Sociedad Peruana de Endocrinologia

XIII Congreso Peruano de Endocrinologia

Agosto 8 a 10, 2013. Lima-Per

Memoria Metablica: Ficcin o realidad

Dr. Jaime E. Villena Chvez
Profesor Principal de Medicina.
Universidad Peruana Cayetano Heredia
Acadmico de Nmero. Academia Nacional de Medicina
Presidente Sociedad Peruana de Endocrinologa

Riesgo de complicaciones microvasculares

vs A1C en Diabetes tipo 1
Resultados del DCCT
20
Progresion de Retinopatia
Progresin de neuropatia
Porgresin de micralbuminuria

RR

15
10

5
0

A1C (%)
Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254

10

11

12

DCCT: Terapia intensiva reduce y mantiene

significativamente la HbA1c
11

Intensiva
Convencional

Grupo convencional
alentado a pasar al
tratamiento intensivo|

HbA1c (%)

10
9
8
7
6
0

1 2 3 4 5 6 7 8 9
DCCT

DCCT

Final

Ao
Adaptado de: N Engl J Med 1993;329:97786, EDIC: JAMA 2002287:25639

3 4
EDIC

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

During DCCT, intensive insulin therapy in people with type 1

diabetes signicantly reduced HbA1c rela=ve to those
receiving conven=onal treatment. The intensively-treated
group achieved a mean HbA1c of 7.1%, while the
conven=onally-treated pa=ents had HbA1c of approximately
9.0%. During the EDIC (Epidemiology of Diabetes
Interven=on and Complica=ons research group) follow-up
of the DCCT cohort, all pa=ents were encouraged to adopt
intensive insulin therapy. During this =me, HbA1c stablised
to a similar level (just over 8%) in both treatment groups.

% de pacientes con
progresin de 3 etapasn

Efecto persistente del control glucmico sobre la

progresin de retinopata

60
50
40
30
20
10

A1C (%)

10
9

Seguimiento a 4 aos despus

del DCCT

Terapia intensiva
75% reduccin
de riesgo

76% reduccin
de riesgo

Fin del DCCT

Terapia convencional

Fin del seguimiento

9.1
8.2

7.2

7.9

6
DCCT mediana a los
6.5 aos
DCCT. N Engl J Med. 2000;342:381-389

Mediana a los 4 aos de seguimiento

Reduccin a largo plazo del riesgo microvascular

en Diabetes tipo 1. DCCT-EDIC

A1C

12
%
10
%
8%

6%

P<0.00
1
DCCT
Fin de
terapia

P<0.00 P=0.61
1
EDIC EDIC
Ao 1 Ao 7

DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569

Convencional
Progresin de retinopata (incidencia

Intensivo

No. Evaluados
Convencional
Intensivo

Aos en EDIC
169
191

203
222

220
197

581
596

158
170

192
218

200
180

DCCT-EDIC: Riesgo a largo plazo de

complicaciones macrovasculares
Cualquier desenlace CV

Convencional

0.12

Intensivo

10%

8%

6%

P < 0.001 P < 0.001

DCCT
Fin del
tratamiento
randomizado

EDIC
Ao 1

P = 0.61

EDIC
Ao 7

Cumulative Incidence

Hemoglobin A1C

12%

42% reduccin del

riesgo P = 0.02

0.10
Convencional

0.08
0.06
0.04

Intensivo

0.02
0.00

4 6 8 10 12 14 16 18 20
Aos desde el enrolamiento

*Diabetes Control and Complications Trial (DCCT) finaliz y el

Epidemiology of Diabetes Interventions and Complications (EDIC)
empez el ao 10 n(1993). Media de seguimiento: 17 aos.

DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569. Copyright 2002 American Medical Association.
All rights reserved. | Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Copyright 2005 Massachusetts
Medical Society. All rights reserved.

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

DCCT-EDIC: Long-term Risk of Macrovascular Complica=ons

At the end of the randomized treatment phase in the Diabetes Control
and Complica=ons Trial, the research group found a dierence in the
concentra=on of hemoglobin A1c between the pa=ents with type 1
diabetes in the intensive treatment group and those in the
conven=onal treatment group. At the end of the trial, there was a
nonsignicant reduc=on in cardiovascular outcome in the intensively
treated group. The trial ended at approximately 9 years; aPerward,
there was convergence of treatments and similar levels of glycemic
control were achieved. There was persistent benet, however, among
the intensively treated group such that there was a sta=s=cally
signicant reduc=on in cardiovascular disease when compared to the
conven=onally treated group in the follow-up phase (up to 20 years) of
the study. These data would indicate that 10 years of intensive
treatment yielded a cardiovascular benet during the rst 10 years
that was sustained and became greater in the follow-up phase.

