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Insulin resistance in the brain: An old-age or new-age problem?
Ritchie Williamson, Alison McNeilly, Calum Sutherland*
Biomedical Research Institute, University of Dundee, United Kingdom
1. Diabetes and dementia
It has long been known that diabetes alters vascular function,
hence it is perhaps not surprising that there is an increased risk of
vascular dementia associated with diabetes . However there is
accumulating evidence that this is not the only effect of diabetes on
the brain. Longitudinal studies have identified a higher risk of
dementia or significant cognitive decline associated with type 2
diabetes mellitus (T2DM) and also insulin resistance without
T2DM (for review see ). The increased risk means that in the 70-
to 90-year old age group around 26% of people with dementia also
have diabetes, and this compares to around 21% of the general
population in this age group. Prospective studies confirm this
association albeit with a lower magnitude of increased risk than
retrospective analysis . In both cases the increased risk is
independent of vascular risk factors. Diabetes increases risk in
three areas of cognitive function: the risk for older adults of
cognitive decline; the rate of cognitive decline; and the risk of
future dementia . Alzheimer’s disease (AD) is the most common
cause of dementia among people with T2DM, while diabetes and
impaired fasting glucose have been linked to increased risk of Mild
Cognitive Impairment (MCI; ), which is also a significant
dementia risk factor. Conditions associated with T2DM, in
particular hypertension and obesity, are specifically linked to
poor cognitive performance in men , and obesity in middle age is
a risk factor for developing dementia in later life . More recently
the Hisayama Study found that impaired glucose tolerance (an
early warning sign of T2DM) increased risk of all-cause dementia
. Duration of diabetes is also a risk factor for increased cognitive
decline, and this may be related to length of exposure to high levels
of insulin combined with severity of disease .
Taking all of these studies into consideration it seems unlikely
that there will be a single major underlying cause for the increased
risk of dementia associated with T2DM, however dysregulated
glucose and insulin homeostasis is common to all populations
studied. This raises the possibility that insulin resistance, or
hyperinsulinaemia and impaired glucose tolerance associated with
insulin resistance, enhances the progression of neurodegeneration,
or synaptic loss, responsible for the symptoms of cognitive decline
and dementia. This may include processes that promote amyloid or
tangle pathology in AD. It will be important to establish whether
the cognitive deficits and risk of AD associated with diabetes are
also found associated with lean diabetes, where insulin resistance
is not induced by high fat intake. In order to understand more
about such processes it is necessary to first understand the
physiological roles of insulin in the periphery and the CNS (which
Biochemical Pharmacology 84 (2012) 737–745
A R T I C L E
I N F O
Received 2 April 2012
Accepted 8 May 2012
Available online 16 May 2012
A B S T R A C T
Life expectancy is rising however with more people living longer there is a concomitant rise in the
incidence of dementia. In addition to age-related cognitive decline there is a higher risk of going on to
develop vascular dementia and Alzheimer’s disease associated with aspects of modern lifestyle. Most
worryingly, recent data reports accelerated cognitive decline in adolescents associated with poor diet
(high fat and calorie intake). Thus the increase in dementia in ‘old-age’ may have as much to do with
‘new-age’ lifestyle as it does with normal ageing. It would seem wise therefore to investigate the
molecular connections between lifestyle and cognitive decline in more detail. Epidemiological evidence
suggests an increased risk of developing dementia (including Alzheimer’s disease) in individuals with
obesity and type 2 diabetes but also in those with poor insulin sensitivity without diabetes, implicating a
mechanistic link between adiposity, insulin sensitivity and dementia. Insulin receptors are expressed in
the brain and physiological roles for insulin in the CNS are starting to be delineated. Indeed disrupted
neuronal insulin action may underlie the link between diabetes and neurodegenerative disorders. This
review discusses the difficulties in quantifying insulin sensitivity of the brain and why it is vital that we
develop technology for this purpose so that we can establish its role in this ‘new-age’ dementia. This has
particular relevance to the design and interpretation of clinical trials in progress to assess potential
benefits of insulin and insulin sensitisers on prevention of cognitive decline.
