Diabetes Mellitus y enfermedades neurodegenerativas
Transcript of Diabetes Mellitus y enfermedades neurodegenerativas
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Diabetes Mellitus y enfermedades neurodegenerativas
LEOCADIO RODRIGUEZ MAÑAS
JEFE SERVICIO DE GERIATRÍA HOSPITAL UNIVERSITARIO DE GETAFE
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Diabetes Mellitus, deterioro cognitivo y demencia
LEOCADIO RODRIGUEZ MAÑAS
JEFE SERVICIO DE GERIATRÍA HOSPITAL UNIVERSITARIO DE GETAFE
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Estructura de la conferencia
• Conexiones fisiopatológicas • Diabetes y Deterioro Cognitivo • Diabetes y Demencia • Control glucémico, DM y Demencia • Demencia y Control glucémico • Conclusiones
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Carencia de Ensayos Clínicos Controlados en esta población
Carencia de estudios observacionales
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Fisiopatología – diabetes y demencia
Disfunción cogni,va
en diabetes
hipoglicemia
Evento isquémicos
cerebrovasculares
Enfermedad micro vascular ((lesión inducida
por hiperglucemia)
Resistencia insulina
Ausencia alelo ApoE 4
Ausencia de pép,do C
Kodl, et al. Endocrinol Rev 2008
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Amiloide, ¿es un epifenómeno?
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Diabetes y Demencia -‐ Fisiopatología
Luchsinger et al. Eur J Pharmacol, 2008
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Fisiopatología
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Angiopatía amiloide • 216 autopsias • DM tipo 2 y el alelo ApoE ε4 tenían un mayor número de placas
neuríticas y ovillos neurofibrilares en la corteza y el hipocampo
Peila R, Rodriguez BL, Launer LJ. Honolulu-Asia Aging Study. 2002. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies:
The Honolulu-Asia Aging Study. Diabetes, 51:1256–62.
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Fisiopatología Insulina
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Resistencia a la insulina, se asocia con hiperinsulinemia compensatoria y la hiperinsulinemia, (incluso en ausencia de diabetes)
Los receptores de insulina se distribuyen con particular abundancia en el hipocampo y la corteza.
La insulina parece estimular la secreción de β-amiloide e
inhibe la degradación de β-amiloide extracelular.
E Duron. Vascular risk factors, cognitve decline, and dementia. Vascular Health and Risk Management 2008:4(2) 363–381
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Insulina como determinante en la relación diabetes-‐demencia
Sims-Robinson et al. Natur Neurol,2010
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Fisiopatología Estrés oxidativo
Hiperglucemia puede tener un efecto tóxico directo sobre las neuronas, causando “estrés oxidativo” y glicocilación avanzada
Afecta el tejido cerebral Cambios microvasculares
11
Yaffe K, Haan M, Blackwell T, et al. 2007. Metabolic syndrome and cognitive decline in elderly Latinos: findings from the Sacramento Area Latino
Study of Aging study. J Am Geriatr Soc, 55:758–62.
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Disfunción mitocondrial, oxidación y homeostasis de calcio
Sims-Robinson et al. Natur Ver Neurol,2010
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Stefan I. Liochev
Reactive oxygen species and the free radical theory of aging
Free Radical Biology and Medicine Volume 60 2013 1 - 4
http://dx.doi.org/10.1016/j.freeradbiomed.2013.02.011
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Estrés oxida,vo e inflamación
Mitochondrial dysfunction
Age-related diseases
Inactive NF-kβ active NF-kβ
Inflammatory factors
(TNF-α)
NADPH oxidase
O2.- ROS
SIRT1
Interleukins (IL-1β, IL-2, IL-6)
TNF-α
Adhesion molecules (ICAM, VCAM)
Enzymes (iNOS, COX-2)
Chemokines (IL-8, RANTES)
Low grade inflammation
Nucleus
Cytoplasm
Nrf2
O2·- / H2O2
Exercise training Caloric restriction
Age-related chronic oxidative stress
Antioxidants
NQO-1, GCS, HO-1
El Assar et al., FRBM 2013
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NOX
02• -
H202
02• - SOD2
H202
02• -
eNOS BH4
02• -
NO eNOS BH4
02• -
NO
NO
SOD1
H202
NO
X
vasodilation
02• -
H202
02• - SOD2
H202
NO
SOD1
H202
NO
X
defective vasodilation
02• -
ONOO-
youth – successful ageing unsuccessful ageing
ONOO-
NOX
02• -
iNOS NO
02• -
Rodríguez-Mañas et al. Aging Cell 2009
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AGING
Increased oxidants / Decreased antiox. def. / Angiotensin II / Pro-inflammatory factors
OXIDATIVE STRESS INFLAMMATION NOX mitochondria eNOS uncoupling MnSOD
Nrf2
NF-κB
iNOS
TNFα
O2·- H2O2 ONOO-
NO
TXA2/PGH2
COX-2
CARDIOVASCULAR DISEASE
ARTERIAL STIFFNESS INFLAMMATION CVRF
ENDOTHELIAL DYSFUNCTION
Endothelium
Smooth muscle
SIRT
NF-κB
+ +
senescence apoptosis
regeneration repair
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Lesión cerebral en demencia
• TX+: Diabetes presente • TX –. Diabetes ausente
• DEM +: Demencia presente • DEM –: Demencia ausente
Sonnen et al. Arch Neurol. 2009
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La lesión vascular es mas pronunciada en diabé,cos
• ♂ 87 años, diabetes y demencia
Nelson et al. Biochim Biophys Acta. 2009
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Diabetes y cognición: cambios fisiológicos, anatómicos e cogni,vos
Nelson et al. Biochim Biophys Acta. 2009
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Zina Kroner, The Relationship between Alzheimer’s Disease and Diabetes:Type 3 Diabetes? (Altern Med Rev 2009; 14 (4) :373-379)
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Cognitive dysfunction should be added to the list of the complications of diabetes, along with retinopathy, neuropathy, nephropathy and cardiovascular disease.