Sustained Effect of Intensive Treatment of Type 1

Diabetes Mellitus on Development and Progression of
Diabetic Nephropathy: The Epidemiology of Diabetes
Interventions and Complications (EDIC) Study

Micralbuminuria: 28 g/min, equivalente a 40 mg/24 horas

JAMA. 2003;290(16):2159-2167. doi:10.1001/jama.290.16.2159!

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

. A, Prevalence at the end of the Diabetes Controland

Complications Trial (DCCT) and during the Epidemiology
of Diabetes Interventionsand Complications (EDIC)
study. The differences between the 2 treatment
groupsare significant at each time point after DCCT
closeout (P<.001). B, Cumulative incidence of new
cases in the EDIC studyfor those participants in the
intensive- and conventional-treatment groupswith normal
albuminuria at the beginning and end of the DCCT. The
differencein cumulative incidences is significant by the
log-rank test (P<.001).

Sustained Effect of Intensive Treatment of Type 1

Diabetes Mellitus on Development and Progression of
Diabetic Nephropathy: The Epidemiology of Diabetes
Interventions and Complications (EDIC) Study

Albuminuria: 208 g/min, equivalente a 300 mg/24 h

JAMA. 2003;290(16):2159-2167. doi:10.1001/jama.290.16.2159!

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

Albuminuria defined as albumin excretion rate 208

g/min,equivalent to 300 mg/24 h. A, Prevalence of
clinical albuminuria at the endof the Diabetes Control
and Complications Trial (DCCT) and during the
Epidemiologyof Diabetes Interventions and
Complications (EDIC) study. The differencesbetween
the treatment groups are significant at each time point
after DCCTclose-out (P<.01). B, Cumulative incidence
ofnew cases in the EDIC study for those participants in
the intensive- and conventional-treatmentgroups with
either normoalbuminuria or microalbuminuria at the
end of theDCCT. The difference in cumulative
incidences is significant by the log-rank-test.(P<.001)

Sustained Effect of Intensive Treatment of Type 1

Diabetes Mellitus on Development and Progression of
Diabetic Nephropathy: The Epidemiology of Diabetes
Interventions and Complications (EDIC) Study

Hipertensin >140/90 mmHg

JAMA. 2003;290(16):2159-2167. doi:10.1001/jama.290.16.2159!

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

Prevalence of hypertension (defined as blood pressure

>140/90 mmHg) at the end of the Diabetes Control and
Complications Trial (DCCT) andduring the Epidemiology
of Diabetes Interventions and Complications
(EDIC)study for participants in the intensive vs
conventional-treatment groups.The aggregate odds
reduction with intensive vs conventional therapy of
emergenthypertension during the EDIC study, adjusted
for DCCT mean arterial pressure,was 40.4% (95%
confidence interval, 33.7%-46.5%; P<.001).!

Complicaciones Microvasculares :
Seguimiento del EDIC

Pirola L y col. Nature Reviews Endocrinology 2010;6:685

UKPDS: Carga de la diabetes tipo 2

Aos de seguimiento

15
14
13
12
11
10
9
8
7
6
5
4
3
2
1

Complicaciones
Ataque cardiaco
ACV
Retinopatia

27 pacientes
10 pacientes
23 pacientes

Mortalidad prematura
Muerte por diabetes
28 pacientes
Expectativa de vida
5-7 aos

100 pacientes - edad 55

UKPDS 33. Lancet 1998;352:837-53

Panzram G et al. Diabetologia 1987;30:123-31

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

Burden of type 2 diabetes

Type 2 diabetes is associated with a heavy burden of
morbidity and mortality arising from long-term complica=ons
of the disease.
Data from the UKPDS main analysis predict that for every 100
pa=ents diagnosed at age 55 years, 27 will suer a myocardial
infarc=on, 10 will have a stroke, 23 will develop diabe=c
re=nopathy (the leading cause of new cases of blindness in
western popula=ons), and 28 will die from a cause related to
their diabetes.
Pa=ents diagnosed with type 2 diabetes at this age can
expect to lose about 5-7 years of life expectancy, on average.

