Neuroprotective effect of insulin signalingicdm2018.diabetes.or.kr/file/slide/S4-3.pdf · 2018-10-22 · 2018 International Congress of Diabetes and Metabolism Neuroprotective Effect

2018 International Congress of Diabetes and Metabolism

Neuroprotective effect of insulinsignaling

Department of Anatomy & Neurology

Ajou University School of Medicine

Sun Ah Park

• Lecture/consultation fee: none

• Grants: NRF-2018M3C7A1056293 & NRF-2018R1A2B6009439

• Stock: none

• Employment: none

• Membership on the board of directors or anyrelationship with another organization: none

Conflict of interest disclosure

Committee of Scientific Affairs


NeuroprotectiveEffect ofInsulin

The impact of Insulinresistance (deficiency)

on the brain

Therapeutic trialsusing Insulin /

Insulin-mimics inbrain disorders

Clinical evidence Experimental evidence


Brain under diabetic condition

• With hyper-(hypoinsulinemia (later)) and hyperglycemia

• Degree & distribution of insulin resistance is not uniform.

Hyperinsulinemia

↓CNS insulin levels

↓CSF/serum insulin ratio in T2DM ↓Responsiveness of

cells to insulin

↓ Brain capillary

insulin receptors

↓ BBB transport

+ With aging ⇒① ↑ Dependency on glycolysis

② ↑ Oxidation (incl. Receptors for NT, Insulin, etc.) ③ ↑ Insulin resistance

(Marks et al., Endocrinology 1990)


Clinical evidence of brain damage in T2DM

Greater Brain Atrophy in T2DM (Moran et al., 2013;Biessels and Reijmer 2014)) Both Gray and White matter atrophy (Biessels et

al., 2014) ↓Brain connectivity on DTI (Reijmer et al., 2013)

Brain total &regional volume,

Connectivity


Higher HOMA-IR = [basal Glucose level (mg/dL) ⅹ basal Insulin(μU/mL)]/405⇒ ↓Glucose metabolism on FDG-PET &⇒ Predict worse memory performance

(Willette et al., JAMA Neurol 2015)

Glucose-uptake:Brain metabolism


Insulin resistance - ↓cerebral glucose uptake in late middle-aged adults (mean60.7 [5.8] years) with AD parental history

Willette et al., JAMA Neurol 2015


T2DM – [No consistent associations] - Brain amyloid or Tau-PETuptake

(Roberts, J Nucl Med 2014; Tomita, Geriatri Gerontol Int 2013, AnnNeurol 2017; Chiang, J Neurol Sci 2017)

Insulin Resistance – ↑Amyloid uptake (PiB)(Willette et al., Alzheimers Dement 2015),

T2DM - ↑Tau uptake (PBB3)(Takenoshita et al., Curr Alzheimer Res 2018)

Aβ, Tau pathology: PET


Association of Insulin resistance with cerebral amyloid deposition in latemiddle-aged adults (mean 60.4 [5.7] years) with normal cognition

Willette et al., Alz Dement 2015

APOE ε4 versus non-APOE ε4 [p = .132]


DM – [Contradictory results] - CSF AD biomarkers in T2DM DM - ↑tTau & pTau in CSF

(Moran et al., Neurology, 2015; Laws et al, Sci Rep 2017) DM - ↑Aβ42 in CSF, ↓Aβ uptake in cortex (Li et al., Alz Dement (Amst)

2018)

Jack Jr, LancetNeurol 2013

Aβ, Tau pathology:

CSF

Decreased Insulin function – a main player inNDD?

T1DM

Learning and memory impairment, often mildEncephalopathy: impaired learning abilities, intelligencedevelopment and memory retrieval.

Hyperglycemia + Hypoglycemic episodeInsulin deficiency ⇒ ↓neurotrophic factors, ↓ the efficiency of neurotransmissionOxidative and apoptotic stressors

Loss of neuronal integrity and connectivity defects in the stilldeveloping brain

T2DM

Impaired multi-domain cognitive function

More in the elderly

More in poor diabetes control

Hyperglycemia + Hypoglycemic episode

Combined metabolic syndrome ⇒ Vascular pathology

Insulin resistance (↓Insulin level in brain, ↓Insulinreceptor sensitivity)

Synergy with aging effect

Insulin deficiency Insulin resistance

Duarte JMN, Aging Dis 2015

Brain imaging: general brain atrophy, increased occurrence of white mater hyper-intensities.Postmortem pathology: neuronal loss, demyelination and gliosis.


