic or various inherited forms of pheochromo-
`in different age groups. The inherited disorders are much more common among
`individuals presenting with pheochromocytoma. (Data from the Freiburg lnternat¡onal
`a nd Paraga nglioma Registry.)
`
`the underlying syndrome is diagnosed, the beneflt ofgenetiç test-
`be extended to relatives. For this purpose, it is necessary to identifr
`mutation in the proband and, after genetic counseling, per-
`sequence analyses of the respohsible gene in relatives to deter-
`they æe affected (Chap. 6a). Other family members may benefrt
`
`I Sporadic from biochemical screening for tumors in indi- 2275
`- ñtì -- -
`viduals who carry a germ-line mutation.
`
`:... SDHD
`SDHC
`T SDHB
`I RET
`I VHL
`
`Iõ'q
`
`rD
`rD
`
`=rÞ
`
`L
`
`8 Diabetes Mellitus
`
`Alvin C. Powers
`
`factors. Depending on the etiology of the DM, factors
`to hypergþemia include reduced insulin secretion, de-
`glucose utilization, and increased glucose production. The
`dysregulation associated with DM causes secondary patho-
`changes ln multiple organ systems that impose a tremen-
`on the individual with diabetes and on the health care
`In the United States, DM is the leading cause of end-stage re-
`(ESRD), nontraumatic lower extremity amputations, and
`It also predisposes to cardiovascular diseases. With an
`incidence worldwide, DM will be a leading cause of mor-
`mortality for the foreseeable future.
`''' /
`
`CATION
`classified on the basis of the pathogenic process tlut leads to hy-
`as opposed to earlier criteria such as age of onset or type of
`(Fie. 338- r) The two broad categones of DM are designated
`). Both tfpes of diabetes are preceded by a
`homeostasis as the pathogenic processes
`
`1n insulin action ahd/or secretion give rlse to the common
`of hypergþpemia 1n tYpe DM and have importaht potential
`2
`
`Hyperglycemia
`
`lmpaired fasting
`glucose or
`impaired glucose
`lolerance
`
`lnsulin lnsulin
`required requ¡red
`Not
`for
`for
`insulin
`requiring control survival
`
`Normal
`glucose
`lolerance
`
`<-{--
`
`<5.6 mmol/L
`(100 mg/dl)
`
`<7.8 mmol/L
`(140 ms/dl)
`
`5.6-6.9 mmol/L i
`(1oo-125 mg/dl) |
`7.8-11.1 mmol/L I
`(140-1ee mg/dl) |
`
`I
`
`>7.0 mmol/L
`(126 mg/dL)
`
`>1 1.1 mmol/L
`(200 mg/dl)
`
`Type of
`Diabetes
`
`Type 1
`Type 2
`Other
`specific types
`Gestational
`Diabetes
`Time (years)
`
`FPG
`
`2-h PG
`
`FIGURE 338.1 Spectrum of glucose homeostasis and diabetes mel-
`litus (DM). The spectrum from normal glucose tolerance to diabetes in
`type 1 DM, type 2 DM, other specifìc types of diabetes, and gestational
`DM is shown from left to right. ln most types of DM, the individual
`traverses from normal glucose tolerance to impaired glucose tolerance
`to overt diabetes. Arrows indicate that changes in glucose tolerance may
`be bi-directional in some types of dlabetes. For example, indlvlduals with
`type 2 DM may return to the impaired glucose tolerance category with
`weight loss; in gestational DM diabetes may revert to impalred glucose
`tolerance or even normal glucose tolerance after delivery. The fasting
`plasma glucose (FPG) and 2-h plasma glucose (PG), after a glucose chal-
`lenge for the different categories of glucose tolerance, are shown at the
`lower part of the fìgure. These values do not apply to the diagnosis of
`gestatlonal DM. Some types of DM may or may not require insulin for sur-
`vlval, hence the dotted line. (Conventional unlts are used in the figure.)
`(Adapted from the American Diabetes Association,2007.)
