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Department of Medical Psychology and Behavioral Neurobiology
Manfred Hallschmid
Central nervous effects of insulin in health and disease
Rio de Janeiro,25 November 2013
Overview
� Diabetes, obesity and Alzheimer‘s disease: a fatal connection?
� Insulin in the brain, and the nose-brain pathway
� The role of central nervous insulin signaling in Alzheimer‘s disease
� Improving brain insulin signaling as a therapeutic perspective
Overview
� Diabetes, obesity and Alzheimer‘s disease: a fatal conn ection?
� Insulin in the brain, and the nose-brain pathway
� The role of central nervous insulin signaling in Alzheimer‘s disease
� Improving brain insulin signaling as a therapeutic perspective
� Most common form of dementia in the elderly
Alzheimer‘s disease
Alois Alzheimer Auguste Deter
Tübingen,Germany
� Most common form of dementia in the elderly
Alzheimer‘s disease
� No efficient treatments are available� Estimated to affect more than 24 million individuals worldwide
(Ballard et al., Lancet 2011)
Alois Alzheimer Auguste Deter
Alzheimer‘s disease
� most common form of dementia in the elderly� estimated to affect more than 24 millions individuals worldwide
(Ballard et al., Lancet 2011)
Number of Americans >65 yrs with Alzheimer‘s disease
Am
eric
ans
in M
illio
ns
13.5
American Alzheimer’s Association 2010
Num
ber
ofA
mer
ican
s in
5.1
2010 2050
Obesity (BMI ≥ 30) in US adults
1985
Behavioral Risk Factor Surveillance System, CDC.
No Data <10% 10%–14%
2009
Obesity (BMI ≥ 30) in US adults
Behavioral Risk Factor Surveillance System, CDC.
No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%
Prevalence of type 2 diabetes
… currently estimated to affect more than 347 million people worldwide(Danaei et al., Lancet 2011)
Diabetologia (2005) 48: 2460-2469
Diabetes and dementia: Epidemiological data
25 Studies, 8656 patients with type 2 diabetes, 2-18 yrs. follow up:
Diabetes increases the relative risk of future:
• cognitive decline RR 1.7• Alzheimer’s disease RR 1.2-2.3
Cognitive dysfunctions in diabetes mellitus: risk f actors
Cognitive Dysfunction in
InsulinResistance
Hyperglycemia-inducedEnd Organ Damage
“Microvascular Disease”“Macrovascular Disease”
CerebrovascularAccident
Kodl & Seaquist, Endocrine Rev 2008
Cognitive Dysfunction inDiabetes Mellitus
Hypoglycemia
Absence ofApo ε4 Allele
Absence ofC-Peptide
Overview
� Diabetes, obesity and Alzheimer‘s disease: a fatal conn ection?
� Insulin in the brain, and the nose-brain pathway
� The role of central nervous insulin signaling in Alzheimer‘s disease
� Improving brain insulin signaling as a therapeutic perspective
Insulin receptors in the brain
Cortex Hippocampus
� Saturable, active transport of insulin across the blood-brainbarrier
� There is no robust evidence for
Wickelgren, Science 1998
Hypothalamus
� There is no robust evidence forinsulin secretion within the CNS
� Central nervous insulin effects areassumed to stem from circulatinginsulin accessing the brain
Euglycemic insulin infusion in humans
min
-60 0 60 120 180 240 300 360
Ser
um In
sulin
(pm
ol/l)
10
100
1000
10000
100000
Kern et al., Neuroendocrinology 2001
Blo
od G
luco
se (
mm
ol/l)
0.0
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
min
-60 0 60 120 180 240 300 360
Euglycemic insulin infusion in humans improves memory fun ction