The frail, elderly pa,ent with diabetes
• Older persons with diabetes are at higher risk than those without diabetes of:
– Cancer mortality and vascular deaths
– Func,onal disability – Geriatric syndromes:
depression – Geriatric syndromes: cogni9ve
impairment
Ageing and Diabetes
Cognitive dysfunction
Falls and fractures
Functional disability and
depression
Cukierman T, et al. Diabetologia. 2005;48(12):2460-9.
CV disease, cancer and all cause
morbidity/ mortality
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When assessed by the Mini-‐Mental State Exam (MMSE) and the Digit Symbol Span tests (DSS), diabetes increased the odds of cogni9ve decline 1.2-‐fold and 1.7-‐fold respec9vely
Cognitive decline as assessed by the MMSE DM (n) No DM (n) OR and 95% CI
Gregg et al 402 584 1.0 (0.8, 1.4)
Fontbonne et al 55 768 1.0 (0.5, 2.2)
Nguyen et al 347 1412 1.1 (0.9, 1.4)
Stewart et al 62 154 1.2 (0.9, 1.6)
Wu et al 585 1204 1.7 (1.2, 2.3)
Kanaya et al 118 632 0.7 (0.3, 1.7)
Total (95% CI) 1569 10014 1.2 (1.05, 1.4)
Cognitive decline as assessed by the DSS DM (n) No DM (n) OR and 95% CI
Fontbonne et al 55 768 2.3 (1.2, 4.3)
Gregg et al 339 5098 1.6 (1.2, 2.2)
Total (95% CI) 394 5866 1.7 (1.3, 2.3)
0.01 0.1 10 100 1
0.01 0.1 10 100 1
Cukierman T, et al. Diabetologia. 2005;48(12):2460-9.
Cogni,ve decline in the elderly diabetes pa,ent
DM= diabetes mellitus
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DM prevalente, DM incidente y Cognición Yaffe K et al., Arch Neurol 2012
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Cognitive dysfunction (MMSE score) is an independent predictor of clinical outcomes in patients with type 2 diabetes, but does not modify the absence of effects of glucose control on these outcomes in the ADVANCE study
Cognitive function was assessed in the 11,140 patients from the ADVANCE study
Cogni,ve dysfunc,on among people with diabetes is associated with morbidity
and mortality
Number of events/patients Favours
intensive Favours standard Intensive
glucose control
Standard glucose control
HR (95% CI)
Major cardiovascular events
All participants 557/5571 590/5569 0.94 (0.84−1.06)
MMSE ≥28 387/4314 417/4375 0.94 (0.82−1.08)
MMSE 24−27 149/1136 155/1095 0.92 (0.74−1.15)
MMSE ≤23 21/117 18/95 0.99 (0.53−1.86)
All cause death
All participants 498/5571 533/5569 0.93 (0.83−1.06)
MMSE ≥28 322/4314 382/4375 0.86 (0.74−0.99)
MMSE 24−27 153/1136 136/1095 1.08 (0.86−1.37)
MMSE ≤23 22/117 15/95 1.22 (0.63−2.35)
HR (95% CI) 0.25 0.5 1.0 2.0 4.0
MMSE (Mini Mental State Examination)
De Galan B.E et al. Diabetologia. 2009;52(11):2328-36
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↑ Progresión demencia en diabé,cos
Xu W et al. Diabetes, 2010
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↑ Progresión demencia en diabé,cos
Xu W et al. Diabetes, 2010
MCI (DCL)
An,cipación 3 años
demencia
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Diabetes tipo 1 y Demencia
• Meta análisis de 33 estudios • Escasos hallazgos (pruebas de velocidad
y flexibilidad mental) • Memoria y aprendizaje, conservados
27
Brands AM, Biessels GJ, de Haan EH, et al. 2005. The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes
Care,28:726–35.