Riesgo de Eventos microvasculares

vs HbA1c en Diabetes tipo 2
Resultados del anlisis epidemiolgico del UKPDS
10

Hazard ratio

Cambio en 37% por cada

cambio de 1% de Hb A1C

6
4
2
0
5
10

Stratton IM et al. BMJ. 2000;321:405-412

7
A1C (%)

UKPDS: la disminucin de HbA1c da como resultado

una reduccin del riesgo relativo de complicaciones

Reduccin del riesgo relativo (%)

asociado con una cada de 1% en HbA1c

Cualquier
parmetro
relacionado
con la diabetes

Muerte
relacionada Cualquier
Infarto
Extraccin Enfermedad
Enfermedad
causa de
con la
Accidente cedel
vascular
de
diabetes mortalidad microvascular cataratas perifrica miocardio rebrovascular

-5
-10
-15
-20
-25

21%
*

21%
*

14%
*

14%
*

19%
*

-30
-35
-40

37 %

-45

-50

43%
*

*p<0.0001 vs valor basal; p=0.035

Amputacin de extremidad inferior o enfermedad vascular perifrica fatal

Stratton I y cols. BMJ 2000;321:40512.

12%

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

En el estudio UKPDS se aleatorizaron aproximadamente 4,000 individuos con nuevo

diagns=co de DMT2 para recibir terapia intensiva de insulina o AOHs (agentes
orales hipoglucemiantes) o para la modicacin convencional del es=lo de vida.
Despus de 10 aos, los valores de HbA1c en los dos grupos fueron 7.0% y 7.9%,
respec=vamente.1
El anlisis de los datos del estudio UKPDS mostr una correlacin entre los valores
altos de HbA1c y el alto riesgo de complicaciones micro y macrovasculares
relacionadas con la diabetes.1
Cada 1% de reduccin del valor de HbA1c estuvo asociado con una reduccin de 21%
del riesgo rela=vo de cualquier parmetro relacionado con la diabetes (p<0.0001).1.
La reduccin del riesgo de complicaciones fue mayor para la enfermedad
microvascular (37% global; p<0.0001) en comparacin con la enfermedad
macrovascular (infarto del miocardio 14%; p<0.0001).
No se observ un umbral para el cambio en el riesgo de complicaciones, por lo que
cualquier reduccin en el valor de HbA1c puede reducir el riesgo de complicaciones.1
Sin embargo, como la terapia intensiva reduce la hiperglucemia en mayor grado que
la terapia convencional, se recomiendan los regmenes intensivos para reducir el
riesgo de complicaciones a largo plazo.

UKPDS monitoreo post estudio

1997

2002

2007
# con datos disponibles

# Cohorte
2,118
Sulfonilurea/Insulina

Clnica

Cuestionario

1,010
Sulfonilurea/Insulina
P

880
Convencional

Clnica

Cuestionario

379
Convencional

P
279
Metformina
Edad media
628 aos

Clnica

Cuestionario

136
Metformina

Mortalidad 44% (1,852)

Perdidos 3.5% (146)

Cambios de HbA1c post finalizacin del UKPDS

Sulfonilurea/insulina vs Tto convencional
Resultados
UKPDS

N Eng J Med 2008;359:1577-89

Mean (95%CI)

UKPDS ptm: HR cualquier evento relacionado a diabetes.

Control intensivo (Ins/SU)vs Convencional

HR (95%CI)

UKPDS 80. N Eng J Med 2008;359:1577-89

UKPDS ptm:HR Enfermedad Microvascular

Tratamiento intensivo(SU/Ins) vs convencional

HR (95%CI)

UKPDS 80. N Eng J Med 2008;359:1577-89

UKPDS ptm: HR Infarto de miocardio

Tratamiento intensivo(SU/Ins) vs convencional

HR (95%CI)

UKPDS 80. N Eng J Med 2008;359:1577-89

UKPDS ptm: HR mortalidad total

Tratamiento intensivo(SU/Ins) vs convencional

HR (95%CI)

UKPDS 80. N Eng J Med 2008;359:1577-89

HR (95%CI)