? 2012 Elsevier Inc. All rights reserved.
* Corresponding author. Tel.: +44 01382 632507; fax: +44 01382 740359.
E-mail address: email@example.com (C. Sutherland).
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may not be identical of course), and also to define what is meant by
the term ‘insulin resistance’.
2. Molecular pathology of insulin resistance and diabetes
Diabetes is a disease defined by hyperglycaemia (?7 mM
fasting plasma glucose on two separate measures is the major
diagnostic criteria of diabetes), with numerous related health
problems including retinopathy, neuropathy, nephropathy, heart
disease and stroke. Loss of beta cell function and hence insulin
secretion is the most common cause of type 1 diabetes mellitus,
while a reduced response to insulin in target tissues (generally
referred to as insulin resistance) is a risk factor for as well as an
early and common feature of T2DM. The most common T2DM
therapeutic is metformin, which may elicit at least some of its
benefits through improving insulin sensitivity.
Insulin resistance is a widely used but rather imprecise term. It
refers to the fact that tissues do not respond sufficiently to
physiological insulin concentrations, hence higher than normal
insulin concentrations are required to maintain glucose homeo-
stasis. Therefore newly diagnosed T2DM is usually associated with
hyperinsulinaemia. It is well documented that poor insulin
sensitivity is closely correlated with obesity and hyperlipidaemia.
Meanwhile, animal models of obesity (e.g. the db/db and ob/ob
mouse, or diet induced obese animals) have progressively
declining insulin sensitivity prior to the development of T2DM
[9,10]. This argues that obesity has a major influence on the
development of insulin resistance, and is considered the underly-
ing cause of the current epidemic of T2DM.
No clear diagnostic criteria exist to define insulin resistance, and
in a healthy population there is huge variability in insulin sensitivity
. The most common technique for assessing whole body insulin
sensitivity in cases where pancreatic beta cell function is maintained
is the Homeostasis Model Assessment (HOMA). This index is based
on fasting plasma insulin and glucose concentrations. However the
gold standard technique for accurate assessment of insulin
sensitivity is the hyperinsulinaemic–euglycaemic clamp (HEC). This
measures the specific ability of a given amount of insulin to regulate
plasma glucose concentration but requires several hours of clinic
time to obtain, making it only viable in specialised clinical research
The molecular pathology of insulin resistance remains contro-
versial. It could be related to development of a post-receptor defect
reducing the insulin ‘sensing’ or ‘signalling’ capacity of individual
cells . This, in turn, results in a requirement for higher levels of
insulin to stimulate glucose uptake into muscle, to reduce glucose
production in liver and to correctly regulate adipose tissue. In
addition, it is assumed that obesity occurs prior to a post-receptor
defect, and indeed promotes the defect(s), although this has not
been formally proven in man. Indeed, as insulin is proposed to
regulate hypothalamic control of satiety (see later) it is interesting
to speculate that insulin resistance in the hypothalamus may
contribute to development of obesity. Consistent with this
possibility animal studies have identified molecular lesions of
the insulin signalling pathways that produce obesity. In addition,
infusion of the adipokine leptin to the obese ob/ob mouse (which
lacks leptin) has clear beneficial effects on glucose metabolism
prior to reduction in body mass, while recent evidence from gastric
bypass surgery suggests improvement in insulin sensitivity prior
to weight loss. Therefore the relationship between obesity and
insulin sensitivity may not be as unidirectional as currently
If the development of insulin resistance occurs as a conse-
quence of defective post-receptor signalling then the earliest
measure of insulin resistance should be a specific defect(s) in
intracellular insulin signalling, and these should be detectable in
tissue samples from insulin resistant individuals (Fig. 1). This has
been attempted in only a few human studies where insulin
sensitivity has also been quantified by HEC . At this time it is
not clear what molecular lesion in liver, muscle and fat of human
patients is responsible for development of insulin resistance and
ultimately T2DM, or if every tissue develops insulin resistance by
the same route. One widely touted mechanism involves the
downregulation of insulin receptor substrate (IRS) proteins (Fig. 2),
FOXO to cytoplasm
PEPCK/G6Pase gene off
Fig. 1. Simplified diagram of insulin signalling pathways thought to regulate glucose uptake (muscle and adipose tissue), gluconeogenesis (liver), protein synthesis and cell
R. Williamson et al. / Biochemical Pharmacology 84 (2012) 737–745
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in response to hyperlipidaemia and inflammation [13,14].