Diabetic characteristics in Alzheimer’s disease

Impaired glucose metabolism in brain① ↓Fluorodeoxyglucose PET signals Brain atrophy Cognitive declineprofile② ↑Glucose level in hippocampus on MRS from AD patients after glucoseintake - ↓Glucose metabolism e (Haley AP et al., Magn Resn Imaging 2006)

baseline After glucose intake


Parameter AD ↑ ↓ Details Study

Blood insulin ↑-Fasting or after glucose tolerance test -In women only (1 study) -Only in non-APOE4 and moderate/severe AD (1 study) -Meta-analysis of 11 studies: 5 report overall ↑, 1 ↑ in women, 1 ↑ with advanced stage (Ma et al., 2016)

Bucht et al., 1983; Fujisawa et al., 1991; Stolk et al., 1997; Craft et al., 1998; Ma et al., 2016

CSF insulin ↑ -Also found small increase with vascular dementia Fujisawa et al., 1991

↓ -Only in non-APOE4 and moderate/severe AD -No relationship to APOE or AD severity Craft et al., 1998; Gil-Bea et al., 2010

No change -No relationship with AD severity or cognition Molina et al., 2002

Brain insulin No change -Comparing controls >65 y/o and AD patients Frölich et al., 1998

↓-Comparing controls <65 y/o and AD patients -mRNA: in hippocampus and hypothalamus -mRNA: progressive reduction with Braak stage

Frölich et al., 1998; Rivera et al., 2005; Steen et al., 2005

Brain IR (total) ↓-Comparing controls <65 y/o and AD patients -mRNA and protein -mRNA: progressive reduction with Braak stage

Frölich et al., 1998; Rivera et al., 2005; Steen et al., 2005

↑ -Comparing controls >65 y/o and AD patients Frölich et al., 1998

No change-Potential changes in cellular distribution -Also no change in p-IR -Only reduced in patients with T2D and AD

Moloney et al., 2010; Liu et al., 2011; Ho et al., 2012; Talbot et al., 2012

Brain p-IR and activity

↓ -In hippocampus -Reduced insulin binding -TK activity reduced compared to all controls Frölich et al., 1998; Rivera et al., 2005; Steen et al., 2005

Brain IRS1 (total) ↓ -mRNA in 3 regions -Also reductions in IRS2 Steen et al., 2005; Moloney et al., 2010

No change -Also no change in IRS2 -Only reduced in patients with T2D and AD Liu et al., 2011; Talbot et al., 2012

Brain p(Ser)-IRS1↑-Regardless of APOE status and reduced ex vivo insulin stimulation -Highest in AD, butalso elevated in some tauopathies

Moloney et al., 2010Talbot et al., 2012Bomfim et al., 2012Yarchoan et al., 2014

Brain AKT (total) ↓ -Reduced in AD and in patients with T2D and AD Griffin et al., 2005; Liu et al., 2011

No change Steen et al., 2005; Talbot et al., 2012

Adopted from Stanley et al., J Exp Med 2016

Insulin related changes in AD patients


Type 3 diabetes (Steen et al., 2005; Rivera et al., 2005): ↓ Glucose utilization beginning at early disease stages ↓ Levels of Insulin receptor mRNA and protein ↓ Levels of IGF-1 and -II polypeptides and their receptors

↓insulin level + insulin resistance = Type3 DM (central insulin resistance)

↓ Insulin receptor number & activity ↓ Insulin concentrations within brain


Conclusions 1

Frequent observation of neuronal damage in T2DM: correlationwith insulin resistance markers, e.g. HOMA-IR

− Atrophy− Disturbed neural connections− ↓ Glucose metabolism− ↓ Cognitive functions− Tends to increase Alzheimer’s pathology, Aβ and Tau

Evidence of insulin resistance in AD brain− ↓ Insulin receptor number & activity− ↓ Insulin concentrations within brain− ↓ Glucose brain metabolism

Harmful effect of Insulin resistance / Insulin deficiency on brain


Source

① Mainly from the periphery through a saturable transport

system of the BBB, 0.5–0.6 μl/g-min

② Different permeability in different regions of the brain

③ Produced by a small group of cells in the olfactory mucosa

(Lacroix et al., 2008)

④ Regulated by various factors

Insulin is for what in brain?


