Historical aspects of diabetes and its management.

1. Diabetes:
Past, Present and Future
Dr Shahjada Selim
Assistant Professor
Department of Endocrinology
Bangabandhu Sheikh Mujib Medical University, Dhaka
Email: selimshahjada@gmail.com
April 1, 2016 Shahjada Selim, MD, MACE.

2. Shahjada Selim, MD, MACE.
In 1500 BC
Diabetes First Described In Writing
Hindu healers wrote that flies and ants were
attracted to urine of people with a
mysterious disease that caused intense
thirst, enormous urine output, and wasting
away of the body.
April 1, 2016

3. Shahjada Selim, MD, MACE.
250 BC
The Word Diabetes First Used
• Apollonius of Memphis coined the name
"diabetes” (διαβήτηςδιαβήτης) meaning "to go through"
‘‘to stand apart’’ or siphon. He understood that
the disease drained more fluid than a person
could consume.
April 1, 2016

4. Shahjada Selim, MD, MACE.
250 BC
The Word Diabetes First Used
• Gradually the Latin word for honey, "mellitus,"
was added to diabetes because it made the urine
sweet.
• FirstFirst recordedrecorded inin EnglishEnglish inin aboutabout 14251425 asas
‘diabetes’‘diabetes’.
April 1, 2016

5. Shahjada Selim, MD, MACE.
Diabetes is a wonderful affection, not very
frequent among men, being a melting down of
the flesh and limbs into urine…The flow is
incessant, as if from the opening of
aqueducts…it takes a long period to form, but
the patient is short-lived…for the melting is
rapid, the death speedy.
150 BC
Aretaeus the Cappadocian
April 1, 2016

6. Shahjada Selim, MD, MACE.
Moreover, life is disgusting and painful; thirst
unquenchable; excessive drinking…and one
cannot stop them either from drinking or
making water... they are affected with
nausea, restlessness, and a burning thirst;
and at no distant term they expire.
150 BC
Aretaeus the Cappadocian
April 1, 2016

7. TheThe sweetsweet tastetaste hadhad beenbeen noticednoticed inin urineurine
byby thethe ancientancient Greeks,Greeks, Chinese,Chinese, Egyptians,Egyptians,
andand IndiansIndians butbut itit waswas onlyonly inin 16751675 thatthat
ThomasThomas WillisWillis addedadded thethe wordword ‘mellitus’.‘mellitus’.
April 1, 2016 Shahjada Selim, MD, MACE.

8. ItIt waswas inin 17761776 thatthat MatthewMatthew DobsonDobson
confirmedconfirmed thatthat thethe sweetsweet tastetaste waswas
becausebecause ofof anan excessexcess ofof sugarsugar inin thethe
urineurine andand bloodblood ofof peoplepeople withwith diabetesdiabetes.
April 1, 2016 Shahjada Selim, MD, MACE.

9. Shahjada Selim, MD, MACE.
Early Diabetes Treatments
• In 1000, Greek physicians recommended
horseback riding to reduce excess urination
• In the 1800s, bleeding, blistering, and doping
were common
• In 1915, Sir William Osler recommended
opium
• Overfeeding was commonly used to
compensate for loss of fluids and weight
• In the early 1900s a leading American
diabetologist, Dr. Frederick Allen,
recommended a starvation diet.
April 1, 2016

10. Shahjada Selim, MD, MACE.
Early Research
• In 1798, John Rollo documented excess
sugar in the blood and urine
• In 1813, Claude Bernard linked diabetes to
glycogen metabolism
• In 1869, Paul Langerhans, a German
medical student, discovered islet cells in the
pancreas.
April 1, 2016

11. Shahjada Selim, MD, MACE.
Early Research
• In 1889, Joseph von Mehring and Oskar
Minkowski created diabetes in dogs by
removing the pancreas
• In 1910, Sharpey-Shafer of Edinburgh
suggested a single chemical was missing
from the pancreas. He proposed calling this
chemical "insulin."
April 1, 2016

12. Shahjada Selim, MD, MACE.
Near Miss
• In 1908, a young internist in Berlin, Georg
Ludwig Zuelzer created a pancreas extract
named acomatrol.
• After injecting acomatrol into a dying diabetic
patient, the patient improved at first, but died
when the acomatrol was gone.
April 1, 2016