`
`MPI EXHIBIT 1136 PAGE 15
`
`
`
`trM!IUII ETIOLOGIC CLASSIFICATION OF DIABETES MELLITUS
`I. Type I diabetes (13-cell destruction, usually leading to absolute insulin
`deficiency)
`A. Immune-mediated
`8. Idiopathic
`II. Type 2 diabetes (may range from predominantly insulin resistance with
`1elative insulin deficiency to a predominantly insulin secretory defect with
`insulin resistance)
`Ill. Other specific types of diabetes
`A. Genetic defects of 13 cell function characterized by mutations In:
`I. Hepatocyte nuclear transcription factor (HNF) 4a (MODY I)
`2. Glucokinase (MODY 2)
`3. HNF-1 a (MODY 3)
`4. Insulin promoter factor-1 (IPF-1; MODY 4)
`5.HNF·113 (MODY 5)
`6. NeuroDl (MODY 6)
`7. Mitochondrial DNA
`8. Subunits of ATP-sensitive potassium channel
`9. Proinsulln or insulin conversion
`B. Genetic defects in insulin action
`1. Type A insulin resistance
`2. Leprechaunism
`3. Rabson-Mendenhall syndrome
`4. Lipodystrophy syndromes
`C. Diseases of the exocrine pancreas-pancreatitis, pancreatectomy,
`neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreat·
`opathy, mutations in carboxyl ester lipase
`D. Endocrinopathies-acromegaly, Cushlng's syndrome, glucagonoma,
`pheochromocytoma, hyperthyroidism, wmatostatinoma,
`aldosteronoma
`E. Drug-or chemical-induced-Vacor, pentamidine, n1cotinic acid, glu·
`cocorticoids, thyroid hormone, diazoxide, 13-adrenergic agonists, thia
`zides, phenytoin, a-interferon, protease Inhibitors, clozapine
`F. Infections-congenital rubella, cytomegalovirus, coxsackie
`G. Uncommon forms of immune-mediated diabetes-·stiff-person· syn
`drome, anti-insulin receptor antibodies
`H. Other genetic syndromes sometimes associated with diabetes
`Down's syndrome, Klinefelter's syndrome, Turner's syndrome, Wol•
`fram's syndrome, Friedreich's ataxia, Huntington's chorea, Laurence
`Moon-Biedl syndrome, myotonlc dystrophy, porphyria, Prader-Willi
`syndrome
`IV. Gestational diabetes meilltus (GDM)
`Note: MODY, m.itumy onset or diabet� of the young.
`Source: Adaptl!ii lrom Amerw:an Diabetes Association, 2007
`
`The P..mericas
`2000�33 �illion.._
`2030: 66.lhnillion';,-).
`
`OOo 0
`
`2000:7
`2030: 18.
`
`8
`
`EPIDEMIOlOGY
`
`Cl
`
`therapeutic implications now that pharmacologic agents arc av
`target specific metabolic derangements. Type 2 DM is preceded
`riod of abnormal glucose homeostasis classified as impaired f:
`cose (JFG) or impaired glucose tolerance ()GT).
`Two features of the current classification of DM diverge fro
`ous classifications. F irst, the terms insulin-dependent diabetes II\.
`(IDDM) and nonins11/i11-depende11t diabetes mellitus (NIDD�l
`solete. Since many individuals with type 2 DM eventually re
`sulin treatment for control of glycemia, the use of the terrn quj
`generated considerable confusion. A second difference is th�
`not a criterion in the classification system. Although type I D�
`commonly develops before the age of 30, an autoimmune beta
`structive process can develop at any age. It is estimated that be
`a�d 1�% of individuals who d�velop DM after �ge_30 have tyPc 1
`L1kew1se, type 2 DM more typically develops with mcreasingag
`now being diagnosed more frequently in children and young f
`particularly in obese adolescents.
`OTHER TYPES OF OM
`Other etiologies for DM include specific genetic defects in insulin
`tion or action, metabolic abnormalities that impair insulin secretion,
`tochondrial abnormalities, and a host of conditions that impair gl1111e,
`tolerance (Table 338-1). Maturity onset diabetes of the young (MODY)
`subtype of DM characterized by autosomal dominant inheritance,flltt
`onset of hyperglycemia (usually <25 years), and impairment in insufa
`secretion (discussed below). Mutations in the insul in receptor cause
`group of rare disorders characterized by severe insulin resistance.
`DM can res_ult from pancreatic exocrine disease when the majom,
`of pancreatic islets are destroyed. Hormones that antagonize insullll
`action can also lead to DM. Thus, DM is often a feature of endocn
`nopathies such as acromegaly and Cushing's disease. Viral infoctiOIII
`have been implicated in pancreatic islet destruction but are an e,,
`tremely rare cause of DM. A form �f acute onset of type I diabete,
`termed f11/mi11ant diabetes, has been noted in Japan and may be relabd
`to viral infection of islets.