Banks et al., Pharmacol Therapeutics 2012*Havrankova et al., PNAS 1978

Insulin transport through BBB

GLUT-2

GLUT-2)

GLU

T-1

GLUT-4

GG

Sense bloodglucoselevels

G Glucose

Higherinsulininthebrainthanintheplasma

(x25, x10~100)*

I


Glucose import

Ultrafiltrated glucose at thecapillary bed

Into cells Through GLUT4 in cell surface Insulin sensitive process

Regulation of glucose levels Through GLUT2 in pancreas

(percept the [Glc]blood ⇒ Insulinrelease)

Glucose import

GLUT1 in BBB, Energy-independent /diffusion, Insulin insensitive process

Into cells

Through GLUT1 (astrocytes), GLUT3(neurons), GLUT5 (microglia)

Insulin insensitive process, ?

S: GLUT4 in cerebellum, hypothalamus,Hippocampus, GLUT8 in intracellularorgan (rER)

Regulation of glucose levels

Sensing blood Glucose level throughGLUT2 in hypothalamus ⇒ Regulation ofhypothalamic factors, sympathetic outflow⇒ counteract Insulin

Peripheral tissue CNS

Banks et al., Pharm & Therapeutics 2012

Comparison of Glucose transport


Functions of Insulin in brain

Function- Physiologic Euglycemic State -

① Maintaining healthysynaptic transmission② Synaptic plasticity,↑NMDA receptorexpression③↑synapse numbers anddendritic spine formation④ Regulation of cellularprocesses including growth,differentiation andmetabolism⑤ Cellular proliferation,Neuron survival, andantioxidant defense⑥ Mediation of vascularfunction through nitric oxide(NO) and endothelin-1

Function

- Counter act withperipheral insulin interms of energyhomeostsis duringhypoglycemia① ↑Serum glucose ② Regulation ofhypothalamic factors,sympathetic outflow③ ↓Feeding, ↓Body wt.

- Thermogenesis- Protein synthesis- Regulation of lipolysis

Function- At BBB -

: Regulate BBBfunction① ↑Transport to brain: Tyr, Trp,Leptin② ↑p-Glycoprotein

(Wan et al., 1997, Zhao et al., 1999, Beattie et al., 2000, Man et al.,2000, Passafaro et al., 2001, Skeberdis et al., 2001, Dou et al., 2005, Valencianoet al., 2006, Chiu et al., 2008, Zhao et al., 1999, Dou et al., 2005, Chiu et al., 2008)Reviewed in Kleinridders, et al., 2014, Neth & Craft, 2017)


Insulin binds only to the IR atphysiological condition

Affinity of IR: Insulin > IGF-2 (ⅹ0.1 affinity,higher for IRA), IGF-1 (ⅹ0.02-0.01 affinity)

Tyrosine kinase receptors Function [metabolic]:

①Glucose import through GLUT4②Glycogenesis, Protein synthesis③Regulation of lipid synthesis④Survival, proliferation in mitosis-competent

cells, growth (hypertrophy)

IR(A & B)

Insulin receptor

Glycogensynthesis

Glycolysis & Fattyacid synthesis

Influx ofGlucose


IGF-1

IGF-1 and IGF-2 > Insulin (ⅹ0.01 affinity) Tyrosine kinase receptors, 60% homology

with Insulin receptor Function [growth promoting effect]:① Survival, proliferation in mitosis-competent cells, growth (hypertrophy),② anti-inflammation, anti-oxidants, CTxresistance

Higashi et al., J Gerontol 2012

IGF-1 binds to IGF-1R &IGF-1/Insulin hybrid-R


Fernandez & Torres-Aleman, Nat Rev Neurosci 2012

Olfactory bulbHippocampusHypothalamus

CerebellumCerebral cortex

Brain stem

H

In mice

Insulin content Insulin receptor content


Haeusler et al., Nat Rev Mol Cell Biol 2018


0.3 mU/kg/min regular human insulin

Normal saline

maintained at euglycemiausing 20% glucose i.v. if necessary

Under the condition of inhibition of basal insulin secretion

Within basal insulin levelsWithin

Insulin dependentglucose import intothe brain cells

Above basal levels No impact on glucose uptake

Bingham et al., Diabetes 2002


Models Metabolism Brain Function

Mouse IR knockout in nestin expressing neurons

↑Food intake, Obesity, ↑Body fat, Mild insulin resistance (Bruning JC et al

., 2000)Defective counterregulatory response to hypoglycemia (Fisher et al., 200

5; Diggs-Andrews 2010)

↓pAkt and pGSK3-beta, ↑pTauNo alteration in neuronal proliferation/survival, memor

y, or basal brain glucose metabolism (Schubert M, et al., 2004)