13. Shahjada Selim, MD, MACE.
Near Miss
• Zuelzer filed an American patent in 1911 for a
"Pancreas Preparation Suitable for the
Treatment of Diabetes”
• Disappointing results, however, caused his
lab to be taken over by the German military
during WWI
April 1, 2016

14. Shahjada Selim, MD, MACE.
Other “Pancreas Extractors”
• American scientist E. L. Scott was partially
successful in extracting insulin with alcohol.
• A Romanian, R. C. Paulesco, made an extract from
the pancreas that lowered the blood glucose of
dogs.
• Some claim Paulesco may have been the first to
discover insulin about 10 years before Banting and
Best.
April 1, 2016

15. Shahjada Selim, MD, MACE.
Before Insulin
Before insulin was discovered in 1921, everyone
with type 1 diabetes died within weeks to years of
its onset.
JL on 12/15/22 and 2 mos later
April 1, 2016

16. Sir William Osler, in the year 1915, is said to
have even recommended opium! Early research
linked diabetes to glycogen metabolism, and the
islet cells of pancreas were discovered by Paul
Langerhans, a young German medical student.
April 1, 2016 Shahjada Selim, MD, MACE.

17. In 1916, Sharpey-Shafer of Edinburgh
suggested that a single chemical was missing
from the pancreas and proposed its name as
“insulin.” The term insulin originates from the
word Insel, which is German for an islet or
island.
April 1, 2016 Shahjada Selim, MD, MACE.

18. NothingNothing muchmuch happenedhappened
forfor thethe nextnext fewfew
centuries…centuries…
InIn thethe latelate 19th19th Century,Century,
OskarOskar MinkowskiMinkowski andand
othersothers discovereddiscovered thethe rolerole
ofof thethe pancreaspancreas inin diabetesdiabetes
byby takingtaking themthem outout ofof dogsdogs
andand realizingrealizing thatthat theythey
dieddied ofof the conditionthe condition.
April 1, 2016 Shahjada Selim, MD, MACE.

19. Researchers like E.L. Scott and Nikolae
Paulesco were successful in extracting insulin
from the pancreas of experimental dogs. The key
breakthrough, though, came from the Toronto
University with the discovery of insulin in 1921.
April 1, 2016 Shahjada Selim, MD, MACE.

20. ItIt waswas ‘ignorant’‘ignorant’ juniorjunior surgeonsurgeon FredFred BantingBanting
whowho tooktook thethe germgerm ofof anan ideaidea toto JRRJRR McLeodMcLeod
–– thethe renownedrenowned physiologistphysiologist
McLeodMcLeod –– whowho knewknew ofof thethe unsuccessfulunsuccessful workwork
ofof othersothers overover thethe precedingpreceding 3030 yearsyears –– gavegave
BantingBanting aa tinytiny room,room, aa fewfew dogs,dogs, andand aa
medicalmedical studentstudent –– CharlesCharles Best.Best.
April 1, 2016 Shahjada Selim, MD, MACE.

21. BantingBanting andand BestBest managedmanaged toto getget throughthrough
dozensdozens ofof dogsdogs tryingtrying differentdifferent methodsmethods toto
getget thethe pancreaspancreas toto failfail andand thenthen toto replacereplace it.it.
DespiteDespite theirtheir poorpoor science,science, andand poorpoor records,records,
theythey eventuallyeventually ‘stumbled’‘stumbled’ onon somethingsomething
Promising.Promising.
April 1, 2016 Shahjada Selim, MD, MACE.

22. 19211921 andand AllAll That……That……
Banting,Banting,
Best,Best,
Collip,Collip,
andand
McLeodMcLeod
At theAt the
UniversityUniversity
ofof
Toronto.Toronto.
April 1, 2016
Shahjada Selim, MD, MACE.

23. FG Banting and JJR Macleod were awarded the
Nobel Prize for Physiology or Medicine in 1923.
They shared their prize money with CH Best and
JB Collip who were “left out” by the prize
committee.
April 1, 2016 Shahjada Selim, MD, MACE.

24. TheyThey hadhad lotslots ofof
dogs –dogs – oftenoften
obtainedobtained fromfrom
dubiousdubious sources.sources.
Marjorie?Marjorie?
April 1, 2016 Shahjada Selim, MD, MACE.