`GESTATIONAL DIABms MELLITUS (GDM)
`Glucose intolerance may develop during pregnancy. Insulin resistanct
`is related to the metabolic changes of late pregnancy, and the increased
`insulin requirements may lead to IGT. GOM occurs in -4% of preg•
`nancies in the United States; most wom
`en revert to normal glucose toleranct
`post-partum but have a substanti�l �
`(30-60%) of developing OM later m hfe.
`The worldwide prevalence of
`OM has risen dramatically over
`the past two decades, from ;
`estimated 30 million cases in 1985 10 Ids,
`million in 2000. Based on current tr�nbe
`>360 million individuals will have dia N
`tes by the year 2030 (Fig. 3)S-Z)j and
`though the prevalence of both ty��
`the
`type 2 DM is increasing wor!d_wi e, ch
`M · rising 11111
`is
`prevalence of type 2 D
`. obdl
`more rapidly because of increasing ntrid
`ty and reduced act ivity levels ash��s tflll
`. I' d T JS I
`become more industna ize · h top 10
`in most countries, and 6 of \: are ill
`countries with the highest r� \,ers (at
`Asia. In the United States, the. t (CDC}
`d p venuon
`.
`:e. 1
`Disease Control an
`ersons, ?'
`estimated that 20.8 miJho� �iabeto il1
`7% of the population, ha . 'th diabetd
`2005 (-30% of individuals"'.'
`telY I,)
`A Proioll13
`were undiagnosed). P
`
`��u':'��o��%s. •
`wilh diabetes, are:
`India China
`USA
`Indonesia
`Japan
`Pakistan
`1::=J3.5 �6-8 ->8
`Russia
`Brazil
`2000=number of people with diabetes in 2000
`2030=number of people with diabetes in 2030
`Italy Banaladesh
`FIGURE 338·2 Worldwide prevalence of diabetes mellitus. The prevalence of diabetes in 2000
`and the projected prevalence in 2030 are shown by geographical region. (Used with permission from
`
`Prevalence of diabetes
`
`(%)
`
`In persons 35-64 years
`
`Diabetes Action Now: An Initiative of the World Health Organization and the International Diabetes Fed·
`eration, 2004, as adapted from 5 Wild et al: Diabetes Care 27: 1047, 2004.)
`
`DIYI II
`;,
`
`.
`
`d
`
`. dividuals (>20 years) were newly diagnosed with diabetes in
`• 11 '.� • icreases with aging. In 2005, the prevalence of DM in the
`5 was estimated to be 0.22% in those <20 years an 9.6% 111
`1.:J�ie ears. In individuals >60 years, the prevalence of DM was
`e 72
`1 yprevalence is similar in men and women throughout most
`f!1&. 1
`' 1\ [0.5% and 8.8% in individuals >20 years) but is slightly
`rJn�es ien >60 years. Worldwide estimates project that in 2030 the
`,.,er 10 �nber of individuals with diabetes will be 45-64 years of age.
`�1csl 11•0 considerable geographic variation in the incidence of both
`'fllere; type 2 DM. Scandinavia has the highest incidence of type I
`� I 311 in Finland, the incidence is 35/100,000 per year). The Pacific
`�(,.g., much lower rate (in Japan and China, the incidence is 1-3/
`Jii11 has ;,er year) of type I DM; Northern Europe and the United
`t<O,� ve an intermediate rate (8-17/100,000 per year). Much of the
`,ii" ; 1 isk of type I OM is believed to reflect the frequency of high
`��LA alleles among ethnic groups iJ1 different geographic loca
`,). The prevalence of type 2 DM and its harbinger, !GT, is highest
`1!1'5· in Pacific islands, intermediate in countries such as IncUa and
`�l�ted States, and relatively low in Russia. This variability is likely
`� n enetic, behavioral, and environmental factors. DM prevalence
`llJe lOS
`.
`.
`. h'
`h .
`d'f"'
`I
`1 ,erent et me popu at10ns wit 111 a given country. •
`ies among
`�;;, the CDC estimated that the prevalence of DM in the United
`• (age> 20 years) was 13.3% in African Americans, 9.5% in Lati-
`5111�5.1% in Native Americans (American Indians and Alaska na
`:), and 8.7% in n�n-Hispanic whit�s. Indivi?uals be!?nging _to
`,\tiln-American or Pacific-Islander ethmc groups 111 Hawau are twice
`�kely to have diabetes compared to non-Hispanic whites. The onset
`If type 2 DM occurs, on average, at an earlier age in ethnic groups
`iaer than non-Hispanic whites.