Mouse IR knockout in tyrosine hydroxylase expre

ssing neurons

↑Body weight, ↑Body fat, and hyperphagia (Konner AC et al., 2011)

Rat hypothalamic IR antisense knockdown

↑Food intake, ↑Body fat (Obici S et al., 2002; Grillo CA et al., 2007)

Impaired insulin action to inhibit glucose production (Obici S et al., 2002)or No change in insulin release (Grill

o CA et al., 2007)

Mouse IR kinase +/−Failure of recognition of a novel object

Difficulty in memory retention of an object (Das et al.,2005)

Mouse IRS-2-knockout

↓ Neuronal proliferation during development by 50%, but no increase in apoptosis

↑p-Tau at S202 in cytoplasmic deposits, No behavior data (Schubert et al., 2003)

Experimental Evidence: Genetic modulationof Insulin Signaling


Tg2576 AD mouse withIRS-2(-/-), IGF-1R(-/-) orIR(-/-) in nestin expressin

g neurons

IGF-1R /IRS-2 deficiency ⇒①Prevent premature mortality in Tg2576, ②↓APP processing and Aβ accumulation

IR deficiency⇒ no effect (Freude et al., 2009)

Tg2576 AD mouse withIR knockout in nestin ex

pressing neurons

nIR (-/-) ⇒ ↓Aβ burden, No rescue from premature mortality nIR (+/-) ⇒ no change in Aβ load, But partial rescues of premature mortality (Stöhr et

al., 2013)

Tg2576 AD mouse withIRS-2 knockout

↓Amyloid deposition↑ p-Tau (at S409, S396/404, S235, S202) with reduced PP2A activity

Improved behavioral deficits (Killick R et al., BBRC 2009)


Conclusions 2

Impact of IR or its signaling modulation on Metabolism is evident. Controversial impact on brain

− ↑p-Tau− ↓/→ Neuronal survival− ↓/→ Cognitive functions

Rather, protective effect of genetic modulation of IR, IRS, on ADTG mice brain

− ↑p-Tau− ↓/→ Aβ burden− ↓/→ premature mortality− ↓ behavioral deficits

Solitary targeting of IR & IRS has controversial impact on brainpathology & function⇒ Additional & Complex mechanism

• Hyperinsulinemia → IDE deficiency → ↓Aβ clearance

Contribution of Insulin resistance in AD pathogenesis 1

IDEAβ

IDEI

I

IDEAβ

Aβ

IDEI

Insulin ↑

IDEI Aβ

Aβ

AβIDEI


from Abcam.com



PP

Insulin

Insulin R

p85

p110PI3 kinase

I

PDK1

Akt

Shc

P

IRS

P

FOXOP

PKC

Ras

Raf

MEK

MAPK

Tau phosphorylation



Insulin Signaling Defects

↓SREBP-2/SCAP in brain

↓ Cholesterol synthesis

↓Synaptogenesis

Cognitive & Mood Disturbances

Altered Glutamate Receptor activities

Altered synaptic plasticity

Impaired neuronal functions


Throughsystemic /metabolicalterations

Dyslipidemia

Hypothermia

Hypothalamichypogonadism

Appetite


Kleinridders et al., Diabetes 2014

Glutamine

GLUT1/3

GlucoseG

Glucose

Fructose-6-P

GFATGlutamate

Glucosamine-6-P

UDP-GlcNAc

Tau Tau

UDPKinase

Phosphatase

Tau

Contribution of↓Glucose metabolism in AD pathogenesis

hex

osa

min

eb

iosy

nth

etic

pat

hw

ay


Insulin, Insulin-mimetic C-peptide

BBZDR/Wor rats, T2DM model [LiZG et al., 2007]

↓Diabetic condition related AD pathology:↓neuronal loss, ↓gliosis, ↓synaptophysin decrease &↓incr

ease of APP, ↓β-secretase, ↓Aβ

GLP-1 analogue:

LiraglutideExendin-4Val(8)GLP-1 analogue

STZ systemic injection to 3xTG ADmice [Li Y et al., 2010]

↓The diabetic effect of STZ; ↑insulin, ↓glucose, ↓HbA1C

↓Soluble Aβ, ↓APP, No change in total tauAPP/PS1 mice [McClean et al., 20

11]↑Memory↓Synapse loss, ↑Synaptic plasticity in hippocampus ↓

Aβ plaques, ↓Soluble AβO, ↓Activated microglia.Aβ40 i.c.v, injected Wistar rats [Wa

ng XH, et al., 2010]↓Aβ-induced LTP detrimentsRestore Aβ-induced impairment of spatial learning &

memoryAPP/PS1 mice & AβO i.c.v. injecte

d primates [Bomfim TR, 2012]↓ Phosphorylation of JNK & IRS-1, ↓Soluble Aβ, ↓Aβ

plaque, ↑Spatial memory, memory retentionRecovery of Aβ-induced memory impairment