25. Banting and Best injected the crude pancreatic
extract “thick brown muck” into a 14-year-old
boy named “Leonard” in January 1922. His
blood sugar levels dropped significantly, but an
abscess developed at the injection site making
him acutely ill.
April 1, 2016 Shahjada Selim, MD, MACE.

26. A refined extract was again administered after 6
weeks, causing drop in blood sugar levels from 520
mg/dl to 120 mg/dl within 24 h. Leonard lived for
13 years before dying of pneumonia (another
disease for which no cure was available in those
days)
April 1, 2016 Shahjada Selim, MD, MACE.

27. TheThe ProblemsProblems
TheirTheir pancreaticpancreatic extractextract waswas impureimpure andand lackedlacked
consistency.consistency.
BantingBanting feltfelt thatthat McLeodMcLeod waswas tryingtrying toto stealsteal
theirtheir thunderthunder byby takingtaking creditcredit forfor theirtheir work.work.
ApparentApparent lacklack ofof progress.progress.
April 1, 2016 Shahjada Selim, MD, MACE.

28. McLeod brought in a
leading biochemist to
help with purification –
James Bertram Collip.
Collip was working on
calcium but agreed to
work with McLeod
during a 1 year
sabbatical.
April 1, 2016 Shahjada Selim, MD, MACE.
The Solution

29. RegardedRegarded asas thethe firstfirst
personperson toto everever receivereceive
insulininsulin onon 11th11th
JanuaryJanuary 19221922 agedaged 1414
HeHe livedlived forfor 1313 yearsyears
beforebefore dyingdying inin aa carcar
accidentaccident
April 1, 2016 Shahjada Selim, MD, MACE.
Leonard

30. Evolution of Insulin
April 1, 2016 Shahjada Selim, MD, MACE.

31. Recognition
InIn 1923,1923, BantingBanting andand McLeodMcLeod werewere
awardedawarded the Nobelthe Nobel PrizePrize forfor MedicineMedicine
BantingBanting gavegave halfhalf hishis prizeprize immediatelyimmediately toto
Best,Best, andand McLeodMcLeod gavegave halfhalf ofof hishis toto
Collip.Collip.
April 1, 2016 Shahjada Selim, MD, MACE.

32. TheThe DiabeticDiabetic Association,Association, waswas setset upup inin 19341934 byby
novelistnovelist HGHG WellsWells andand DrDr RDRD Lawrence “ToLawrence “To promotepromote
thethe study,study, thethe diffusiondiffusion ofof knowledge,knowledge, andand thethe properproper
treatmenttreatment ofof diabetesdiabetes inin thisthis country.”country.”
1923 - “I’ve got some insulin. It works. Come back quick.”
April 1, 2016 Shahjada Selim, MD, MACE.

33. On May 1922, Eli Lilly signed an agreement to
pay royalties to the Toronto University to
increase the production of insulin. In 1923,
August Krogh and Hans Christian Hagedorn
began the mass production of insulin extracted
from porcine pancreas in Denmark.
April 1, 2016 Shahjada Selim, MD, MACE.

34. The Nordisk Insulin Laboratorium (now Novo
Nordisk) was thus established. In 1955, Sir
Frederick Sanger characterized the amino acid
sequence of human insulin, making it the first
protein to whose sequence was determined. He
was awarded the 1958 Nobel Prize in Chemistry
for this work.
April 1, 2016 Shahjada Selim, MD, MACE.

35. Subsequently, Hans Christian Hagedorn
discovered the prolonged effect of insulin by
adding protamine to the insulin molecule. Various
intermediate acting preparations were formulated
to provide 24-h control of blood glucose.
April 1, 2016 Shahjada Selim, MD, MACE.

36. Purified versions of animal insulin were developed
in 1974 by chromatographic techniques (less than 1
pmol/l of protein impurities) known as
“monocomponent MC” “single peak” insulin in
order to reduce the allergic reactions and
lipodystrophy.
April 1, 2016 Shahjada Selim, MD, MACE.

37. In 1978, recombinant DNA technology was used
to produce synthetic human insulin in E. coli. In
early 1980s, mass production of rDNA human
insulin was commenced.
April 1, 2016 Shahjada Selim, MD, MACE.

38. By the mid of nineties, the structure of human
insulin was modified by altering the amino acid
sequence (addition, deletion, or exchange of
amino acids) to produce insulins with better
pharmacokinetic properties, which came to be
known as a “modern insulin” or “designer
April 1, 2016 Shahjada Selim, MD, MACE.