`Diabetes is a major cause of mortality, but several studies indicate
`.cdiabetes is likely underreported as a cause of death. In the United
`SUte.,diabetes was listed as the sixth-leading cause of death in 2002; a
`�nt estimate suggested that diabetes was the fifth leading cause of
`lltth worldwide and was responsible for almost 3 million deaths an
`awi)' (1.7-5.2% of deaths worldwide).
`IIA6NOSIS
`111c National Diabetes Data Group and World Health Organization
`Ille issued diagnostic criteria for DM (Table 338·+) based on the fol
`'awir,g premises: (1) the spectrum of fasting plasma glucose (FPG)
`Dlthe response to an oral glucose load (OGTI-oral glucose toler
`llkttest) varies among normal \ndividuals, and (2) DM is defined as
`1111 level of glycemia at which diabetes-specific complications occur
`llhtr than on deviations from a population-based mean. For exam
`ik, the prevalence of retinopathy in Native Americans (Pima Indian
`fel>ulation) begins to increase at a FPG > 6.4 mmol/L ( 116 mg/dL)
`ig,338-3).
`�lucose tolerance is classified into three categories based on the
`'l\l(Fig. 338-1): (I) FPG < 5.6 mmol/L (100 mg/dL) is considered
`llilnnal; (2) FPG = 5.6-6.9 mmol/L (100-125 mg/dL) is defined as
`:;and (3) FPG 2:7.0 mmol/L ( 126 mg/dL) warrants the diagnosis of
`�Based on the OGTT, !GT is defined as plasma glucose levels be-
`7.s and I 1.1 mmol/L (140 and 199 mg/dL) and diabetes is de-
`tallll CRITERIA FOR TKE DIAGNOSIS OF DIABETES MELLITUS
`�Ptoms or diabetes plus random blood glucose concentration � 11. 1
`a� (200 mg/dLJ0 or
`l ing plasma glucose � 7.0 mmol/L ( 126 mg/dl)0 o,
`'lio-hour plasma glucose � 11 I mmol/L (200 mg/dl) during an oral
`0se tolerance test<
`Is defined as without r�ard 10 time since the las1 meat
`'i
`1"9 ,s de0ned as no caloric Intake for at least 8 h.
`. �!sh
`� ·
`,
`0\Jld be performed using a gluwse 103d contam_;')9 t� �u1valent of 75 g
`.
`:,s Qlucose dissolved 1n wat�; not recommended fQr iii.tine clinical use.
`lhe ab5ence of unequivocal hyperglycem1a and at\Jte me1abolk decompen
`�'�se criteria should be confirmed by repeat testing on a differenI day
`• Adapted from American Diabetes Association. 2007
`
`----------------
`
`2277
`
`0 a:;· Oro
`..... ro V'I 3: !P_. ;:::;: C:
`
`V,
`
`A
`
`15
`10
`5
`
`>-
`� a:
`
`Q.
`0
`C:
`
`70· 89-
`FPG (mg/dl)
`93. 97. 100- 105- 109- 116· 136· 226-
`2-h PG (mg/dl)
`38-
`94· 106· 116· 126· 138· 156- 185- 244- 364-
`HbA1c (%)
`3.4· 4.8-
`5.0· 5.2- 5.3· 5.5· 5.7· 6.0· 6.7· 9.5·
`FIGURE 338·3 Relationship of diabetes-specific complication and
`glucose tolerance. This figure shows the incidence of retinopathy in
`Pima Indians as a function of the fasting plasma glucose (FPG), the 2-h
`plasma glucose after a 75-g oral glucose challenge (2-h PG), or gly
`cated hemoglobin (A 1 C). Note that the incidence of retinopathy
`greatly increases at a fasting plasma glucos�1,> 116 mg/dl, or a 2-h
`plasma glucose of 185 mg/dl, or a A 1C >6.0%. (Blood glucose values
`are shown in mg/dL; to convert to mmol/L, divide value by 18.) (Copy
`
`right 2002, American Diabetes Association. From Diabetes Care 25(5uppl
`I): 55-520, 2002.)
`
`fined as a glucose > I I.I mmol/L (200 mg/dL) 2 h after a 75-g oral
`glucose load (Table 338-2). Some individuals have both IFG and !GT.
