A History of Diabetes Mellitus: From Tasting to TestingProduced by the Institute of Biomedical Science History Committee

Alchemy to Chemistry

A Taste of Honey• Polyuria,acommon,butnotspecificsymptom

ofdiabetes,recordedinEgyptianpapyrusdated1552BCEandmayrepresentearliestrecordofdiabetes.

• ArchaeologicalclaimschangesinhumanskeletonfromEgypt(2055-1650BCE)indicativeoftype2diabetes.

• Sushruta(c500BCE)Indianphysician,describedsweettasteofdiabeticurinehetermed‘madhumeha’orhoneyurine,commonpracticetotasteurineifdiabetessuspected.Alsoobservedantsattractedtourineofdiabetics,maystillbeusedfordiagnosisinAfrica.Hedescribedtwodifferentformsofpresentation,youngerthinnerpatientsandolderandmoreobesepatientswholivedlonger.

Copper Reduction• Manysugars,includingglucose,havereducingproperties,exploitedbyprogressivecolourchanges duringreductionofbluecoppersulphatesolutionstogreen,yellowtobrown/redwithincreasing

amountsofsugar.

• 1841Karl Trommer (1806-1879),Germanchemistfirstdevisedacopperreductiontest,morestablecoppersulphatereagentbyHermann von Fehling (1812-1885)in1850.

• Sensitivecopperreagentdescribedin1908byStanley Benedict (1884-1936)withfurthermodificationtwoyearsmainstayofurinemonitoringofdiabetesforoverfiftyyears.1945AmesdevelopedClinitest,amoreconvenientsolidtabletformofcopperreductionandClinistix,adipandreadspecificreagentstripforurineglucosedevelopedbyAmesresearchteamledbyAlbert & Helen Freein1957.

Why Diabetes Mellitus?• Aretaeus (130-200 CE)gavemoredetailed

descriptionofsymptoms,notablyexcessivethirst,weightlossasa‘meltingdownoffleshandlimbs’intourine.HenameddiabetesfromGreek‘siphon’and‘flowingout’.

• In1778William Cullen (1710-1790)addedmellitus (Greekforhoney)forsweetnessofurineofdiabetics.

Searching for the Cause• Polyuriawithglycosuriakeyfeaturesofdiabetesinearly19thcentury,thecauseremainedelusive.

ClaudeBernard(1813-1878)in1846showedsugarabsorbedfromintestineconvertedtoglycogeninliverforreleaseintobloodasrequired.Varioustheoriesraisedthatdiabeteswasduetoinfectionororiginatedintheliver,brainornervoussystem.

Tasting and Testing (500CE until 17thC)• Urinecollectedintospecialglassflask,amatula,examinedby‘physick’forvolume,colour,clarity,

sediment,odourandtasteforpredictive‘diagnosis’ofwiderangeofdiseases.

• ThesweetnessoftheurineofdiabeticsrecognisedinIndia,China,AfricaandPersia,butnotrecordedinEuropeuntilthe17thcentury.Paracelsus (1493-1541)suggestedchemicalanalysisofurineandobtainedwhiteresidueonevaporationhebelievedsaltandproposedthecauseofdiabeteswasdepositionofsaltaffectingkidneysandstomach.

• BritishphysicianThomas Willis (1621-1675) regardeddiabetesasthe‘pissingevil’andwrotetreatiseonurinalysis,hisobservationsondiabetesrecordedin‘Pharmaceuticerationalis’(1674).Hedescribedtheurineas‘exceedinglysweet’and‘wonderfullysweetlikesugarorhoney’!

• 1772Matthew Dobson (1735-1784)showedsugarlikesubstancepresentinurineandbloodofadiabeticpatient.Hefoundthatevaporationofurineleftaresiduewhichtastedlikebrownsugarandserumalsotastedsweet.

• 1780Francis Home (1719-1813)demonstratedthaturinecontainingsugarundergoesfermentationwithyeast.

• 1815Michel-Eugene Chevreul (1786-1889)Frenchorganicchemistdemonstratedsugarpresentidenticaltograpesugar(glucose).

• 1862William Roberts (1830-1899)adaptedfermentationtestusingurinometertomeasurethechangeinspecificgravityonfermentationwhichrelatedtoconcentrationofurineglucose.Usedbyphysicians,notablyFrederickPavy(1829-1911)ofGuy’sHospital,tostudyeffectofdietaryvariation.