39. • 19221922 Banting,Banting, Best,Best, CollipCollip useuse bovinebovine insulininsulin extractextract
inin humanhuman
• 19231923 EliEli LillyLilly producesproduces commercialcommercial quantitiesquantities ofof muchmuch
purerpurer bovinebovine insulininsulin thanthan BantingBanting etet alal hadhad usedused
• 19231923 FarbwerkeFarbwerke Hoechst,Hoechst, oneone ofof thethe forerunner'sforerunner's ofof
today'stoday's SanofiSanofi Aventis,Aventis, producesproduces commercialcommercial quantitiesquantities
ofof bovinebovine insulininsulin inin GermanyGermany
• 19231923 HagedornHagedorn foundsfounds thethe NordiskNordisk
• InsulinlaboratoriumInsulinlaboratorium inin DenmarkDenmark –– forerunnerforerunner ofof today'stoday's
NovoNovo NordiskNordisk
April 1, 2016 Shahjada Selim, MD, MACE.
AA BriefBrief HistoryHistory ofof InsulinInsulin

40. • 19261926 NordiskNordisk receivesreceives aa DanishDanish chartercharter toto produceproduce insulininsulin asas
aa non-profitnon-profit
• 19361936 CanadiansCanadians D.M.D.M. Scott,Scott, A.M.A.M. FisherFisher formulateformulate aa zinczinc
insulininsulin mixturemixture andand licenselicense itit toto NovoNovo
• 19361936 HagedornHagedorn discoversdiscovers thatthat addingadding protamineprotamine toto insulininsulin
prolongsprolongs thethe durationduration ofof actionaction ofof insulininsulin..
• 19461946 NordiskNordisk formulatesformulates IsophaneIsophane porcineporcine insulininsulin akaaka
NeutralNeutral ProtamineProtamine HagedornHagedorn oror NPHNPH insulininsulin
• 19461946 NordiskNordisk crystallizescrystallizes aa protamineprotamine andand insulininsulin mixturemixture
• 19501950 NordiskNordisk marketsmarkets NPHNPH insulininsulin
• 19531953 NovoNovo formulatesformulates LenteLente porcineporcine andand bovinebovine insulinsinsulins byby
addingadding zinczinc forfor longerlonger lastinglasting insulininsulin
April 1, 2016 Shahjada Selim, MD, MACE.

41. • 19551955 FrederickFrederick SangerSanger determinesdetermines thethe aminoamino acidacid sequencesequence
ofof insulininsulin
• 19651965 SynthesizedSynthesized byby totaltotal synthesissynthesis byby andand coworkerscoworkers
• 19691969 DorothyDorothy CrowfootCrowfoot HodgkinHodgkin solvessolves thethe crystalcrystal
structurestructure ofof insulininsulin byby x-rayx-ray crystallographycrystallography
• 19731973 PurifiedPurified monocomponentmonocomponent (MC)(MC) insulininsulin isis introducedintroduced
• 19781978 GenentechGenentech producesproduces syntheticsynthetic 'human''human' insulininsulin inin
EscheriaEscheria colicoli bacteriabacteria usingusing recombinantrecombinant DNADNA techniques,techniques,
licenseslicenses toto EliEli LillyLilly
• 19811981 NovoNovo NordiskNordisk chemicallychemically andand enzymaticallyenzymatically convertsconverts
porcineporcine toto humanhuman insulininsulin
• 19821982 GenentechGenentech syntheticsynthetic 'human''human' insulininsulin (above)(above) approvedapproved
April 1, 2016 Shahjada Selim, MD, MACE.

42. • 19831983 EliEli LillyLilly andand CompanyCompany producesproduces syntheticsynthetic 'human''human'
insulininsulin withwith recombinantrecombinant DNADNA technology,technology, HumulinHumulin
• 19851985 AxelAxel UllrichUllrich sequencessequences aa humanhuman cellcell membranemembrane
insulininsulin receptor.receptor.
• 19881988 NovoNovo NordiskNordisk producesproduces recombinantrecombinant humanhuman insulininsulin
• 19961996 LillyLilly HumalogHumalog "lispro""lispro" insulininsulin analogueanalogue approved.approved.
• 20002000 SanofiSanofi AventisAventis LantusLantus "glargine""glargine" insulininsulin analogueanalogue
approvedapproved forfor clinicalclinical useuse inin thethe USUS andand Europe.Europe.
• 20042004 SanofiSanofi AventisAventis insulininsulin glulisineglulisine insulininsulin analogueanalogue
approvedapproved forfor clinicalclinical useuse inin thethe US.US.
• 20062006 NovoNovo NordiskNordisk LevemirLevemir "detemir""detemir" insulininsulin analogueanalogue
approvedapproved forfor clinicalclinical useuse inin thethe US.US.
April 1, 2016 Shahjada Selim, MD, MACE.