min
-60 0 60 120 180 240 300 360
Ser
um In
sulin
(pm
ol/l)
10
100
1000
10000
100000
Word list recall
*
Wor
ds re
calle
d 20
22
24
Kern et al., Neuroendocrinology 2001
Blo
od G
luco
se (
mm
ol/l)
0.0
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
min
-60 0 60 120 180 240 300 360
low insulinhigh insulin
Wor
ds re
calle
d
10
12
14
16
18
Intranasal insulin administration
40 IU Insulin
Insulin in plasma (RIA)
Samples –10 0 +10 +20 +30 +40 +50 +60 +70 Min
Insulin in plasma (RIA)
Insulin in cerebrospinalfluid (RIA)
5 Men3 Women
**
Cerebrospinal Fluid Blood
60
80
Insulin
20
40
pmol
/L
*Placebo
Insulin
Intranasal insulin administration and CSF levels of insulin
Born et al., Nat Neurosci 2002
-10 0 10 20 30 40 60 80
20
30
40
min-10 0 10 20 30 40 60 80
6
10
40 IU
Placebo
min
pmol
/L
pmol/L
40 IU
Placebo
Placebon = 197 women12 men
Placebo Placebo
Longterm administration of i.n. insulin
Insulin 4 x 40 IU/day
0 2 4 6 8 10weeks
Placebon = 197 women12 men
Benedict et al., Psychoneuroendocrinology 2004
Placebon = 197 women12 men
Placebo Placebo
Baseline
test session
1st treatment
week
test session
8th treatment
week
test session
Longterm administration of i.n. insulin: Declarativ e memory
Insulin 4 x 40 IU/day
0 2 4 6 8 10weeks
Placebon = 197 women12 men
Benedict et al., Psychoneuroendocrinology 2004
Placebon = 197 women12 men
Placebo Placebo
Baseline
test session
1st treatment
week
test session
8th treatment
week
test session
Longterm administration of i.n. insulin: Declarativ e memory
Schnitzel
Loneliness
Soup
Nipple
Flag
Ananas
Sun flower
Insulin 4 x 40 IU/day
0 2 4 6 8 10weeks
Placebon = 197 women12 men
Benedict et al., Psychoneuroendocrinology 2004
Cheese
Sex
Wind
Salad
Girlfriend
Fear
Bend
Rye field
Wor
ds r
ecal
led
91011121314
PlaceboInsulin
n.s.
Declarative memory after 8 weeks of treatment
Longterm administration of i.n. insulin: Declarativ e memory
immediate delayed
Wor
ds r
ecal
led
123456789
p<0.04
Benedict et al., Psychoneuroendocrinology 2004
Potential mechanisms of memory improvement by insuli n
� Enhancement of local cerebral glucose utilization via GLUT-4/8
(Henneberg & Hoyer, Neurosci Lett 1994; Vannucci et al., Brain Res 1998; Schulingkamp et al., Neurosci Biobehav Rev 2000; Bingham et al., Diabetes 2002)
� Enhancement of cholinergic activity
(Figlewicz et al., Brain Res 1993; Messier & Destrade, Psychobiol 1994; Hajnal et al., Brain Res 1998; Kopf & Baratti, Neurobiol Learn Mem 1999)
� Modulation of synaptic activity via effects on NMDA and AMPA signaling in LTP
(Christie et al., J Neurochem 1999; Man et al., Neuron 2000; Skeberdis et al., PNAS 2001)
� Interaction with endocrine signals relevant to memory formation, e.g. glucocorticoids?
(Stranahan et al., Nat Neurosci 2008)
Placebon = 208 women12 men
Placebo Placebo
BMI < 25 kg/m2
Longterm administration of i.n. insulin
Hallschmid et al., Diabetes 53(11) 2004
Insulin 4 x 40 IU/day
0 2 4 6 8 10weeks
Placebon = 208 women12 men
Bod
y w
eigh
t (kg
)
79
80
81
* **
Body fat
p<0.05
kg
11
12
13
14
Longterm administration of i.n. insulin decreases body fat
Treatment duration (weeks)
0 1 2 3 4 5 6 7 8 follow up
Bod
y w
eigh
t (kg
)
77
78
79
PlaceboInsulin
kg
8
9
10
11
placeboInsulin
4.5 months
Hallschmid et al., Diabetes 53(11) 2004
Overview
� Diabetes, obesity and Alzheimer‘s disease: a fatal conn ection?