Claude Bernard (1813-1878)

Helen Free Stanley Benedict (1884-1936)

Physick examining matula

A History of Diabetes Mellitus: From Tasting to TestingProduced by the Institute of Biomedical Science History Committee

Islets to Insulin

Charles Herbert Best (1899-1978) & Frederick Banting (1891-1941)

Frederick Banting (1891-1941)

Dietary Control & Quack Remedies For Diabetes• 1792-96BritisharmysurgeonJohn Rollo (d

1809)reducedglycosuriawithhighmeat,lowgrainsandbreaddiet.Branmuffinsandalmondbiscuitsweregivenasbreadsubstitutesin19thcentury.Faddietsearly20thcenturyincludepotato,oatmealcureandquackremediesegvinuranepesqui,Dillsdiabeticmixturecontainedbromides,opium,arsenic,uraniumnitrateofteninalcohol.

• 1912Frederick Allen (1876-1964)completedstudiesofglycosuriaanddiabetestointroducecaloriecontrolleddiet,commonlycalleda‘starvation’diet.However,despiteprolonginglifeexpectancy,patientsdangerouslyunderweight,physicallyweakandoftenregressedintocoma.

• Elliot Joslin (1869-1962)specialistindiabetesbecamepioneerinpromotingglucoseregulation,patientselfmanagementandeducation.TodaythereareJoslinDiabetesCentresacrossUSAandCanada.

Pancreatic Extracts• Treatmentwiththyroidextractinmyxoedemain1891byEnglishphysicianGeorge Murray (1865-1939)

raisedpotentialofpancreaticextractsindiabetes.Potentialdifficultiespurityofbetacellsofisletswhichconstituteonly1%ofthepancreas,minimisingdigestiveenzymeaction.

• 1899Leonid Sobolev (1876-1919)suggestedligationofpancreaticductisolatesisletcellstoprovideextractsuitablefortreatment.Between1900&1921atleast5researchgroupsattemptedunsuccessfullytoobtainsafeandeffectiveextract.Impuritiescausedseveresideeffectsandvariationin‘batch’potencycouldproduceextremehypoglycaemicepisodes.

Insulin: A Medical Miracle • 1920Frederick Grant Banting (1891-1941),

beganresearchworkatUniversityofTorontounderJohn JR Macleod (1876-1935).BantingrealisedfromearlierobservationsofSobolevandMoses Barronin1919thatprolongedligationofpancreaticductwoulddestroyacinarcellsbutnotaffectisletcellsbelievedtocontainpancreatichormone‘insuline’(Latin-insula-island),asnamedbySharpey-Shafferin1916.

• BantingandCharles Herbert Best (1899-1978)usinglaboratorydogs,excisedpancreasandpreparedextractsinjectedintodepancreatiseddogs.BestskilledinbloodsugarmicromethoddevelopedbyRC Lewis and Stanley Benedictin1913onlyrequired0.2mlblood,foundextractsloweredbloodsugarandurinewassugarfreewithphysicalandclinicalimprovement.Similarresultsobtainedfromextractsoffreshfoetalcalfandadultbeefpancreas.

• James Bertram Collip (1892-1965)joinedresearchinlate1921tohelpimprovequalityandpurityofextracts,assessmentofpotencywithmeasurementofbloodsugarofrabbits.Alsofoundthatdailyadministrationofextractcouldextendthelifeofdiabeticdogs.

• FirstrecordeduseofinsulinonhumansJanuary1922;apancreaticextractpreparedbyBestgiventoa14-year-oldboywithseverediabetes,withafallinbloodsugar.Repeated12dayslaterwithextractpreparedbyCollipwithevenmoresignificantreductioninbloodsugar.

The Pancreas: A Hidden Organ• 100ADRepos,Greekanatomist,named

pancreas(panall,kreas flesh)littleknownoffunction;believedprotective‘cushion’formajorbloodvesselsandnerves.

• 1689Johann Brunner (1653-1727)inducedtemporarysymptomsofextremethirstandpolyuriaindogswithoutpancreas.

• 1788Thomas Cawleyobservedpancreatictissuedamageinautopsyofpatientwithdiabetes,suggestedanassociation.