UKPDS ptm: HR evento relacionado a diabetes

Tratamiento intensivo (met) vs convencional

UKPDS 80. N Eng J Med 2008;359:1577-89

UKPDS ptm: HR Infarto de miocardio

Tratamiento intensivo (met) vs convencional

HR (95%CI)

HR (95%CI)
HR (95%CI)

UKPDS 80. N Eng J Med 2008;359:1577-89

HR (95%CI)

UKPDS ptm: HR Mortalidad total

Tratamiento intensivo (met) vs convencional

HR (95%CI)

UKPDS 80. N Eng J Med 2008;359:1577-89

HR (95%CI)

UKPDS ptm: HR Enf. Microvascular

Tratamiento intensivo (met) vs convencional

HR (95%CI)
HR (95%CI)

UKPDS 80. N Eng J Med 2008;359:1577-89

Lograr un control metablico tempranamente

genera un legado metablico bueno
Median HbA1c (%)

Convencional
Metformina

8
7
Efecto de legado
6
0
UKPDS 1998

1997

Holman et al 2008

2007

La diferencia en HbA1c se perdi el 1er

ao pero los pacientes en el brazo intensivo
aun tenan menor incidencia de :
Reduccin de 24% en Co. microvasculares
Reduccin del 15% en Infarto de Miocardio
Reduccin del 13% en mortalidad por todas las
causas.
HbA1c=haemoglobin A1c.
Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set.
Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/. Accessed
12 September, 2008; Holman RR, et al. N Engl J Med. 2008; 359: 1577
1589; UKPDS 33. Lancet. 1998; 352: 837853.

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

Achieving early glycaemic control may generate a good legacy eect

In the UKPDS, newly diagnosed pa=ents were assigned to conven=onal
or intensive therapy arms. Those in the intensive therapy arm
achieved early and op=mal glycaemic control (mean HbA1c 7.0%,
compared with 7.9% for conven=onal therapy).
During the post-trial follow up from 19972007, the dierence in
HbA1c levels between the intensive and conven=onal arms was lost
aPer just 1 year. Despite this, pa=ents who ini=ally received intensive
therapy had a lower incidence of any complica=on.
This suggests that strict glycaemic control, early in the disease course,
leaves a benecial legacy eect of reduced risk of complica=ons later.
Therefore, it is crucial to achieve glycaemic targets early in the disease.

UKPDS: Efecto de Legado metablico de la Terapia

de la Glucosa
Good Diabetes control for 10 years aPer diagnosis will prevent late
complica=ons even if the condi=on deteriorates thereaPer.
Despus de una mediana seguimiento de 8.8 aos post-estudio
Desenlace agregado
1997
2007
Cualquier evento en relacion a DM
RRR:
12%
9%
P: 0.029
0.040
Enfermedad microvascular

RRR:
P:

25%
0.009

24%
0.001

Infarto de miocardio

RRR:
P:

16%
0.052

15%
0.014

Mortalidad global

RRR:
P:

6%
0.44

13%
0.007

RRR = Reduccin del reisgo relativo P = Log Rank

Holman RR, et al. New England Journal of Medicine 2008; 359:1577-1589

Pacientes que alcanzan metas de tratamiento

intensivo a una media de 7.8 aos (%)

Eficacia de la Intervencin sobre mltiples factores de reisgo

en sujetos de alto riesgo (DM-2 con Micralbuminu-ria):
Steno-2
Terapia Intensiva

80

Terapia Convencional
P=0.21

P<0.001

70

P=0.19

60

P=0.001

50
40
30
20

P=0.06

10
0

Hb A1c
<6.5%

Colesterol
<175 mg/
dl

Gde P et al. N Engl J Med 2003;348:383-393.