However it seems likely that there will not be one single molecular
problem that promotes insulin resistance and T2DM, and this may
partly explain why there is such variability in response to diabetes
therapeutics. Therefore the analysis of intracellular signalling
pathways in specific tissues may prove to be a means to establish
the insulin sensitivity of each tissue. This is most important in the
more unusual insulin target tissues such as the brain, where tissue
insulin sensitivity currently cannot be assessed by HOMA or clamp
techniques. Indeed there are no accurate techniques available at
present even to establish that animal or cell models truly exhibit
‘neuronal insulin resistance’.
3. Insulin action in the periphery
The best characterised actions of insulin combine to maintain
postprandial plasma glucose at 5 mM. Following a meal increasing
glucose levels promote insulin secretion from pancreatic beta cells.
Insulin targets liver, muscle and adipose to alter glucose uptake,
glycogen synthesis and glucose production, as well as lipid, fatty
acid and protein metabolism, promoting storage of the incoming
nutrients as glycogen, protein and fat. This continues until plasma
glucose returns to 5 mM and insulin secretion is switched off. Not
only does this generate fuel supplies for periods of prolonged
fasting but it also prevents the deleterious effects of hypergly-
caemia and hyperlipidaemia.
4. Insulin signalling in the periphery
Insulin action requires induction of a signalling network of
molecules that connects the insulin receptor (IR) to the various
proteins required to control metabolism (Fig. 1). The insulin
receptor consists of a tetramer (2x alpha and 2x beta subunits
generated from two distinct gene products). Insulin binds to the
extracellular face of the receptor, inducing a conformational
change that promotes activation of an intrinsic tyrosine kinase
activity within the intracellular domain of the receptor, leading to
autophosphorylation of the b-subunit of the IR. IRS proteins are
recruited to the plasma membrane through an interaction with the
phosphorylated IR, and these also become phosphorylated by the
receptor on tyrosine residues . This promotes recruitment of
additional signalling proteins to the complex. For example, the
lipid kinase phophatidylinositol (PI) 3-kinase which converts
3,4,5-trisphosphate (PIP3). This second messenger then attracts
more proteins (including pleckstrin homology (PH) domain
containing proteins) to the membrane, inducing co-localisation
of enzymes and substrates, and activating protein kinase cascades
(Fig. 1). The best characterised of these is the phosphoinositide
dependent protein kinase (PDK1) pathway. PDK1 is a master
regulator of a number of protein kinases, including protein kinase B
(PKB, also known as Akt), PKC, p90 RSK, p70 S6K and SGK (see 
for review). These protein kinases then phosphorylate and regulate
a wide variety of proteins involved in metabolism. For example,
PKB phosphorylates and inactivates GSK3 , and FOXO
transcription factors . These actions are involved in the proper
regulation of hepatic gene transcription by insulin . In addition,
the inhibition of GSK3 by PKB modulates insulin induction of
glycogen synthesis in muscle , while the activation of PKB is
also required for insulin induction of glucose uptake into muscle
. PKB regulates the activity of mTOR, an intracellular nutrient
sensor that is part of the pathway that controls protein synthesis
. Thus, the IRS/PI 3-kinase/PDK1/PKB pathway is considered a
major pathway in the control of the metabolic actions of insulin.
