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Type2Diabetes Anoverview

DrPaulPeter
ConsultantPhysician
DiabetesandEndocrinology
CountyDurhamandDarlingtonFoundationTrust
Plan
Theepidemic
Cardiovascularimpactofdiabetes
Insulinresistance/metabolicsyndrome
Currentoptions
Newoptions!!
NICEguidelines
Amos AF et al. Diabet Med 1997; 14 (Suppl 5): S1S85.
Thesizeoftheproblem
D
i
a
b
e
t
e
s

p
r
e
v
a
l
e
n
c
e

(
t
h
o
u
s
a
n
d
s
)
0
500
1000
1500
2000
2500
3000
1995 2000 2010
Type 1
Type 2
3 million by 2010 3 million by 2010
0
10
20
30
40
50
No history of MI History of MI
7
-
y
e
a
r

i
n
c
i
d
e
n
c
e

o
f

c
a
r
d
i
o
v
a
s
c
u
l
a
r

e
v
e
n
t
s

(
%
)
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
Remember Remember look at a person with Type 2 diabetes as if look at a person with Type 2 diabetes as if
they have already had an MI they have already had an MI
UKPDS:benefitsofcontrollingHbA
1c
*p < 0.0001
**p = 0.016
Epidemiological extrapolation showing benefit of a 1% reduction in mean HbA
1c
at 12 years
R
i
s
k

r
e
d
u
c
t
i
o
n

(
%
)

a
s
s
o
c
i
a
t
e
d

w
i
t
h

a


1
%

l
o
w
e
r

H
b
A
1
c
-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.
DiabetesandSugar..??
Oscarminkowski..If hewas
ageusic.!!!
Diabetescare2004.
DiabetesItaint aboutsugar!!
G
l
u
c
o
s
e

(
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
G
G
G
G
G
G
I
G
G
G
Improves hyperglycaemia
to achieve tight glycaemic
control and reduce
microvascular complications
TreatingType2diabetes
Improves
cardiovascular risk factors
Target
Target
Insulin
resistance
a root
cause of
Type 2
diabetes
IDFDefinitionofMetabolicSyndrome(April2005)
CentralObesitydefinedbywaistcircumference
Plusany2ofthefollowing
RaisedTG
(>1.7mmol/Lorspecifictreatmentforthisabnormality)
ReducedHDLcholesterol (<
1.0inmalesand<1.3mmol/Linfemalesorspecific
treatmentforthisabnormality)
RaisedBP
(systolic>or=130mm,diastolic>or=85mmHgortreatmentof
previouslydiagnosedhypertension)
RaisedFastingPlasmaGlucose (>or=5.6mmol/L) or
PreviouslydiagnosedType2Diabetes
Ifglucose>5.6anOGTTisstronglyrecommendedbutisnot
necessarytodiagnosemetabolicsyndrome
EthnicSpecificValuesforWaistCircumference
Country/Ethnic Group Waist Circumference
Male > or = 94 cms Europids
Female > or = 80 cms
Male > or = 90 cms South Asians
Chinese, Malay and Asian-
Indian
Female > or = 80 cms
Male > or = 85 cms Japanese
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
HDL
M < 1.0
mmol/L
W < 1.3
mmol/L
TGs
>1.7 mmol/L
Fasting
Glucose
> 5.6
mmol/L
BP
> 130/85 mmHg
IDF Criteria of the Metabolic Syndrome
Waist
M > 94 cm
W > 80 cm
+ 2 out of 4
Currentoptions
Pharmacologicaltargets
glucosidase inhibitors
Delayintestinalcarbohydrateabsorption
Glitazones
Decreaseinsulinresistance
Sulphonylurea
Increaseinsulinsecretionfrom
pancreaticcells
Biguanide (metformin)
Decreasesinsulinresistance
DDP4=dipeptidyl peptidase4;GLP1=glucagonlikepeptide1;T2DM=type2diabetesmellitus
AdaptedfromChengAY,Fantus IG.CMAJ.2005;172:213226.
Meglitinides
Increaseinsulinsecretionfrom
pancreaticcells
14
ADA=AmericanDiabetesAssociation;HbA1c=hemoglobinA1c
AdaptedfromUKPDSGroup.Lancet.1998;352:854865.
Glycaemiccontrolworsensovertime
M
e
d
i
a
n