Triglicridos PA Sistlica PA Diastlica

<150 mg/dl <130 mm
<80 mm Hg
Hg

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

Ecacy of mul=ple risk factor interven=on in high-risk subjects (type 2 diabetes with
microalbuminuria): Steno-2
The Steno-2 study showed the eect of a mul=ple risk factor interven=on strategy in
160 subjects with type 2 diabetes with microalbuminuria. Although all these subjects
had type 2 diabetes, the results suggest that mul=ple risk factor interven=on may also
be highly benecial in subjects with the metabolic syndrome. Subjects in the intensive
therapy group were to follow a reduced-fat diet and exercise regularly, oered
smoking cessa=on counseling, prescribed an angiotensin-conver=ng enzyme (ACE)
inhibitor or angiotensin IIreceptor blocker (ARB) regardless of blood pressure, and
received vitamin supplementa=on and aspirin; stepwise an=glycemic and
an=hypertension medica=ons were also prescribed as well as lipid-modifying therapy
with a sta=n and/or brate. Subjects receiving intensive therapy were much more
likely to reach their total cholesterol goal (<175 mg/dL) and systolic blood pressure
goal (<130 mm Hg) and to rou=nely use ACE inhibitors or ARBs (data not shown). Note
that it was much more dicult to achieve systolic blood pressure goal than diastolic
blood pressure goal. The dierence between intensive and conven=onal therapy for
hemoglobin A1c (glycosylated hemoglobin) was only 0.6%.

Intervencin multifactorial en DM-2: Steno-2

Treatment strategies for pa/ents with T2DM should be individually tailored according to
pa/ents risk-factor proles, and appropriate treatment targets should be dened.
Intervencin multifactorial en base a metas en 7.8 aos
Variable

Riesgo relativo
(95% Cl)

Nefropata

0.39 (0.17-0.87)

0.003

Retinopata

0.42 (0.21-0.86)

0.02

Neuropata
Autonmica

0.37 (0.18-0.79)

0.002

Neuropata
Periferica

1.09 (0.54-2.22)

0.66

Enfermedad
cardiovascular

0.47 (0.24-0.73)

0.008

Terapia Intensiva mejor

0
Gaede P, et al. N Engl J Med 2003;348:38393.

Terapia Convencional mejor

1.0

2.0

STENO-2: Reduccin dramtica en eventos CV

en pacientes con DM-2 con intervencin
farmacolgica
40
35

Terapia intensiva

Numero de eventos
Cardiovascular es

30

Terapia convencional

25
20
15
10
5
0
ACV
Muerte CV

Revascularizacin
Infarto de Cirugia
Miocardio Coronaria

Gaede P, et al. N Engl J Med. 2003;358:580591.

Intervencin
coronaria
percutnea

Amputacin

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

STENO-2: No Other Clinical Trial of Pa=ents With Type 2

Diabetes Has Shown Such a Drama=c Reduc=on in
Cardiovascular Events With a Pharmacologic Interven=on
The pa=ents in the STENO-2 study had fewer deaths from
cardiovascular disease, had fewer strokes and myocardial
infarc=ons, and had less need for bypass surgery or
angioplasty and revasculariza=on or amputa=ons when
compared to the pa=ents randomized to the conven=onal-
therapy group.

Manejo intensivo de multiples factores de

riesgo en pacientes con DM-2: STENO-2
Punto fin al compuesto* (%)

60

N=160; seguimiento= 7.8 aos

50
Terapia convencional

40

20% Reduccin
absoluta de
riesgo

30
20

Tratamiento agresivo de:

Terapia intemnsiva

10
0

12

24

36

48

60

72

Months of Follow-up

84

96

Micralbuminuria con
IECAS, ARA 2, combinacion
Hiperglicemia
Hypertension
Dislipidemia
Prevencion secundaria
de ECV

Punto final compuesto: terapia convencional (44%) y tratamiento intensivo (24%).

*Muerte CV,, IMA no fatal, CABG, PCI, Acv no fatal, amputacin o ciruga por E. vascular perifrica.
Modificacin de comportamiento y terapia farmacolgica..
Adaptado de Gaede P et al. N Eng J Med 2003;348:383393.

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

Intensive mul=ple risk factor management in pa=ents with type 2

diabetes: STENO-2
The STENO-2 study randomized 160 pa=ents (mean age of 55 years)
with type 2 diabetes and microalbuminuria to targeted intensive
mul=factorial interven=on or conven=onal treatment of cardiovascular
risk factors for 8 years. The targeted interven=on involved
pharmacologic therapy and behavior modica=on targe=ng
dyslipidemia, hyperglycemia, hypertension, microalbuminuria, and
secondary preven=on of cardiovascular disease with aspirin. The
primary end point was a composite of nonfatal myocardial infarc=on,
cardiovascular death, revasculariza=on, nonfatal stroke, and
amputa=on. The hazard ra=o for the primary end point in the intensive
group was 0.47 (95% CI, 0.22 to 0.74; P=0.01).