� Insulin in the brain, and the nose-brain pathway
� The role of central nervous insulin signaling
in Alzheimer‘s disease
� Improving brain insulin signaling as a therapeutic perspective
Cognitive dysfunctions in diabetes mellitus: risk f actors
Cognitive Dysfunction in
InsulinResistance
Hyperglycemia-inducedEnd Organ Damage
“Microvascular Disease”“Macrovascular Disease”
CerebrovascularAccident
Kodl & Seaquist, Endocrine Rev 2008
Cognitive Dysfunction inDiabetes Mellitus
Hypoglycemia
Absence ofApo ε4 Allele
Absence ofC-Peptide
Impaired brain insulin signaling in Alzheimer‘s diseaseC
SF
/Tru
e P
lasm
a In
sulin
Rat
io
6
8
10*
CS
F/T
rue
Pla
sma
Insu
lin R
atio
0
2
4
Normal Mild AD Moderate/Severe AD
Craft et al., Neurology 1998
Impaired brain insulin signaling in Alzheimer‘s diseaseC
SF
/Tru
e P
lasm
a In
sulin
Rat
io
6
8
10* � Reduction of insulin receptors and
markers of insulin signaling in thebrain of Alzheimer‘s patients (Frolichet al., J Neural Transm 1998)
CS
F/T
rue
Pla
sma
Insu
lin R
atio
0
2
4
Normal Mild AD Moderate/Severe AD
Craft et al., Neurology 1998
Impaired brain insulin signaling in Alzheimer‘s diseaseC
SF
/Tru
e P
lasm
a In
sulin
Rat
io
6
8
10* � Reduction of insulin receptors and
markers of insulin signaling in thebrain of Alzheimer‘s patients (Frolichet al., J Neural Transm 1998)
� Inducing peripheral insulin resistance via high fat/sucrose diets increases brain amyloid concentrations and impairs memory function in mouse models of Alzheimer’s disease (Cao
CS
F/T
rue
Pla
sma
Insu
lin R
atio
0
2
4
Normal Mild AD Moderate/Severe AD
Craft et al., Neurology 1998
models of Alzheimer’s disease (Cao et al., J Biol Chem 2007; Ho et al., FASEB J 2004).
Impaired brain insulin signaling in early Alzheimer’ s disease
� Accumulation of amyloid β oligomers stimulates stress-sensitive kinase pathways, resulting in serine phosphorylation of insulin receptor substrate protein-1 (IRS-1) , which decreases downstream insulin signaling.
de Felice, JCI 2013
Alzheimer’s disease symptoms and brain insulin signa ling
Talbot et al., JCI 2012
� The density of hippocampal CA1 neuronsdisplaying phosphorylation of IRS-1 atserine 616 was inversely associated withepisodic memory, working memory, and global cognition in AD patients.
Overview
� Diabetes, obesity and Alzheimer‘s disease: a fatal conn ection?
� Insulin in the brain, and the nose-brain pathway
� The role of central nervous insulin signaling in Alzheimer‘s disease
� Improving brain insulin signaling as a therapeutic perspe ctive
Intranasal insulin acutely improves memory in older adults
Total story recall130
110
90
20 IU Ins
40 IU Ins
Reger et al., Neurobiol Aging 2006
Per
cent
chan
gefr
ompl
aceb
o
90
70
50
30
10
-10
Normal MI/ε4+
40 IU Ins
MI/ε4-
Four months of in. insulin treatment in patients wi th mild AD
Craft et al., Arch Neurology 2011
Delayed story recall Dementia Severity Rating Scale
Four months of in. insulin treatment in patients wi th mild AD
Craft et al., Arch Neurology 2011
Reduced progression of
hypometabolism during
insulin treatment.