H
b
A
1
c

(
%
)
0 2 4
0
6
7
8
9
6 8 10
TimeFromRandomization(y)
Upperlimitofnormalrange(6.2%)
ADAgoal(7.0%)
Conventional(n=200) Insulin(n=199)
Chlorpropamide (n=129) Glibenclamide (n=148)
Metformin(n=181)
12
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

C
e
l
l

F
u
n
c
t
i
o
n

(
%
)
*
Progressivelossofcellfunction
occurspriortodiagnosis
Metformin(n=159)
Diet(n=110)
Sulphonylurea(n=511)
22
ADOPT:weightchangeovertime
*Significantdifferencerosiglitazone vs.othertreatmentgroupswithHochbergadjustment.
CI=confidenceinterval.
KahnSE,etal.NEngl JMed 2006;355:24272443.
Treatmentdifference(95%CI)
Rosiglitazonevs.metformin,6.9(6.3to7.4);P<0.001
Rosiglitazonevs.glyburide,2.5(2.0to3.1);P<0.001
Rosiglitazone,0.7(0.6to0.8)
Metformin,0.3(0.4to0.2)*
Glyburide,0.2(0.3to0.0)*
Annualizedslope(95%CI)
Years
0
W
e
i
g
h
t

(
k
g
)
1 2 3 4 5
No.ofPatients4117 3439 3068 2646 2263 851
6
8
4
2
0
2
4
6
+5kgRosi
18
IFG=impairedfastingglucose;IGT=impairedglucosetolerance;NGT=normalglucosetolerance
AdaptedfromInternationalDiabetesCenter.Type2DiabetesBASICS.Minneapolis,Minn:InternationalDiabetesCenter;2000.
Prediabetes
(IFG/IGT)
NGT
Diabetes
Insulinresistance
Isletcellfunction
Diagnosis
Treatingtype2diabetes:
Deterioratingisletcellfunctioninthesettingof
insulinresistance/Obesity
21
Isletcellfunction..
Pancreaticisletdysfunctionleadstohyperglycaemia inT2DM
Glucose
Uptake
Glucose
Fewer
Cells
Cells
Hypertrophy
Insufficient
Insulin
Excessive
Glucagon

+
Hepatic
Glucose
Output
+
HGO=hepaticglucoseoutput
AdaptedfromOhneda A,etal.JClin Endocrinol Metab. 1978;46:504510;Gomis R,etal.DiabetesResClin Pract.1989;6:191198.
23
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
Sulphonylureas Glitazones
Metformin
Most frequently prescribed OADs either address insulin resistance or
elements of pancreatic islet dysfunction
25
TheIncretin effect
28
IV=intravenous
AdaptedfromNauck MA,etal.JClin Endocrinol Metab.1986;63:492498.
OralglucosetolerancetestandmatchedIVinfusion
P
l
a
s
m
a

G
l
u
c
o
s
e

(
m
g
/
d
L
)
0
50
100
150
200
30 0 30 60 90 120 150 180 210
Time(Min)
P
l
a
s
m
a

I
n
s
u
l
i
n

(
p
m
o
l
/
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
Thestructureoftheincretins
Y
A
E
G
T
F
I
S
D
Y
S
I
A
M
D
K
I
H
Q
Q
D
F
V
N
W
L
L
A
Q
K
G
K
K
N
D
W
K
H
N Q
T
I
GIP:GlucoseDependentInsulinotropic Peptide
H
A
E
G
T
F
T
S
D
V
S
S
Y
L
E
G
Q
A
A
K
E
F
I
A
W
L
V
K
G
R
G
GLP1:GlucagonLikePeptide1
Aminoacidsshowninviolet arehomologouswiththestructureofglucagon
30
LCell
(ileum)
Proglucagon
GLP1[737]
GLP1[736NH
2
]
KCell
(jejunum)
ProGIP
GIP[142]
GIP=glucosedependentinsulinotropic peptide;GLP1=glucagonlikepeptide1
AdaptedfromDrucker DJ.DiabetesCare. 2003;26:29292940.
GLP1andGIParesynthesizedandsecretedfromthegutinresponse
tofoodintake
31
GLP1=glucagonlikepeptide1;T2DM=type2diabetesmellitus
*P <0.05