43.  TheThe firstfirst oraloral agentsagents werewere launchedlaunched inin 19421942 ––
thethe SulphonylureasSulphonylureas
 TheThe BritishBritish DiabeticDiabetic AssociationAssociation waswas formedformed
inin 19541954 –– thethe NorwichNorwich branchbranch launchedlaunched inin
19581958
 BiguanidesBiguanides werewere launchedlaunched inin thethe 1950’s1950’s ––
withwith metforminmetformin beingbeing launchedlaunched inin 19791979
 TheThe aminoamino acidacid sequencesequence ofof insulininsulin waswas
reportedreported inin 19551955 byby FredFred SangerSanger (another(another
NobelNobel Prize)Prize)
April 1, 2016 Shahjada Selim, MD, MACE.

44.  InIn 19881988 GeraldGerald ReavenReaven describeddescribed thethe
constellationconstellation ofof conditionsconditions makingmaking upup thethe
MetabolicMetabolic SyndromeSyndrome
 IInn thethe midmid 1990’s1990’s acarboseacarbose andand metaglinidesmetaglinides
becamebecame availableavailable
 TroglitazoneTroglitazone waswas launchedlaunched inin thethe UKUK inin
MarchMarch 19971997 andand withdrawnwithdrawn inin MayMay 19971997
April 1, 2016 Shahjada Selim, MD, MACE.

45.  InIn 2005 Incretin based therapy wasIncretin based therapy was
introduced.introduced.
April 1, 2016 Shahjada Selim, MD, MACE.

46. Shahjada Selim, MD, MACE.
Demands On Intelligent Devices
• Intuitive interface and language
• Must be impartial and fair
• Outcome driven – user feels better and
is more confident about control
• Compatible with clinic workflow
• Well funded
• Able to rapidly evolve as errors appear
• Must close the data loop between user
and MD
April 1, 2016

47. Shahjada Selim, MD, MACE.
Smart Phones And PDAs
• Fast internet & email communication
• Convenient remote insulin delivery
• Larger food and carb database
• Better graphics for BG analysis,
display of patterns, etc
• Larger event database for long-term
analysis
April 1, 2016

48. Shahjada Selim, MD, MACE.
Intelligent Devices
• 300 personal carb selections
with accurate carb counts
• Carb factor (1:1 TO 1:100)
• Correction factor (1:4 to 1:
400)
5 sec microdraw BG meter
0.1 unit precision motor
Non-volatile memory
3,000 events
Bluetooth data transfer
April 1, 2016

49. Shahjada Selim, MD, MACE.
Thoughts And Developments
For The Future
April 1, 2016

50. Shahjada Selim, MD, MACE.
New: Rapid Basal Reduction
A rapid basal reduction offsets excess BOB and
eliminates the need to eat at bedtime.April 1, 2016

51. Shahjada Selim, MD, MACE.
New: The Super Bolus
A Super Bolus helps cover high GI foods and prevent
postmeal hyperglycemia. A 3 or 4 hour block of basal
insulin is turned into a bolus to speed its effect.
A Super Bolus
can be
activated at a
user-selected
quantity, such
as 40 or 50
grams
April 1, 2016

52. Shahjada Selim, MD, MACE.
New: The Super Bolus
• To ensure safety and success, the Super Bolus will
require some clinical testing:
– How long can basal delivery be stopped or reduced
without increasing the risk for clogging of the infusion line
– How long (3, 4, 5 hours?) can the basal be lowered before
a rebound high will occur once the Super Bolus is gone?
– Is a reduction of the basal delivery rather than complete
stoppage a better policy?
– If a person sets their basal delivery too low or too high, will
this affect a Super Bolus?
April 1, 2016

53. Shahjada Selim, MD, MACE.
New: High BG Super Bolus
If a pumper misjudges the carb content of a meal, a
super bolus enables a faster, safe correction.
April 1, 2016