National plan to address Alzheimer‘s disease
� Development of effective prevention and treatment approaches for Alzheimer’s disease and related dementias by 2025
National plan to address Alzheimer‘s disease
� Development of effective prevention and treatment approaches for Alzheimer’s disease and related dementias by 2025
� Funding of two major clinical trials� Funding of two major clinical trials� $16 million for the first prevention trial in people at the highest
risk for the disease
National plan to address Alzheimer‘s disease
� Development of effective prevention and treatment approaches for Alzheimer’s disease and related dementias by 2025
� Funding of two major clinical trials� Funding of two major clinical trials� $16 million for the first prevention trial in people at the highest
risk for the disease� $7.9 million to test an insulin nasal spray for treating
Alzheimer’s disease: 240 volunteers participate in a year-long treatment trial at multiple sites across the U.S. that is coordinated by Suzanne Craft
“Changing the trajectory of Alzheimer’s disease”
Assuming that the onset of Alzheimer‘s disease can be delayed by fiveyears due to a novel treatment available from 2015 on…
Am
eric
ans
> 6
5 ye
ars
Mill
ions
American Alzheimer‘s Association, 2010
Num
ber
ofA
mer
ican
s >
65
in M
illio
ns
2010 2050
Thank you
Jan BornChristian Benedict Susanne Diekelmann Horst-Lorenz FehmStefan FischerGraham FinlaysonWilliam H. Frey IIFabian Griebe
Rosi KrugHendrik LehnertFelix MachleidtLisa Marshall Matthias MölleAnja NiepeltAnja OtterbeinBernd SchultesFabian Griebe
Sabine Groch Suzanne HiggsWerner Kern
Dpt. of Neuroendocrinology and Medical Clinic I, University of Lübeck, GermanyInst. of Medical Psychology and Behavioural Neurobiology, University of Tübingen, GermanyDpt. of Neuroscience, Uppsala University, SwedenInterdisciplinary Obesity Centre, Kantonsspital St. Gallen, SwitzerlandSchool of Psychology, University of Birmingham, UKInst. of Psychological Sciences, University of Leeds, UKAlzheimer’s Research Center at Region’s Hospital, St. Paul, MN, USA
Bernd SchultesUllrich WagnerInes Wilhelm
Thank you
Jan BornChristian Benedict Susanne Diekelmann Horst-Lorenz FehmStefan FischerGraham FinlaysonWilliam H. Frey IIFabian Griebe
Rosi KrugHendrik LehnertFelix MachleidtLisa Marshall Matthias MölleAnja NiepeltAnja OtterbeinBernd SchultesFabian Griebe
Sabine Groch Suzanne HiggsWerner Kern
Dpt. of Neuroendocrinology and Medical Clinic I, University of Lübeck, GermanyInst. of Medical Psychology and Behavioural Neurobiology, University of Tübingen, GermanyDpt. of Neuroscience, Uppsala University, SwedenInterdisciplinary Obesity Centre, Kantonsspital St. Gallen, SwitzerlandSchool of Psychology, University of Birmingham, UKInst. of Psychological Sciences, University of Leeds, UKAlzheimer’s Research Center at Region’s Hospital, St. Paul, MN, USA
Bernd SchultesUllrich WagnerInes Wilhelm
• 10 276 men and women, age 40-45 yrs, 27 yrs follow up
BMJ 330:1360-62, 2005
Obesity and dementia: Epidemiological data
• 10 276 men and women, age 40-45 yrs, 27 yrs follow up
• Overweight increased the risk of future dementia by 35%
• Obesity increased the risk of future dementia by 74%
Insulin i.c.v. improves memory in rats
Training