A second major pathway downstream of the IRS proteins is the
Ras-ERK pathway. Grb2/mSOS is a protein complex that interacts
with phospho-IRS (at distinct phosphotyrosines to those that
recruit PI 3-kinase). Once bound, mSOS exchanges GDP for GTP on
the small G-protein Ras, thereby activating Ras. This promotes
activation of c-Raf, which phosphorylates and activates MAP/ERK
kinase (MEK), leading to phosphorylation and activation of ERK1/2
(Fig. 1). ERK1/2 has multiple cellular substrates, most of which are
related to growth, hence this pathway is generally considered to be
important in insulin regulation of cell growth, although this is
almost certainly an oversimplification.
There are many other signalling proteins known to be regulated
at some level by insulin, including Rab, PKCz, CAP and GLUT4 (all
involved in glucose transport), c-jun (gene transcription), PDE3b,
hormone sensitive lipase and ATP citrate lyase (fat metabolism)
and BAD (apoptosis).
Insulin Receptor Substrate-1
Positive and negative regulation of insulin
signaling through IRS1 phosphorylation
•Reduced tyrosine phosphorylation by the
•Reduced binding of PI3K
•Increased ubiquitination and degradation
•REDUCED INSULIN SENSITIVITY
Fig. 2. Model of potential molecular site for obesity induced insulin resistance. Insulin signalling through IRS1 is abrogated by post-translational modification of IRS1 in
response to obesity leading to its degradation.
R. Williamson et al. / Biochemical Pharmacology 84 (2012) 737–745
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Therefore the regulation of each of these pathways is a potential
marker of insulin sensitivity. However many of these proteins are
regulated by insulin in a tissue specific manner, and most are also
regulated by alternative cell stimuli (in particular growth factors).
This means that care must be taken when analysing single points in
these pathways, with assessment of the actual response to direct
insulin application (preferably at more than one concentration) being
vital when attempting to quantify a true change in insulin sensitivity.
5. Insulin and the blood–brain barrier
Insulin enters the CNS by crossing the blood–brain barrier in a
regulated and saturable fashion . The specific receptor/
transporter has not been identified but the transport appears to
saturate at euglycaemic concentrations of insulin, and therefore
chronic plasma hyperinsulinaemia may not promote parallel
increases in insulin in the CNS. Indeed, acute induction of type 1
diabetes (streptozotocin injection of rodents), which reduces
plasma insulin, enhanced the rate of insulin uptake into brain .
In addition there is evidence that prolonged hyperinsulinaemia (as
would be present in early stages of T2DM) generates insulin
deficiency in the CNS (see  for review). Conversely, hyper-
insulinaemia in the periphery in insulin resistant individuals has
been reported to promote hyperinsulinaemia in the CNS . In
complete contrast to the protective effects of physiologic levels of
insulin, hyperinsulinaemia in culture can sensitise neurons to
toxin and stress-induced insults . Therefore it remains
controversial whether neurons are insulin resistant, insulin
deficient or are exposed to hyperinsulinaemia in T2DM, but
clearly the design of therapeutics targeting insulin action requires
this issue to be resolved.