Steno-2 Study: Intervencion multifactorial en DM-2

Gaede P, et
al. N Engl J
Med.
2008;358:58
0591.
Copyright
2008
Massachuset
ts Medical
Society. All
rights
reserved.

Cumulative Incidence
Cardiovascular Event (%)

80
70
60
50

P<0.001

40
30

Terapia intensiva

20
10
0

No. en riesgo
Terapia intensiva
Terapia convencional

Terapia convencional

10 11 12 13

Aos de seguimiento
80
80

72
70

65
60

61
46

56
38

50
29

47 31
25 14

Steno-2 Study: Mul=factorial Interven=on for Type 2 Diabetes

The mul=factorial interven=on used in the Steno-2 study markedly improved the cumula=ve
incidence of cardiovascular events. Note that the curves in the graph start to splay at 1 year.

Comparacin de 3 EC sobre control intensivo

de glucosa y eventos CV
ACCORD

ADVANCE

VADT

10,251

11,140

1,791

Edad

62

66

60

Dx de Dm, aos

10

11.5

% varones

39

42

97

Historia de ECV %

35

32

40

IMC Kg/m2

32

28

31

Media de HbA1c, %

8.1

7.2

9.4

% en insulina

35

1.5

52

Adaptado de Skyler y col Diabetes care 2009;32:187

Caracteristicas clnicas y efectos del tratamiento intensivo

de la DM vs el estandar en eventos CV y mortalidad
ACCORD, ADVANCE VADT
10,251
11,140
1,791

n
Duracin del estudio,
aos

3.5

5.0

5.6

Meta de Hb A1c, %

<6

6.5

Eventos CV, %

10

13

Mortalidad total, %

22 *

6.5

Mortalidad CV, %

35**

12

25

*p=0.04 ** p=0.02
Frier BM y col. Diabetes Care.2011; 34 (Supplement 2): S132-S137

Lograr un control metabolico tardio puede generar un legado

metabolico malo, que puede aumentar las complicaciones.
Antes de entrar al brazo intensivo
de tratamiento del estudio VADT

Despus de entrar al brazo intensivo de tratamiento del estudio.

9.5
9.0
8.5

HbA1c (%)

8.0
7.5
7.0

Generacin de un legado
metablico malo puede
las complicaciones

6.5

Ideal HbA1c

6.0
1
2
3
4
5
6
7
8
Tiempo desde el diagnstico (aos)

HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus.

Adapted from Del Prato S. Diabetologia. 2009; 52: 12191226.

10

11

12

13

14

15

16

17

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

Achieving late glycaemic control may generate a bad legacy eect

The lack of eect of intensive therapy on reducing risk of complica=ons in VADT is
likely to be due to the long-term consequences of an extended period of poor
glycaemic control.
The VADT study included pa=ents with poorly controlled T2DM with an inadequate
response to maximal dose oral or insulin therapy (mean =me since diagnosis = 11.5
years).1 At the =me of diagnosis, it is likely that pa=ents had high HbA1c levels and
were started in dietary therapy and/or oral hypoglycaemic agents that improved but
did not normalise glycaemic control.
Over =me it is likely that HbA1c levels worsened progressively prior to entering the
VADT study. Intensive therapy implemented in the trial resulted in a rapid lowering
of plasma glucose levels and subsequent maintenance if HbA1c was close to target.
However, this =me course is far from ideal and may have generated a bad glycaemic
legacy, priming pa=ents for a high risk of complica=ons later in the disease, even if
they were then under improved glycaemic control.2

Progression of incipient diabetic retinopathy during

good glycemic control.
35 perros en 4 grupos: normales, diabticos por aloxano
con buen control por 5 aos (BC) , mal control por 5
aos (MC) y mal control por 2.5 aos seguido de buen
control por 2.5 aos (MBC)
Retinopata desarrollaron durante los 5 aos de mal control, la cual se previno si se instauraba un buen control a
los 2 meses.
En el grupo de MBC la retinopata estuvo ausente a los
2.5 aos, pero luego progres a pesar del buen control
subsiguiente.