54. Shahjada Selim, MD, MACE.
New: A Reminder Timer
• A simple timer alerts the user 25 minutes after a
bolus that it is safe to begin eating a high GI meal.
April 1, 2016

55. Shahjada Selim, MD, MACE.
New: An Intelligent Reminder
An intelligent
pump alerts the
user when their
BG is likely to
cross a selected
threshold value,
such as 120
mg/dl. They can
then eat without
exposure to
extremely high
readings.
April 1, 2016

56. Shahjada Selim, MD, MACE.
New: Less Glucose Exposure
The lower the blood
glucose is at the
start of a meal, the
less exposure to
glucose there will
be.
April 1, 2016

57. Shahjada Selim, MD, MACE.
New: An Intelligent Reminder
An intelligent pump
alerts the user
when their blood
glucose is low
enough to begin
eating
April 1, 2016

58. Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Useful reminders
April 1, 2016

59. Shahjada Selim, MD, MACE.
Future Pattern Management
• Finding problem patterns enables solutions
• Set BG targets
• Gather and record data
• Analyze patterns in data
• Assess factors that influence
patterns
• Recommend action
April 1, 2016

60. Shahjada Selim, MD, MACE.
Only A Few Patterns
The relatively low number of BG patterns in
diabetes makes them easy to identify:
• High most of the time
• Frequent lows
• High mornings (lunches, dinners, bedtime)
• Low mornings (lunches, dinners, bedtime)
• Postmeal spiking
• High to low
• Low to high
• Poor control with little or no pattern
April 1, 2016

61. Shahjada Selim, MD, MACE.
Low High Pattern Alert
• Insulin dose suggestions and an alert about
past overtreatment of lows.
April 1, 2016

62. Shahjada Selim, MD, MACE.
Low High Pattern Alert
• An intelligent device can provide a
person’s precise carb requirement when
the blood glucose is tested.
April 1, 2016

63. Shahjada Selim, MD, MACE.
Overnight Basal Patterns
bedtime 2 am breakfast
100
200
300
basal too low
Dawn
Phenomeno
n
just right
too high
Goal for overnight BG change = +/- 30 mg/dl
just right
April 1, 2016

64. Shahjada Selim, MD, MACE.
User Interface – Critical Component
Despite 30 years of pump and meter development,
device communication to the user is still in it’s infancy.
April 1, 2016

65. Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Carb database for accurate carb counts.
April 1, 2016

66. Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Suggestion for carb intake or to limit intake based
on weight/calorie/carb goals
April 1, 2016

67. Shahjada Selim, MD, MACE.
Future Intelligent Devices
• A high glucose can be analyzed to
determine the magnitude of the error
April 1, 2016

68. Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Recommended carb intake (or insulin
reduction) to balance activity.
April 1, 2016

69. Shahjada Selim, MD, MACE.
Future Intelligent Devices
• New dose recommendations based on A1c,
% of TDD given as correction boluses, and
frequency of hypoglycemia
April 1, 2016

70. Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Pattern alerts and advice
April 1, 2016

71. Shahjada Selim, MD, MACE.
Future Intelligent Devices
• Fast lab results without calling. Messaging allows
physician to make recommendations.
April 1, 2016

72. Shahjada Selim, MD, MACE.
Pump Plus Continuous Monitor
• Automatic basal and bolus testing
• Trends allow exact short-term BG
predictions for rapid recognition of
pending highs or lows
• Both user and device can relate problems
to their source
Unfortunately, insulin delivery from an
external pump is too slow to create an
effective artificial pancreas with this
combination
April 1, 2016

73. 22 BIGBIG TrialsTrials
I.I. TypeType 11 diabetesdiabetes -- DiabetesDiabetes ControlControl andand
ComplicationsComplications StudyStudy (DCCT)(DCCT)
NEJMNEJM 19931993 329(14):977-86329(14):977-86
II. TypeType 22 diabetesdiabetes -- UnitedUnited KingdomKingdom ProspectiveProspective
DiabetesDiabetes StudyStudy (UKPDS)(UKPDS)
LancetLancet 19981998 352:837-853352:837-853 && BMJBMJ 19981998 317:703-713317:703-713
April 1, 2016 Shahjada Selim, MD, MACE.

74. Shahjada Selim, MD, MACE.
Questions
???
April 1, 2016