6. Insulin action on cognition
Insulin receptors are found in many areas of the brain, and IR
expression was increased in the hippocampal dentate gyrus and
CA1 field following training of rodents on a spatial memory task
. This implies that neuronal insulin sensitivity could be
enhanced during learning. In addition, insulin administration can
have direct actions on memory. For example, i.c.v. administration
of insulin to rats improved performance on a passive-avoidance
task , and intranasal insulin improved some aspects of
cognition in mice . Meanwhile memory was improved in
healthy humans, and in patients with memory impairments, by
intranasal insulin application , and by i.v. administration of
Insulin resistance and impaired glucose tolerance are consid-
ered early warning signs (major risk factors) for the development
of T2DM. Insulin resistance was associated with impaired verbal
memory , while memory impairment and reduced hippocam-
pal volume was observed in elderly individuals with impaired
glucose tolerance . These studies highlight the fact that
cognitive deficits may be developing in the pre-diabetic condition,
for some time prior to diagnosis of diabetes or the initiation of any
treatments. However they remain observations needing mecha-
nistic evidence to confirm insulin resistance is the cause of these
Interestingly neuronal IR numbers are thought to decline with
age . Some believe that the accelerated cognitive decline in AD
is related to a reduction of IR in the brain of AD patients (for review
see ). However IR expression is not trivial to quantify in post-
mortem tissue and there is evidence for [38,39] and against 
this hypothesis. However this controversial observation has led to
a suggestion that some forms of AD may be a ‘type 3 diabetes’ .
As mentioned above the diagnosis of diabetes is defined by plasma
glucose, not by insulin sensitivity, and the cognitive impairments
associated with metabolic abnormalities appear to occur in pre-
diabetic conditions (i.e. with insulin resistance and impaired
glucose tolerance rather than just diabetes). Therefore it seems to
be rather inaccurate to label AD with defects in neuronal insulin
action as a type of diabetes. In fact there is as yet little evidence that
reduced IR expression even in the periphery is a cause of any major
form of diabetes.
How insulin exerts its beneficial effects on the brain is not yet
clear, however one proposal is that insulin induces glucose uptake
and metabolism in specific neuronal populations. For example
insulin administration to rats has been shown to increase cerebral
glucose metabolism . This could be through a similar
mechanism found in muscle and adipose, namely the induction
of membrane localisation of the glucose transporter GLUT4. This
isoform is expressed in several areas of the brain including the
hippocampus and cortex , however direct evidence for loss of
insulin regulation of glucose uptake in the brain causing cognitive
impairment is currently lacking, even in animals lacking a neuronal
IR (see below). Recently a defect in control of neuronal cholesterol
biosynthesis was observed in mice with insulin deficiency, and the
deficits could be reversed by i.c.v. insulin administration. This
suggests a direct regulation of cholesterol content by insulin in
some areas of the brain . In addition insulin may regulate the
production of acetylcholine  and uptake of norepinephrine 
in the brain, and also the expression of NMDA receptors at synaptic
membranes . Therefore there are many potential mechanisms
by which insulin could directly affect neuronal activity, all
requiring more detailed study.
7. Genetic deletion of the insulin receptor in the brain
To fully investigate the importance of insulin and insulin like
growth factors (IGF)-1 action on the CNS a number of different
approaches have been used to remove insulin or IGF1 receptors
specifically in neurons. Neuronal specific insulin receptor knock-
out (NIRKO) mice were generated using nestin cre-mediated
ablation . Perhaps surprisingly, neuronal inactivation of the IR
had no effect on brain development or neuronal survival. In
addition the NIRKO mice had no deficit in spatial memory, long-
term learning or brain glucose metabolism . Instead, these
mice exhibited hyperphagia, mild insulin-resistance, and en-
hanced sensitivity to diet-induced obesity, suggesting that CNS IR
contributes to the regulation of whole body energy homeostasis.
The NIRKO mice have relatively low basal PKB and GSK3
phosphorylation in the brain, at residues targeted by insulin to
regulate their activity. This suggests that these residues may well
be regulated by insulin in the brain and that loss of insulin action
reduces basal activity of the pathway (resulting in higher GSK3
activity). Interestingly the NIRKO model had an impairment of the
counter-regulatory response to hypoglycaemia, manifest in a
reduced sympathoandrenal response when compared to littermate
controls . This blunted counter-regulatory response was
related to alterations in glucose sensing in the ventromedial
hypothalamus and arcuate nucleus (possibly due to reduced
GLUT4 expression), although glucose uptake across all brain
regions during a HEC was not impaired . More recently, NIRKO
mice were reported to have a deficit in IGF1-induced hyperther-
mia, a response mediated through the preoptic area of the
hypothalamus to activate brown adipose tissue . Insulin action
on the brain is directly implicated in the regulation of white
adipose tissue (WAT) lipolysis. Scherer et al. reported that insulin
infusion into the mediobasal hypothalamus suppressed lipolysis,
while increasing WAT lipogenic protein expression. Conversely,
NIRKO mice display decreased WAT lipogenesis and unchecked
lipolysis . This implicates the IR in IGF1 action on the brain, the
control of body temperature and whole body fat storage.
