Manfred Hallschmid Central nervous effects of … · Manfred Hallschmid Central nervous effects of insulin ... Modulation of synaptic activity via effects on NMDA and AMPA ... Reger

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?




� Most common form of dementia in the elderly

Alzheimer‘s disease

Alois Alzheimer Auguste Deter




Tübingen,Germany



� No efficient treatments are available� Estimated to affect more than 24 million individuals worldwide

(Ballard et al., Lancet 2011)



� 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

Ron Mueck, Big Man (2003)

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%

Projected prevalence of overweight (BMI ≥ 25)

Sturm, Arch Intern Med 2003

Wang et al., Lancet 2011

Prevalence of type 2 diabetes

… currently estimated to affect more than 347 million people worldwide(Danaei et al., Lancet 2011)

BMJ 330:1360-62, 2005

Obesity, diabetes and dementia: Epidemiological data

BMJ 330:1360-62, 2005

Obesity, diabetes and dementia: Epidemiological dat a

BMJ 330:1360-62, 2005


BMJ 330:1360-62, 2005


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





Insulin receptors in the brain

Cortex Hippocampus

Wickelgren, Science 1998

Hypothalamus

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

Peripheral side effectsFast degradation

Blood-brain barrier

The nose -brain pathway

Peripheral side effectsFast degradation

Blood-brain barrier

Extracellular delivery of intranasal substances to the C NS

© Thorne & Frey

William Frey II

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

Intranasal insulin :cognitive effectsin healthy humans

Placebon = 197 women12 men

Placebo Placebo

Longterm administration of i.n. insulin

Insulin 4 x 40 IU/day

0 2 4 6 8 10weeks


Benedict et al., Psychoneuroendocrinology 2004


Placebo Placebo

Baseline

test session

1st treatment

week

test session

8th treatment

week

test session

Longterm administration of i.n. insulin: Declarativ e memory


0 2 4 6 8 10weeks




Placebo Placebo

Baseline

test session

1st treatment

week

test session

8th treatment

week

test session


Schnitzel

Loneliness

Soup

Nipple

Flag

Ananas

Sun flower


0 2 4 6 8 10weeks



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


immediate delayed

Wor

ds r

ecal

led

123456789

p<0.04


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)

Intranasal insulin : Metabolic effects


Placebo Placebo

BMI < 25 kg/m2

Longterm administration of i.n. insulin

Hallschmid et al., Diabetes 53(11) 2004


0 2 4 6 8 10weeks


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


Overview



� The role of central nervous insulin signaling

in Alzheimer‘s disease


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


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




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



models of Alzheimer’s disease (Cao et al., J Biol Chem 2007; Ho et al., FASEB J 2004).

Brain insulin signaling in healthy aging

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.

Fernanda de Felice: a “cumulative” hypothesis

JCI 2013

Overview




� Improving brain insulin signaling as a therapeutic perspe ctive

Intranasal insulin in cognitive disorders: Suzanne C raft’s work

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-

Intranasal insulin improves memory in early Alzheime r patients

Reger et al., Neurology 2008

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.

Boosting brain insulin signaling in early Alzheimer’ s disease

de Felice, JCI 2013

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



� 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

Thank you for your attention!Thank you for your attention!

• 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


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


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 )

Regulation of energy balance by adiposity signals

Schwartz et al., Diabetes 2003

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


*

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



Central nervous insulin resistance in obesity: MEG studies

Tschritter et al., PNAS 2006

Central nervous insulin resistance in obesity: MEG studies

Tschritter et al., PNAS 2006

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

Dieting to improve insulin sensitivity and memory

Witte et al., PNAS 2009

Manfred Hallschmid Central nervous effects of … · Manfred Hallschmid Central nervous effects of insulin ... Modulation of synaptic activity via effects on NMDA and AMPA ... Reger

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