GLP1(736amide)infusedat1.2pmol/kg/minfor240minutes.
AdaptedfromNauck MA,etal.Diabetologia.1993;36:741744.
GLP1restoresinsulinandglucagon responsesinaglucosesensitive
mannerinpatientswithT2DM
0.0
0.5
1.0
1.5
2.0
2.5
3.0
*
*
*
*
*
*
*
*
30 0 30 60 90 120 150 180 210 240
Time(Min)
GLP1infusion
CPeptide(nmol/L)
30 0 30 60 90 120 150 180 210 240
Time(Min)
0
5
10
15
20
25
30
*
*
* *
GLP1infusion
Glucagon (pmol/L)
GLP1

Placebo
0
50
100
150
200
250
300
*
*
*
*
*
*
*
30 0 30 60 90 120 150 180 210 240
Time(Min)
GLP1infusion
Glucose(mg/dL) N=10
32
GLP1effectsinhumans
Adapted from
1
Nauck MA, et al. Diabetologia 1993;36:741744;
2
Larsson H, et al. Acta Physiol Scand 1997;160:413422;
3
Nauck MA, et
al. Diabetologia 1996;39:15461553;
4
Flint A, et al. J Clin Invest 1998;101:515520;
5
Zander et al. Lancet 2002;359:824830.
GLP-1 secreted upon
the ingestion of food
1.-cell: cell:
Enhances glucose Enhances glucose- -dependent dependent
insulin secretion in the insulin secretion in the
pancreas pancreas
1 1
3.Liver: 3.Liver:
reduces hepatic glucose reduces hepatic glucose
output output
2 2
2. 2. - -cell: cell:
Suppresses p Suppresses postprandial ostprandial
glucagon glucagon secretion secretion
1 1
4.Stomach: 4.Stomach:
slows the rate of slows the rate of
gastric emptying gastric emptying
3 3
5.Brain: 5.Brain:
Promotes satiety and Promotes satiety and
reduces appetite reduces appetite
4,5 4,5
Insulin gene
transcription and
synthesis
Decreasing apoptosis,Increasing
replication and Neogenesis
SoWhatstheproblem??
http://www http://www
GLP1 secretion in the intestine
DPP4
GLP1
inactive
(>80%ofpool)
Active
GLP1
Meal
DPP4
Intestinal
GLP1
release
GLP1t

=12min
DPP4=dipeptidyl peptidase4;GLP1=glucagonlikepeptide1
AdaptedfromRothenbergP,etal.Diabetes.2000;49(suppl 1):A39.Abstract160OR.
AdaptedfromDeaconCF,etal.Diabetes.1995;44:11261131.
33
ToincreaseGLP1.
Preventdegradation
Createanalogues
InhibitionofDPP4increasesactive
GLP1
GLP1
inactive
(>80%ofpool)
Active
GLP1
Meal
DPP4
Intestinal
GLP1
release
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
Sitagliptin
Vildagliptin
Saxagliptin
DecreaseinHba1cof1%
Weightneutral
Nohypoglycemia
Elderly
Overweight type 2 diabetes
as second / third line
GLP1analogues
Exenatide
Liraglutide
*
Decreaseofhba1c>1%
Weightlossof3 6kgs 6months
Decreaseinwaistcircumference
Littlehypoglycemia
*submittedformarketingauthorisation
Overweight--- BMI>35??
NICEguidelines
DontForget
Diabetesaint justaboutsugar
Treatweight,lipids,BPand.sugar.
Neweragentswithmultiplebenefits
?longtermbenefit
Questions

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