Engerman Rl y col. Diabetes. 1987 Jul;36(7):808-12

Islet Transplantation Inhibits Diabetic Retinopathy in

the Sucrose-fed Diabetic Cohen Rat
Despus de 26 semanas de diabetes las ratas desarrollan
aumento de clulas endoteliales capilares, prdida de pericitos, vasos acelulares ocluidos y microaneurismas
Despus de 6 semanas de diabetes el trasplante pancretico disminuye la perdida de pericitos (2950 140 vs 2390
40 en controles, P < 0.01). Persistan capilares acelulares ocluidos (31 14 vs 8 2, P < 0.01).
El trasplante despus de las 12 semanas solo parcialmente restaura la composicin capilar y no previene la
oclusin de vasos retinales

Hammes HP y col. Invest Ophthalmol Vis Sci 1993;34:2092-2096.

Fisiopatologa de la Memoria
cardiometabolica
Hay evidencia que el incremento del estrs oxidativo a
nivel mitocondrial seria responsable de interactuar con
protenas de larga vida media, modificndolas en su
estructura y funcin.
Esto lleva a la formacin de productos avanzados de
glicosilacin, condicionando progresin de complicaciones micro y macrovasculares.

Jermendy G. Medical Hypotheses 73 (2009) 7379

Efecto de la hiperglicemia sobre

el estrs oxidativo
Hiperglicemia

Mitocondria
Mitocondria

Ncleo

Cromatina

AGEs: Productos finales de glicosilacion; GAPDH, gliceraldehide 3-fosfato dehidrogenasa; H, histonas; M, metilacion;
MCP-1, monocito chemoatractant protein-1; NF-B, factor nuclear B; PARP, poli(ADP-ribose) polimerasa; PKC, proteina
kinasa C; RAGE:receptor de AGE; ROS: especies reactivas de; VCAM-1, molecula de adhesion vascular -1.
Aschner PJ y col. Diabetes Technology & Therapeutics. 2012;14 (Supplement 1):s68-75

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

Mechanisms involved in the eect of hyperglycemia on superoxide anion produc=on in the

mitochondria of
endothelial cells that lead to overac=va=on of pathways responsible for the metabolic memory
of complica=ons in diabetes.
Epigene=c changes produced by histone methyla=on depicted in the lower right corner also
contribute to the metabolic
memory (see text for full explana=on). AGEs, advanced glyca=on end-products; GAPDH,
glyceraldehyde 3-phosphate
dehydrogenase; H, histones; M, methyla=on; MCP-1, monocyte chemoaoractant protein-1; NF-
jB, nuclear factor jB; PARP,
poly(ADP-ribose) polymerase; PKC, protein kinase C; RAGE, advanced glyca=on end-products
receptors; ROS, reac=ve
oxygen species; VCAM-1, vascular cell adhesion molecule-1.

Mecanismos epigenticos de la memoria

metablica
Hiperglicemia
Infeccion,
drogas

Modulacion epigenetica
Metilacion de DNA
Metilacion de histonas
Acetilacion de histonas
Rna no codificante
Reposicionamiento
de nucleosomas

Set 7
LSD1

DNMT1

Metabolismo:
Estrs oxidativo
MAPK
Productos Avanzados de g;icosilacion (AGES)

Regulacin de la
expresin gentica
Complicaciones micro y Macrovasculares,
Aterosclerosis
Falla orgnica terminal
MAPK: Quinasa activada por nitrgenos, LSD1: demtilasa especifica de lisina: DNMT1: DNA metil trnsferasa
Jayaraman S Circulation Research 2012;110:1039-1041

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

A model depicting the epigenetic mechanisms

involved in metabolic memory. Environmental cues such

as hyperglycemia can employ epigenetic mechanisms to alter

gene expression, leading to diabetes-associated complications.
Exposure to transient hyperglycemia is associated with metabolic
changes including the engagement of the mitogen activated
protein kinase (MAPK) pathway. The resulting nuclear
translocation of Set7 influences gene expression as a
consequence of interaction with DNA methyl transferase 1
(DNMT1), which in turn is influenced by lysine specific
demethylase 1 (LSD1).

Conclusiones
La hiperglicemia produce cambios estructurales y
funcionales irreversibles sobre las proteinas, actuando a travs de mecanismos epigenticos.
Existe evidencia experimental y clnica de este fenmeno
El control metablico temprano de la diabetes e-vitar
o retardar la aparicin de complicaciones, no as si
se optimiza el control mas tardamente.