• However,mostattentiongiventoexocrineroleofpancreasindigestionuntil19thcentury

The ‘Active’ Principle• ConceptofinternalsecretionbyglandsCharles Edouard Brown Sequard (1817-1893)appliedtodiabetes

byEdward Sharpey -Shaffer (1850-1935)in1895.

• Exactly200yearsafterBrunnerstudies,Oskar Minkowski (1858-1931)andJosef von Mering (1849-1908)inducedseverediabetesafterremovingpancreasindogsandGustave Laguesse (1861-1927) suggestedin1893that‘internalsecretion’producedbyisletsofirregularpolygonalcellsfirstdescribedbyPaul Langerhans (1847-1888)in1869.

• 1901Eugene Opie (1873-1971)proposedantidiabeticsubstancepresentinisletcellsalteredindiabetes.InnextyearErnest Starling (1866-1927)andWilliam Bayliss (1860-1924)introducedconceptofhormonesaschemicalmessengerstransmittedbybloodinseminalstudiesofsecretinandpancreaticsecretion.

Frederick Allen (1876 -1964)

Elliot Joslin (1869-1962)

A History of Diabetes Mellitus: From Tasting to TestingProduced by the Institute of Biomedical Science History Committee

Insulin - A Therapeutic Miracle

Early Experience • 1922Largescaleproductionofhighquality

insulinwithcollaborationofEliLilly

• 1923BritishmedicalresearchcouncilacceptspatentrightsandwithdrugcompaniesinsulinavailableinUKhospitals

• 1926John Abel (1857-1938)preparedcrystallineinsulin,10,20,40units/mlavailableworldwide

Living on the Edge• Variationininsulinquality,personal

requirementsandpoorassessmentoftreatmentwithsustainedperiodsofuncertainty,fearfulofhypoglycaemiaandhyperglycaemia.Onlyeffectivebyinjectionandrequiredlifelonginseverecases.

• Lifeexpectancyofseverediabeticsextendedbutgreaterawarenessofcomplicationsandlessemphasisonstrictdiets.

• 1934BritishDiabeticAssociationfounded,twoyearslaterHarold Himsworth (1905-1993)BritishphysicianconfirmedearlierworkofWilhelm Falta (1875-1950)toidentifytwoformsofdiabetes-insulinsensitiveorthoseinsensitiveorresistant.

Different Types of Insulin from 1936• Toavoidinjectionspremealsandduringthe

night,longeractinginsulindevelopedatNordisklaboratories,Copenhagenunderdirectionof

Hans Christian Hagedorn (1888-1971).

• 1936Insulincombinedwithprotaminetoreleaseinsulinover6-8hours.ProtamineZincInsulin(PZI)developedatTorontoUniversityinsameyear,effectivefor24hoursbuttendencytohypoglycaemia.

• 1940NeutralProtamineHagedorn(NPH)orIsophaneavailableandLenteseriesdevelopedbyNovoLabs1952.

Structure of Insulin• 1951Aminoacidsequenceofinsulinby

BritishbiochemistFrederick Sanger (b1918)polypeptideof51aminoacidsintwochainslinkedbydisulphidebonds.1969BritishchemistDorothy Hodgkin (1910-1994)determinedspatialconformationbyxraydiffraction.

Developments in Insulin Therapy from 1952• SingleinjectionofPZIortwicedailysoluble

insulinandNPH.Toreduceinfectionrisksdisposablesyringe/needleintroduced1961byBectonDickinson,needlefreedeliverydevicesbyDerata1979andpopular‘penjet’,combinedsyringeandinsulinvialassingleunitdesignedbyGlasgowphysicianJohn Ireland (1932-1987)in1981marketedbyNovo1985.

• 1964InsulinpumpsbyDr Arnold KadishinLos

Angelesbutheavy,1972Dean Kamerdesignedlightweightformwornonbody.1978studiesbyJohn PickupandHarry KeenatGuy’swithcontinuoussubcutaneousinsulininfusioninshortpulsesfrombatteryoperatedpumpimprovedglycaemiccontrol.2003Medtronic/BectonDickinsoncombinedminipump/glucosemonitorworndiscreetly.Pumpsimprovedpersonalfreedombutwereexpensive.

Human Insulin• 1974byCibaGeigyexpensivewithallergic

sideeffects.1981geneticengineeringprojectbyGenentechandEliLillyusedgeneinsertionintoE.Coli.During1990’smanyUKpatientstransferredtobiosyntheticinsulin.MinoralterationsininsulinaminoacidstructuregaveinsulinanaloguessuchasLispro(Humalog)byEliLillyin1996withfastshortactingpropertiestocovermeals.Combinationwithregularinsulineg

HumulinR,NPH(NovolinN)andLente(HumulinL)nowavailable.

