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Type2DiabetesAnoverview
DrPaulPeter
ConsultantPhysician
DiabetesandEndocrinology
CountyDurhamandDarlingtonFoundationTrust
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Plan
Theepidemic
Cardiovascularimpactofdiabetes
Insulinresistance/metabolicsyndrome
Currentoptions
Newoptions!!
NICEguidelines
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Amos AF et al. Diabet Med 1997; 14 (Suppl 5): S1S85.
Thesizeoftheproblem
Dia
be
tespreva
lence
(thousands
)
0
500
1000
1500
2000
2500
3000
1995 2000 2010
Type 1
Type 2
3 million by 20103 million by 2010
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0
10
20
30
40
50
No history of MI History of MI7-year
inc
idenceo
fc
ard
iovascu
lar
even
ts
(%)
No history of MI History of MI
Haffner SM et al. N Engl J Med 1998; 339: 229234.
Increasedriskofmyocardialinfarctionin
Type2diabetes
Non-diabetic
Type 2 diabetes
RememberRemember look at a person with Type 2 diabetes as iflook at a person with Type 2 diabetes as if
they have already had an MIthey have already had an MI
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UKPDS:benefitsofcontrollingHbA1c
*p < 0.0001**p = 0.016
Epidemiological extrapolation showing benefit of a 1% reduction in mean HbA1c at 12 years
Risk
reduc
tion
(%)assoc
iatedwit
ha
1%
lower
HbA
1c
-40
-35
-30
-25
-20
-15
-10
-5
0
43%
Amputation or
death due to
peripheral
vascular disease
*
*21%
Any diabetes-
related
endpoint
*
37%
Microvascular
complications
*
14%
Myocardial
infarction
*
19%
Cataract
extraction
16%
**
Heart
failure
Stratton IM et al. BMJ 2000; 321: 405412.
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DiabetesandSugar..??
Oscarminkowski..If hewas
ageusic.!!!
Diabetescare2004.
DiabetesItaint aboutsugar!!
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Glucose
(G)
Carbohydrate
Glucose
DIGESTIVE ENZYMES
Insulin
(I)
I
I
I
I
Insulin resistance
Insulin resistance
Insulin resistance
I
I
I
I
I
I
I
G
G
GG
G
G
G
GI
G
G
G
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Improves hyperglycaemia
to achieve tight glycaemic
control and reduce
microvascular complications
TreatingType2diabetes
Improves
cardiovascular risk factors
TargetTarget
Insulin
resistance
a rootcause of
Type 2
diabetes
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IDFDefinitionofMetabolicSyndrome(April2005)
CentralObesitydefinedbywaistcircumference Plusany2ofthefollowing
RaisedTG
(>1.7mmol/Lorspecifictreatmentforthisabnormality)
ReducedHDLcholesterol (or=85mmHgortreatmentofpreviouslydiagnosedhypertension)
RaisedFastingPlasmaGlucose (>or=5.6mmol/L) or
PreviouslydiagnosedType2Diabetes
Ifglucose>5.6anOGTTisstronglyrecommendedbutisnotnecessary todiagnosemetabolicsyndrome
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EthnicSpecificValuesforWaistCircumference
Country/Ethnic Group Waist Circumference
Male > or = 94 cmsEuropidsFemale > or = 80 cms
Male > or = 90 cmsSouth Asians
Chinese, Malay and Asian-Indian Female > or = 80 cms
Male > or = 85 cmsJapanese
Female > or = 90 cms
Ethnic South & Central
Americans
Use South Asian recommendation until
more specific data are available
Sub-Saharan Africans Use European recommendation until
more specific data are available
Eastern Mediterranean &
Middle East (Arab)
populations
Use European recommendation until
more specific data are available
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HDLM < 1.0mmol/L
W < 1.3mmol/L
TGs
>1.7 mmol/L
FastingGlucose
> 5.6mmol/L
BP> 130/85 mmHg
IDF Criteria of the Metabolic Syndrome
Waist
M > 94 cm
W > 80 cm
+ 2 out of 4
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Currentoptions
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Pharmacologicaltargets
glucosidase inhibitorsDelayintestinalcarbohydrateabsorption
GlitazonesDecreaseinsulinresistance
SulphonylureaIncreaseinsulinsecretionfrom
pancreaticcells
Biguanide(metformin)Decreases
insulinresistance
DDP4=dipeptidyl peptidase4;GLP1=glucagonlikepeptide1;T2DM=type2diabetesmellitus
AdaptedfromChengAY,Fantus IG.CMAJ.2005;172:213226.
MeglitinidesIncreaseinsulinsecretionfrom
pancreaticcells
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ADA=AmericanDiabetesAssociation;HbA1c=hemoglobinA1c
AdaptedfromUKPDSGroup.Lancet.1998;352:854865.
Glycaemiccontrolworsensovertime
MedianHb
A1c
(%)
0 2 4
0
6
7
8
9
6 8 10TimeFromRandomization(y)
Upperlimitofnormalrange(6.2%)
ADAgoal(7.0%)
Conventional(n=200) Insulin(n=199)
Chlorpropamide (n=129)Glibenclamide (n=148)
Metformin(n=181)
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Cellfunctioncontinuestodecline
T2DM=type2diabetesmellitus
*cellfunctionmeasuredbyhomeostasismodelassessment(HOMA)
AdaptedfromUKPDSGroup.Diabetes.1995;44:12491258.44
0
20
40
60
80
100
5 4 3 2 1 0 1 2 3 4 5 6
Yearssincediagnosis
CellFunction
(%)*
Progressivelossofcellfunction
occurspriortodiagnosis
Metformin(n=159)
Diet(n=110)
Sulphonylurea(n=511)
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ADOPT:weightchangeovertime
*Significantdifferencerosiglitazone vs.othertreatmentgroupswithHochbergadjustment.