ICV: 4 mU insulin,
heat-deactivated insulin or
Park et al., Physiol Behav 2000
heat-deactivated insulin or
saline vehicle
24-h retention interval
Recall
Drugs: Cocaine, Albumin, Apomorphine, L-Dopa, Dextran, Dihydroergotamine
Antibiotics: Cephalexin, Sulfonamides, Zidovudine
Metals: Cadmium, Aluminium, Mercury, Magnesium, Gold
Hormones: IGF-1, Insulin, Estradiol, Progesterone
The nose-brain pathway: Animal studies
Hormones: IGF-1, Insulin, Estradiol, Progesterone
Viruses/Microorganisms: Rabies, Pneumococci, Borna, Salmonella enteritidis, Corona, Bazillus piliformis, Amebie, Equine encephalo-myelitis, Hepatitis, Herpes simplex, Influenca, Mice encephalitis, Poliomyelitis, Pseudorabies, Vaccinia, Yellow fever
Misc.: Leucine, Nerve growth factor, Horseradish peroxidase, wheatgerm agglutinine
Arousal
Sensitiveness
Anger
Anxiety
DreaminessPlacebo Insulin
*
*Depression
Well -being
8th treatment week
Longterm administration of i.n. insulin: Mood
0 2 4 6 8 10 12
Activation
Concentration
Deactivation
Fatigue
Benumbed
Introversion **Well -being
Self-confidence
*Extroversion
Benedict et al., Psychoneuroendocrinology 2004
Plasma cortisol
p<0.05
16
18
20
22 placeboInsulin
Longterm administration of i.n. insulin: Cortisol concentrati ons
µg/dl
8
10
12
14
16
Benedict et al., Psychoneuroendocrinology 2004
Longterm administration of i.n. insulin aspart
12 men
Placebo Placebo
Placebo Human insulin 4 x 40 IU/day
12 men
Insulin aspart 4 x 40 IU/day
0 2 4 6 8 10weeks
Placebo12 men
Wor
ds r
ecal
led 9
101112131415 Placebo
Human InsulinInsulin Aspart
n.s.
p<0.03
Declarative memory after 8 weeks of treatment
Longterm administration of i.n. insulin aspart
Benedict et al., Neuropsychopharmacology 2007
immediate delayed
Wor
ds r
ecal
led
0123456789
p<0.05
Potential mechanisms of memory improvement by insuli n
� Enhancement of local cerebral glucose utilization via GLUT-4/8
(Henneberg & Hoyer, Neurosci Lett 1994; Vannucci et al., Brain Res 1998; Schulingkamp et al., Neurosci Biobehav Rev 2000; Bingham et al., Diabetes 2002 )
Waist circumference
cm
78
80
82
84
86
Leptin
ng/ml
1,5
2,0
2,5
3,0
Feelings of hunger
0,5
1,0
1,5
Longterm administration of i.n. insulin decreases body fat
*
**
cm
70
72
74
76
placeboinsulin
ng/ml
0,0
0,5
1,0
1,5
placeboinsulin
-1,0
-0,5
0,0
placeboinsulin
Hallschmid et al., Diabetes 53(11) 2004
*
Decreased CSF insulin concentrations in Alzheimer‘s and obesity
CS
F/p
lasm
a in
sulin
ratio
0.10
0.12
0.14n = 45R = -0.393p = 0.008
CS
F/T
rue
Pla
sma
Insu
lin R
atio
6
8
10*
Kern et al., Diabetologia 2006
Fat mass (kg)
0 10 20 30 40 50 60C
SF
/pla
sma
insu
lin ra
tio
0.00
0.02
0.04
0.06
0.08
CS
F/T
rue
Pla
sma
Insu
lin R
atio
0
2
4
Normal Mild AD Moderate/Severe AD
Craft et al., Neurology 1998
Peripheral insulin resistance impairs brain glucose metab olism
Insulin-resistant adults display Baker et al., Arch Neurol 2011� Insulin-resistant adults display
hypometabolism in default modenetwork regions such as theposterior cingulate/precuneus (in fluorodeoxyglucose positronemission tomography, FDG-PET).
� Reduced metabolism was associatedwith subtle reductions in memoryencoding.
Baker et al., Arch Neurol 2011
Acute intranasal insulin administration to memory-i mpaired patients
Reger et al., Neurobiol Aging 2006