`Individuals with IFG and/or IGT, recently designated pre-diabetes by
`the American Diabetes Association (ADA), are at substantial risk for
`developing type 2 DM (25-40% risk over the next 5 years) and have an
`increased risk of cardiovascular disease.
`The current criter ia for the diagnosis of DM emphasize that the FPG
`is the most reliable and convenient test for identifying DM in asympto
`matic individuals. A random plasma glucose concentration :i. I 1.1
`mmol/L (200 mg/dL) accompanied by classic symptoms of DM (poly
`uria, polydipsia, weight loss) is sufficient for the diagnosis of DM (Ta
`ble 338-2). Oral glucose tolerance testing, although still a valid means
`for diagnosing DM, is not recommended as part of routine care.
`Some investigators have advocated the hemoglobin A 1 C (A IC) as a
`diagnostic test for DM. Though there is a strong correlation between
`elevations in the plasma glucose and the AlC (discussed below), the
`relationship between the FPG and the AIC in individuals with normal
`glucose tolerance or mild glucose intolerance is less clear, and thus the
`use of the AIC is not currently recommended to diagnose diabetes.
`The diagnos is of OM has profound implications for an individual
`from both a medical and financial standpoint. Thus, these diagnostic
`cr iteria must be satisfied before assigning 1he diagnosis of DM. Abnor
`malities on screening tests for diabetes should be repeated before mak
`ing a definitive diagnosis of DM, unless acute metabolic derangements
`or a markedly elevated plasma glucose are present (Table 338-2). The
`revised criteria also allow for the diagnosis of DM to be withdrawn in
`situations where the PPG reverts to normal.
`SCREENING
`Widespread use of the PPG as a screening test for type 2 OM is recom
`mended because: ( l) a large number of individuals who meet the cur
`rent criteria for DM are asymptomatic and unaware that they have the
`disorder, (2) epidemiologic studies suggest that type 2 DM may be
`present for up to a decade before diagnosis, (3) as many as 50% of in
`dividuals with type 2 DM have one or more diabetes-specific compli
`cations at the time of their diagnosis, and (4) treatment of type 2 OM
`may favorably alter the natural history of DM. The ADA recommends
`screening all individuals >45 years every 3 years and screening indi
`viduals at an earlier age if they are overweight (body mass index
`(BM!) > 25 km/m2] and have one additional risk factor for diabetes
`"'
`
`MPI EXHIBIT 1136 PAGE 16
`
`
`
`trM!IUII ETIOLOGIC CLASSIFICATION OF DIABETES MELLITUS
`I. Type I diabetes (13-cell destruction, usually leading to absolute insulin
`deficiency)
`A. Immune-mediated
`8. Idiopathic
`II. Type 2 diabetes (may range from predominantly insulin resistance with
`1elative insulin deficiency to a predominantly insulin secretory defect with
`insulin resistance)
`Ill. Other specific types of diabetes
`A. Genetic defects of 13 cell function characterized by mutations In:
`I. Hepatocyte nuclear transcription factor (HNF) 4a (MODY I)
`2. Glucokinase (MODY 2)
`3. HNF-1 a (MODY 3)
`4. Insulin promoter factor-1 (IPF-1; MODY 4)
`5.HNF·113 (MODY 5)
`6. NeuroDl (MODY 6)
`7. Mitochondrial DNA
`8. Subunits of ATP-sensitive potassium channel
`9. Proinsulln or insulin conversion
`B. Genetic defects in insulin action
`1. Type A insulin resistance
`2. Leprechaunism
`3. Rabson-Mendenhall syndrome
`4. Lipodystrophy syndromes
`C. Diseases of the exocrine pancreas-pancreatitis, pancreatectomy,
`neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreat·
`opathy, mutations in carboxyl ester lipase
`D. Endocrinopathies-acromegaly, Cushlng's syndrome, glucagonoma,
`pheochromocytoma, hyperthyroidism, wmatostatinoma,
`aldosteronoma
`E. Drug-or chemical-induced-Vacor, pentamidine, n1cotinic acid, glu·
`cocorticoids, thyroid hormone, diazoxide, 13-adrenergic agonists, thia
`zides, phenytoin, a-interferon, protease Inhibitors, clozapine
`F. Infections-congenital rubella, cytomegalovirus, coxsackie
`G. Uncommon forms of immune-mediated diabetes-·stiff-person· syn
`drome, anti-insulin receptor antibodies
`H. Other genetic syndromes sometimes associated with diabetes
`Down's syndrome, Klinefelter's syndrome, Turner's syndrome, Wol•
`fram's syndrome, Friedreich's ataxia, Huntington's chorea, Laurence
`Moon-Biedl syndrome, myotonlc dystrophy, porphyria, Prader-Willi
`syndrome
`IV. Gestational diabetes meilltus (GDM)
`Note: MODY, m.itumy onset or diabet� of the young.