CI=confidenceinterval.
KahnSE,etal.NEngl JMed2006;355:24272443.
Treatmentdifference(95%CI)
Rosiglitazonevs.metformin,6.9(6.3to7.4);P
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IFG=impairedfastingglucose;IGT=impairedglucosetolerance;NGT=normalglucosetolerance
AdaptedfromInternationalDiabetesCenter.Type2DiabetesBASICS.Minneapolis,Minn:InternationalDiabetesCenter;2000.
Prediabetes
(IFG/IGT)NGT Diabetes
Insulinresistance
Isletcellfunction
Diagnosis
Treatingtype2diabetes:
Deterioratingisletcellfunctioninthesettingof
insulinresistance/Obesity
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Isletcellfunction..
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Type2diabetesisacombinationofinsulinresistanceandpancreatic
isletdysfunction
Pancreaticisletdysfunction
Inadequate
glucagon
suppression
(cell
dysfunction)
Impairedglucose
dependent
response
Insufficientinsulin
secretion
(cell
dysfunction)
Insulinresistance
(impairedinsulinaction)
Triplitt C et al. Pharmacotherapy 2006:26:360-374
Krentz AJ, Bailey CJ. Drugs 2005:65(3):385-411
SulphonylureasGlitazones
Metformin
Most frequently prescribed OADs either address insulin resistance orelements of pancreatic islet dysfunction
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TheIncretin effect
28
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IV=intravenous
AdaptedfromNauck MA,etal.JClin Endocrinol Metab.1986;63:492498.
OralglucosetolerancetestandmatchedIVinfusion
PlasmaGluco
se(mg
/dL)
0
50
100
150
200
30 0 30 60 90 120 150 180 210
Time(Min)
PlasmaInsulin(pmol/L)
0
100
200
300
400
30 0 30 60 90 120 150 180 210
Time(Min)
Proofofagastrointestinalincretin effect:differentresponses
tooralvs.IVglucose
Oral IV
50gGlucose
N=6
29
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LCell
(ileum)
Proglucagon
GLP1[737]
GLP1[736NH2]
KCell
(jejunum)
ProGIP
GIP[142]
GIP=glucosedependentinsulinotropic peptide;GLP1=glucagonlikepeptide1
AdaptedfromDrucker DJ.DiabetesCare.2003;26:29292940.
GLP1andGIParesynthesizedandsecretedfromthegutinresponse
tofoodintake
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GLP1=glucagonlikepeptide1;T2DM=type2diabetesmellitus*P
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GLP 1 effects in humans
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GLP1effectsinhumans
Adapted from 1Nauck MA, et al. Diabetologia 1993;36:741744; 2Larsson H, et al.Acta Physiol Scand 1997;160:413422; 3Nauck MA, etal. Diabetologia 1996;39:15461553; 4Flint A, et al. J Clin Invest 1998;101:515520; 5Zander et al. Lancet 2002;359:824830.
GLP-1 secreted upon
the ingestion of food
1.-cell:cell:
Enhances glucoseEnhances glucose--dependentdependentinsulin secretion in theinsulin secretion in the
pancreaspancreas11
3.Liver:3.Liver:
reduces hepatic glucosereduces hepatic glucose
outputoutput22
2.2.--cell:cell:Suppresses pSuppresses postprandialostprandial
glucagonglucagon secretionsecretion11
4.Stomach:4.Stomach:slows the rate ofslows the rate of
gastric emptyinggastric emptying33
5.Brain:5.Brain:Promotes satiety andPromotes satiety and
reduces appetitereduces appetite4,54,5
Insulin gene
transcription and
synthesis
Decreasing apoptosis,Increasing
replication and Neogenesis
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SoWhatstheproblem??
GLP1 secretion in the intestineDPP4
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htt ://wwhtt ://ww
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GLP1inactive
(>80%ofpool)
Active
GLP1
Meal
DPP4
IntestinalGLP1release
GLP1t=12min
DPP4=dipeptidyl peptidase4;GLP1=glucagonlikepeptide1
AdaptedfromRothenbergP,etal.Diabetes.2000;49(suppl 1):A39.Abstract160OR.AdaptedfromDeaconCF,etal.Diabetes.1995;44:11261131.
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ToincreaseGLP1.
Preventdegradation
Createanalogues
Inhibition of DPP 4 increases active
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InhibitionofDPP4increasesactive
GLP1
GLP1inactive
(>80%ofpool)
Active
GLP1
Meal
DPP4
IntestinalGLP1release
GLP1t=12min
DPP4
inhibitor
DPP4=dipeptidyl peptidase4;GLP1=glucagonlikepeptide1
AdaptedfromRothenbergP,etal.Diabetes.2000;49(suppl 1):A39.Abstract160OR.AdaptedfromDeaconCF,etal.Diabetes.1995;44:11261131.
GLIPTIN
33
Gliptins
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Gliptins
Sitagliptin
Vildagliptin
Saxagliptin
DecreaseinHba1cof1%
Weightneutral
Nohypoglycemia
Elderly
Overweight type 2 diabetes
as second / third line
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GLP1analogues
Exenatide
Liraglutide*
Decreaseofhba1c>1% Weightlossof3 6kgs 6months
Decreaseinwaistcircumference Littlehypoglycemia
*submittedformarketingauthorisation
Overweight--- BMI>35??
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NICEguidelines
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DontForget
Diabetesaint justaboutsugar
Treatweight,lipids,BP and.sugar.
Neweragentswithmultiplebenefits
?longtermbenefit
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Questions