Experimental Treatment-Transplantation• 1916pancreaticgraftbyEnglishsurgeonFrederick Pybus (1883-1975),firstpancreatictransplantas

treatment1966byRichard Lillelei (1927-1981)professorofsurgery,MinnisotaUniversity.ImprovedisletcellisolationbyPaul Lacy (1924-2005)allowedtheirtransplantation.Relativelyfewtransplantsduetotechnicalproblemsandlimitedsuccess(10%)forinsulinindependence.Isletcelltransplantimproved2000byCanadianteamledbyJames Shapirousing‘Edmonton’protocolandmoreeffectiveimmunosuppression.

A Brief History of Oral Hypoglycaemic Agents (OHA) in Type 2 Diabetes• 1942oralsulphonamidefoundtolower

bloodglucosebutserioustoxiceffects.1955carbutamine,asulphonylurea,effectiveinoldernoninsulindependentdiabeticsstimulatingbetacellstoproducemoreinsulin.Othersaferfirstgenerationsulphonylureasincludetolbutamide(1956),andchlorpropamide(1958)andsecondgenerationglyclopyramide(1965),glybenclamide(1965)andgliclazide(1985).Metformin,biguanideintroduced1958increasedsensitivitytoinsulin,suppressingdigestionandglucoseabsorptionusedaloneorwithsecondgenerationsulphonylurea.MorerecentOHAincludealphaglucosidaseinhibitorsegBayeracarbosedecreaseglucoseabsorptionandthiazolidinethionesegpioglitazoneincreaseinsulinsensitivity.

Type 1 Diabetes is an Autoimmune Disorder• PioneerworkbySolomon Berson (1919-1972)

andRosalyn Yalow (1921-2011)developedaninsulinradioimmunoassaywhichshowedaninsulinbindingglobulininserumofinsulintreateddiabeticsandmeasureableinsulinconcentrationsintype2butlowconcentrationsintype1.1965BelgianpathologistWilly Gepts (1922-1991)reportedahighfrequencyofinsulitis,lymphocyteinfiltrationofisletcells,intype1patientsdyingwithinsixmonthsofdiagnosissuggestingan‘immunological’cause.Isletcellautoantibodiesdescribed1974byD Doniach (1912-2004)andGF BottazzoatMiddlesexHospitalassociatedwithspecificHLAtypesinjuvenileorinsulindependentdiabetes.Comparisonwithotherautoimmunedisordersandstudiesbynotably,Jon Nerupandcolleaguesin1975confirmedHLAlinktoB8&B15,andtheconceptthatgenestransmitatendencytodevelopdiabetes.However,the’trigger’forautoimmuneresponsehasnotbeenestablishedbutviralcauseshavebeenproposed..

Type 2 Diabetes and Genetic Vulnerability• Asearlyas600BCEobservedthatdiabetes

oftenraninfamiliesbutitwasnotuntilthe20thcenturygeneticstudiesbyG Pincus (1903-1967)in1933withfurtherworkin1947byH Harris (1919-1994)allwithinconclusiveresults.Theassociationbetweengeneticpredisposition,insulinresistance,centralobesityandhypertensionwasproposedin1988byGerald Reaven (b1928)andraisedthecurrentemphasisforlifestylemodificationindietandincreasedexercise.

FrederickSanger(b1918)

Dorothy Hodgkin(1910-1994)

Hans Christian Hagedorn (1888-1971)

Complications, Control & Testing

A History of Diabetes Mellitus: From Tasting to TestingProduced by the Institute of Biomedical Science History Committee

Complications of DiabetesNeonatal mortality• 1937increasehighlightedbyRaymond Titus

(1883-1949).AtKing’sCollegecaesareansectionbetween36thto38thweeksofpregnancyintroducedfrom1942.In1954improvedoutcomeswithbloodglucosenearnormalduringpregnancyreportedbyJorgen Pedersen (1914-1978).