`Source: Adaptl!ii lrom Amerw:an Diabetes Association, 2007
`
`The P..mericas
`2000�33 �illion.._
`2030: 66.lhnillion';,-).
`
`OOo 0
`
`2000:7
`2030: 18.
`
`8
`
`EPIDEMIOlOGY
`
`Cl
`
`therapeutic implications now that pharmacologic agents arc av
`target specific metabolic derangements. Type 2 DM is preceded
`riod of abnormal glucose homeostasis classified as impaired f:
`cose (JFG) or impaired glucose tolerance ()GT).
`Two features of the current classification of DM diverge fro
`ous classifications. F irst, the terms insulin-dependent diabetes II\.
`(IDDM) and nonins11/i11-depende11t diabetes mellitus (NIDD�l
`solete. Since many individuals with type 2 DM eventually re
`sulin treatment for control of glycemia, the use of the terrn quj
`generated considerable confusion. A second difference is th�
`not a criterion in the classification system. Although type I D�
`commonly develops before the age of 30, an autoimmune beta
`structive process can develop at any age. It is estimated that be
`a�d 1�% of individuals who d�velop DM after �ge_30 have tyPc 1
`L1kew1se, type 2 DM more typically develops with mcreasingag
`now being diagnosed more frequently in children and young f
`particularly in obese adolescents.
`OTHER TYPES OF OM
`Other etiologies for DM include specific genetic defects in insulin
`tion or action, metabolic abnormalities that impair insulin secretion,
`tochondrial abnormalities, and a host of conditions that impair gl1111e,
`tolerance (Table 338-1). Maturity onset diabetes of the young (MODY)
`subtype of DM characterized by autosomal dominant inheritance,flltt
`onset of hyperglycemia (usually <25 years), and impairment in insufa
`secretion (discussed below). Mutations in the insul in receptor cause
`group of rare disorders characterized by severe insulin resistance.
`DM can res_ult from pancreatic exocrine disease when the majom,
`of pancreatic islets are destroyed. Hormones that antagonize insullll
`action can also lead to DM. Thus, DM is often a feature of endocn
`nopathies such as acromegaly and Cushing's disease. Viral infoctiOIII
`have been implicated in pancreatic islet destruction but are an e,,
`tremely rare cause of DM. A form �f acute onset of type I diabete,
`termed f11/mi11ant diabetes, has been noted in Japan and may be relabd
`to viral infection of islets.
`GESTATIONAL DIABms MELLITUS (GDM)
`Glucose intolerance may develop during pregnancy. Insulin resistanct
`is related to the metabolic changes of late pregnancy, and the increased
`insulin requirements may lead to IGT. GOM occurs in -4% of preg•
`nancies in the United States; most wom
`en revert to normal glucose toleranct
`post-partum but have a substanti�l �
`(30-60%) of developing OM later m hfe.
`The worldwide prevalence of
`OM has risen dramatically over
`the past two decades, from ;
`estimated 30 million cases in 1985 10 Ids,
`million in 2000. Based on current tr�nbe
`>360 million individuals will have dia N
`tes by the year 2030 (Fig. 3)S-Z)j and
`though the prevalence of both ty��
`the
`type 2 DM is increasing wor!d_wi e, ch
`M · rising 11111
`is
`prevalence of type 2 D
`. obdl
`more rapidly because of increasing ntrid
`ty and reduced act ivity levels ash��s tflll
`. I' d T JS I
`become more industna ize · h top 10
`in most countries, and 6 of \: are ill
`countries with the highest r� \,ers (at
`Asia. In the United States, the. t (CDC}
`d p venuon
`.
`:e. 1
`Disease Control an
`ersons, ?'
`estimated that 20.8 miJho� �iabeto il1
`7% of the population, ha . 'th diabetd
`2005 (-30% of individuals"'.'