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Diabetes tipo 2 y Demencia • 10.963 personas • Edades entre 47 a 70 años • Seguimiento por 6 años • Relación entre HTA y demencia • Relación entre DM tipo 2 y Demencia
– Atención – Razonamiento lógico – Aprendizaje verbal – Memoria episódica
28
Knopman D, Boland LL, Mosley T, et al. 2001. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology, 56:42–8.
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DM (n) No DM (n) Risk and 95% CI
Hassing et al 38 220 2.1 (0.99−4.4)
Leibson et al 1455 NA 1.7 (1.3−2.0)
Macknight et al 503 5071 1.2 (0.9, 1.7)
Ott et al 689 4532 1.9 (0.9−1.7)
Peila et al 900 1674 1.5 (1.0−2.2)
All participants 2723 10044 1.6 (1.4−1.8)
0.01 0.1 1 10 100
• Development of future demen,a
u The odds of future dementia is increased 1.6-fold
Cukierman T, et al. Diabetologia. 2005;48(12):2460-9.
Development of demen,a in pa,ents with type 2 diabetes
DM= diabetes mellitus
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Relación entre DM y Demencia
30 E Duron. Vascular risk factors, cognitve decline, and dementia. Vascular Health and Risk Management
2008:4(2) 363–381
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Relación entre DM y Demencia vascular
31 E Duron. Vascular risk factors, cognitve decline, and dementia. Vascular Health and Risk Management
2008:4(2) 363–381
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Relación entre DM y enfermedad de Alzheimer
32 E Duron. Vascular risk factors, cognitve decline, and dementia. Vascular Health and Risk Management
2008:4(2) 363–381
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Modulación de la relación DM/Demencia
33
VARONES MUJERES
ü Insuf. Cardiaca ü Enf. Parkinson ü Sint. depresivos ü Historia familiar ü Edad
ü Edad ü Sint. Depresivos ü Glucemia > 109 mg/dl ü IMC < 24,1 Kg/m2
5632 participantes, 65-84 años, seguimiento 7,8 años
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34
Modulación de la relación DM/Demencia
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Estructura de la conferencia
• Conexiones fisiopatológicas • Diabetes y Deterioro Cognitivo • Diabetes y Demencia • Control glucémico, DM y Demencia • Demencia y Control glucémico • Conclusiones
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DM prevalente, DM incidente y Cognición Yaffe K et al., Arch Neurol 2012
36
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Tratamiento hipoglucemiante y cognición
37 Launer LJ et al. Lancet Neurology 2011
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Relación glucemia/riesgo de demencia PACIENTES SIN DIABETES
PACIENTES CON DIABETES
HAZ
ARD
RAT
IO
HAZ
ARD
RAT
IO
5-years Mean Glycemia (mg/dl)
5-years Mean Glycemia (mg/dl)
Crane PK et al., NEJM 2013
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Hypoglycemia and risk of incident dementia
Whitmer RA, et al. JAMA 2009;301:1565-72
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Frequency of hypoglycemic episodes by dementia status
Whitmer RA, et al. JAMA 2009;301:1565-72
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These data suggest that severe hypoglycaemia does not cause cognitive impairment, but confirms that older diabetic patients with dementia are at increased risk of hypoglycaemia.
u Dementia at baseline was a strong independent predictor of severe hypoglycaemia over the subsequent 5 years
u In patients with normal cognition at baseline, severe hypoglycaemias were not associated with further cognitive decline
The Fremantle Diabetes Study recruited patients with diabetes from an urban Australian community u This sample had a mean age of 76 years:
u Dementia was present in 9.3% u Cognitive impairment without dementia in 20%
Time after study entry (years)
Pat
ien
ts r
emai
nin
g f
ree
of s
ever
e h
ypog
lyca
emia
0.6
1
0.8
0.9
0.7
0.5 6 0 1 2 3 4 5
cognitive impairment at baseline normal cognition at baseline
Patients with dementia at baseline
Bruce DG, et al. Diabetologia. 2009;52(9):1808-15.
Dementia and hypoglycaemia
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Resistance variable machines for upper and lower extremity muscles
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Age, 2013
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Conclusiones
Diabetes
neuropada
Pie diabé,co
arteriosclerosis Dificultad visual
nefropada
Diabetes
neuropada
Pie diabé,co
arteriosclerosis
Dificultad visual
nefropada
Declinar cogni,vo
depresión
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• Existe una relación causal entre DM y trastornos de la cognición/Demencia, aunque su naturaleza exacta está por definir
• No conocemos el impacto del control glucémico en la aparición o en la evolución de la demencia, pero…
• La hipoglucemia se asocia a un incremento sustancial del riesgo de desarrollar demencia
• La demencia incrementa el riesgo de hipoglucemias. En estos pacientes los fármacos con bajo riesgo de hipoglucemia están especialmente indicados
• La demencia influye en el impacto funcional de la DM
• La actividad física mejora el status funcional y el control glucémico en estos pacientes, sin riesgo de hipoglucemia.
CONCLUSIONES