New Technology & the Complications Control Trials• Impactofseriouscomplicationsfuelledaglobaldebateonneedforbloodglucosecontrolledtotwo

majortrials.USA1985-1993fortype1andUK1977-1997fortype2.Newtechnologieswereusedtoassessoutcomesofmoreintensivetreatmentandmaintainingbloodglucoseclosetonormalrangeandincludedglucosemeters,HbA1candurinemicroalbumin.

Glucose meters• FurtheradvancesinreagentstriptechnologyatAmesresultedinDextrostix(1964)usedtomeasure

wholebloodglucose.ToimproveprecisionandreliabilityAmesdevelopedtheAmesReflectanceMeterin1970.IntensecommercialdevelopmentshavetakenplaceduringthelastfourdecadesandawidevarietyofreagentstripmetersystemsareavailabletoGP’s,Clinicsandsignificantlythepatientsthemselves.Laboratorystafftodayplayanimportantrolein‘pointofcaretesting’andmanagementofglucosemeters.

Glycated haemoglobin (HbA1c) • HbA1cinbloodhaemolysatesofdiabeticsfirstdemonstratedbySamuel Rahbarin1968.In1976itwas

shownbyA CeramiandRonald Koenigthat%formedcouldberelatedtotheaveragebloodglucoseoverprevious4months,thelifecycleofredbloodcell.Thiswasasignificantfactorintheretrospectiveassessmentofbloodglucosecontroltotargetlimitsinthetrials.HbA1cisnowahighvolumeworkloadassayinalllaboratoriesusingmethodssuchasaffinitychromatography,HPLCorimmunoassay.

Microalbumin• Moresensitiveimmunoassayforurinealbuminwasdevisedin1963byHarry Keenandusedasanearly

indicatorofimpairedrenalfunction.Ithasbeenreplacedbyautomatedrenalfunctiontests.

ResultsDCCT (type 1 diabetes)• Foundsignificantlyreducedrisksofretinopathy,nephropathyandneuropathy.Ahigherriskof

hypoglycaemiawasreportedandnoreductionofriskofcardiovasculardisease.

UKPDS (type 2 diabetes)• Positivebenefitswerefoundforretinopathyandnephropathybyimprovedbloodglucoseandblood

pressurecontrol.Duetothemixoftreatmenteginsulin,sulphonylureas,metforminthiswasalongertrialandinterpretationofresultsmorecomplex.

2000: DIABETES BECOMES EPIDEMICWorldHealthOrganisationestimatedthat171millionintheWorldhavediabetesandprojectedto366millioninyear2030

2012: MOST NHS COSTS ON DIABETES ARE WASTEFUL (Diabetes UK)80%ofNHScostsindiabetesinvolvetreatmentofcomplications.2012: 24,000 WITH DIABETES ARE DYING NEEDLESSLY (Diabetes UK)Referstothenumberofpeoplefailingtohave9recommendedtestsfordiabetesatGPannualreview.

2013: DIABETES UK TOLL HITS 3 MILLION (Diabetes UK)Anincreasefrom2.2millionin2006andafurther850,000maybeundiagnosedtype2

DAILY NEWS‘Read All About It’:

Diabetes Makes the Headlines

Retinal scarring

Diabetic NodularNephropathy

Ame Reflectance Meter 1970

A Range of Modern Meters

Retinopathy• 1934MayoClinicstudies

showedrepeatedretinalhaemorrhagescauseofblindnessindiabetes.Around1950laserphotocoagulationfirstusedandmanylaservariationsfollowed.Morerecentlyspecialisedsurgeryintroduced.

Nephropathy• 1936Paul Kimmelsteil (1900-1970)and

Clifford Wilson (1906-1997)atHarvarddemonstratednoduleswithinrenalglomeruliwhichimpairedrenalfunction.Treatedfirstbyproteinrestriction,laterrenaldialysisandtransplantation

Neuropathy• ObservedbyJohn Rolloin1798andreported

byFrederick Pavyin1885affectingsensoryesp.hands,feetandtheautonomicnervoussystems.1954William Oakley (1906-1998)proposeddiabeticnervedamagesignificantfactorinperforatingfootulcersandgangrene.

Cardiovascular disease• Duringthe20thcenturyrepeatedreportsof

vascularlesions,earlymyocardialinfarctionandstrokesmorecommonintype2diabetesconfirmedby1950Framinghamheartstudy.Variouspathologicalmechanismsproposedforincreasedriskofatherosclerosis.Blockedarteriestothelowerlimbsarecommoncauseofgangreneaffectingtoes.