`telY I,)
`A Proioll13
`were undiagnosed). P
`
`��u':'��o��%s. •
`wilh diabetes, are:
`India China
`USA
`Indonesia
`Japan
`Pakistan
`1::=J3.5 �6-8 ->8
`Russia
`Brazil
`2000=number of people with diabetes in 2000
`2030=number of people with diabetes in 2030
`Italy Banaladesh
`FIGURE 338·2 Worldwide prevalence of diabetes mellitus. The prevalence of diabetes in 2000
`and the projected prevalence in 2030 are shown by geographical region. (Used with permission from
`
`Prevalence of diabetes
`
`(%)
`
`In persons 35-64 years
`
`Diabetes Action Now: An Initiative of the World Health Organization and the International Diabetes Fed·
`eration, 2004, as adapted from 5 Wild et al: Diabetes Care 27: 1047, 2004.)
`
`DIYI II
`;,
`
`.
`
`d
`
`. dividuals (>20 years) were newly diagnosed with diabetes in
`• 11 '.� • icreases with aging. In 2005, the prevalence of DM in the
`5 was estimated to be 0.22% in those <20 years an 9.6% 111
`1.:J�ie ears. In individuals >60 years, the prevalence of DM was
`e 72
`1 yprevalence is similar in men and women throughout most
`f!1&. 1
`' 1\ [0.5% and 8.8% in individuals >20 years) but is slightly
`rJn�es ien >60 years. Worldwide estimates project that in 2030 the
`,.,er 10 �nber of individuals with diabetes will be 45-64 years of age.
`�1csl 11•0 considerable geographic variation in the incidence of both
`'fllere; type 2 DM. Scandinavia has the highest incidence of type I
`� I 311 in Finland, the incidence is 35/100,000 per year). The Pacific
`�(,.g., much lower rate (in Japan and China, the incidence is 1-3/
`Jii11 has ;,er year) of type I DM; Northern Europe and the United
`t<O,� ve an intermediate rate (8-17/100,000 per year). Much of the
`,ii" ; 1 isk of type I OM is believed to reflect the frequency of high
`��LA alleles among ethnic groups iJ1 different geographic loca
`,). The prevalence of type 2 DM and its harbinger, !GT, is highest
`1!1'5· in Pacific islands, intermediate in countries such as IncUa and
`�l�ted States, and relatively low in Russia. This variability is likely
`� n enetic, behavioral, and environmental factors. DM prevalence
`llJe lOS
`.
`.
`. h'
`h .
`d'f"'
`I
`1 ,erent et me popu at10ns wit 111 a given country. •
`ies among
`�;;, the CDC estimated that the prevalence of DM in the United
`• (age> 20 years) was 13.3% in African Americans, 9.5% in Lati-
`5111�5.1% in Native Americans (American Indians and Alaska na
`:), and 8.7% in n�n-Hispanic whit�s. Indivi?uals be!?nging _to
`,\tiln-American or Pacific-Islander ethmc groups 111 Hawau are twice
`�kely to have diabetes compared to non-Hispanic whites. The onset
`If type 2 DM occurs, on average, at an earlier age in ethnic groups
`iaer than non-Hispanic whites.
`Diabetes is a major cause of mortality, but several studies indicate
`.cdiabetes is likely underreported as a cause of death. In the United
`SUte.,diabetes was listed as the sixth-leading cause of death in 2002; a
`�nt estimate suggested that diabetes was the fifth leading cause of
`lltth worldwide and was responsible for almost 3 million deaths an
`awi)' (1.7-5.2% of deaths worldwide).
`IIA6NOSIS
`111c National Diabetes Data Group and World Health Organization
`Ille issued diagnostic criteria for DM (Table 338·+) based on the fol
`'awir,g premises: (1) the spectrum of fasting plasma glucose (FPG)
`Dlthe response to an oral glucose load (OGTI-oral glucose toler
`llkttest) varies among normal \ndividuals, and (2) DM is defined as
`1111 level of glycemia at which diabetes-specific complications occur
`llhtr than on deviations from a population-based mean. For exam
`ik, the prevalence of retinopathy in Native Americans (Pima Indian
`fel>ulation) begins to increase at a FPG > 6.4 mmol/L ( 116 mg/dL)
`ig,338-3).
`�lucose tolerance is classified into three categories based on the
`'l\l(Fig. 338-1): (I) FPG < 5.6 mmol/L (100 mg/dL) is considered
`llilnnal; (2) FPG = 5.6-6.9 mmol/L (100-125 mg/dL) is