APP/PS1-21 mice [Gengler et al., 2012]

Protect LTP, ↓ Age-related synaptic degeneration, ↓Dense-core plaque number

Therapeutic trials using Insulin or mimics

AD


Leptin CRND8 (K670N & M671L & V717F) mice [Greco SJ et al., 2010]

↓Aβ1-40, ↓Amyloid burden in hippocampus, ↓C99-CTF,↓β-secretase activity maybe through PPAR gamma agonistic effect↓P-tau at AT8 & Ser396Improve cognitive performance in novel object recognition & fear conditioning tests

Rosiglitazone APPV717I mice [Heneka MT et al.,2005]

↓Reactive astrogliosis & microglial activation, ↓COX-2, ↓iNOS and inflammatory markers, ↓BACE-1 mRNA & protein, ↓Soluble Aβ42, ↓Aβ42 deposits

Tg2576 mice [Pedersen WA et al.,2006]

↑ Spatial learning, ↓Serum corticosterone levelAttenuate reduction in IDE mRNA and activity↓ Aβ42 without affecting deposition

PDAPP (J20) mice [Escribano L etal., 2010]

↑ Aβ clearance, ↓ Aβ aggregates & AβO↓ Neuropil thread containing phosphorylated tau↓ Proinflammatory markers↑ Object recognition & spatial memory

APPswe/PS1E9 mice [Toledo EMet al., 2010; O’Reilly JA et al., 2012]

↓ Insoluble Aβ42, ↓Reactive astrogliosis & microglial activation

Improved behavioral deficitsPioglitazone PDAPP (J20) mice [Nicolakakis N

et al., 2008]↑Cerebrovascular reactivity, ↑Cerebral glucose utilizationReverse SOD2 increase, ↓Reactive astrogliosis, ↑Fibers

of cholinergic neurons, No change in Aβ plaque and spatial memory

Comparison 1: glibenclamide (glyburide) versus repaglinide

Comparison 2: intensive glycemic control versus standard glycemic controlComparison 3: rosiglitazone plus metformin versus glibenclamide (glyburide) plus metforminComparison 4: Metformin versus placebo

Global cognitive function Incidence of MCI Incidence of dementia

2008-2016Cochrane Database of Systematic Reviews 2017, Issue 6. Art. No.: CD003804.

DOI: 10.1002/

No good evidence

Meta-analysis of the prevention of dementia by anti-DM strategy


Pioglitazone (insulin sensitizer, PPAR-r agonists)

3,494 cognitively normal participants based on their ApoE and TOMM40 (Translocase of the outer

mitochondrial membrane 40 homolog rs 10524523) genotype (in normal participants with high risk of

MCI-AD)

⇒ 5-year follow-up: no difference in the delay of MCI-AD onset by piogliotazone

NCT01931566

Clinical trials 1


Intranasaldelivery ofinsulin

High insulinreceptor

Deliverinsulindirectly intothe brainalongolfactoryperivascularchannels

Clinical trials 2


Name Synonyms FDA Status

Nasal Insulin Detamir, Levemir, Humulin, NovolinAD (Phase 2/3), MCI (Phase 2),PD (Phase 2), MSA (Phase 2)

Champman et al., Neuropharmacology 2017

Clinical trials 3


Conclusions 3

Therapeutic trial studies using Insulin & anti-DM in animals:protective

Therapeutic trial studies in human: negative result by not, butnot-yet

More evidences are needed in human.


Epidemiological / Clinical study inDM or preDM condition

Genetic modulation of IR (IRS) in wildtype: controversial Genetic modulation of IR (IRS) in AD -

TG mice: rather contradictory

Therapeutic trial studies usingInsulin & anti-DM in animals:beneficial & protective

Therapeutic trial studies in human:beneficial, but need more data

Need of more sophisticated strategy- time, duration, stage on disease process, genetic background

- More detailed / combined targeting

Thank you

Documents

Neuroprotective effect of insulin signalingicdm2018.diabetes.or.kr/file/slide/S4-3.pdf · 2018-10-22 · 2018 International Congress of Diabetes and Metabolism Neuroprotective Effect