R. Williamson et al. / Biochemical Pharmacology 84 (2012) 737–745
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An alternative approach to classical gene knockout studies is to
selectively downregulate the IR gene later in life, even in adult
mice. Bruning and colleagues compared the phenotype of an
inducible whole body IR deficient mouse with that of an inducible
IR knockout restricted to peripheral tissues of adult mice . The
study was a direct comparison of the effects of peripheral versus
whole body insulin resistance in the adult mouse, allowing
assessment of the contribution of neuronal insulin resistance to
whole body energy homeostasis. While deficiency in IR expression
produced severe hyperinsulinaemia in both models, hyperglycae-
mia only developed when IR was lost from all tissues. Similarly,
deficiency of IR in all tissues produced a greater reduction in WAT
mass and severe hypoleptinaemia. Leptin replacement normalised
glucose metabolism, indicating that alterations in glucose metab-
olism occur largely as a consequence of lipoathrophy following
whole body IR deficiency. This data is consistent with the neuron
specific deletion of IR, indicating that central insulin action plays
an important role in regulating WAT mass and whole body glucose
More acute depletion of IR can be achieved using antisense
oligodeoxynucleotide or siRNA directed against the insulin receptor
precursor protein introduced directly into the brain. Obici and
colleagues generated a specific decrease in IR in the medial portion of
the arcuate nucleus using antisense, resulting in hyperphagia and
increased fat mass in the rats . In addition, the ability of insulin to
reduce hepatic glucose production was significantly blunted.
Reduction of IR in the ventromedial hypothalamus using lentiviral
infection of an siRNA resulted in a similar impairment of peripheral
glucose metabolism . These studies both point to a direct action
of insulin on hypothalamic neurons to modulate hepatic glucose
metabolism, however a previous study found that lentiviral IR siRNA
injection into the third ventricle did not alter peripheral glucose
metabolism but rather regulated body weight and fat mass .
The IR has also been selectively downregulated in specific
neuronal subpopulations. For example, targeted inactivation of IR in
steroidogenic factor-1 expressing neurons in the ventromedial
hypothalamus revealed a role for these neurons in mediating insulin
dependent alterations in diet-induced development of obesity .
Similarly, targeted inactivation of IR in pro-opiomelanocortin and
agouti-related peptide (AgRP)-expressing neurons in the arcuate
nucleus revealed that IR in AgRP-expressing neurons modulated
hepatic glucose production during a HEC . In addition, targeted
inactivation of IR in tyrosine hydroxylase expressing dopaminergic
midbrain neurons generated hyperphagia with concomitant in-
creased weight and fat mass. This implicates the control of these
specific neurons by insulin (and/or IGF1) in the normal regulation of
food intake and energy homeostasis .
In summary, gene knockout or knockdown studies have
highlighted key physiological roles for the neuronal IR, particularly
in the hypothalamus, in the control of peripheral glucose and fat
metabolism but potentially in more fundamental neuronal
processes. However there is little evidence to date from neuronal
IR knockout studies for a key role in learning and memory. In
addition, as discussed below, the IR can complex with other
receptors, hence simply deleting the IR could be altering sensitivity
to more than insulin (e.g. IGF1). Therefore, although these studies
are compelling and clearly demonstrate the importance of the IR in
specific neurons, the evidence that insulin directly regulates the
cognitive function of the brain is not as clear-cut. This requires
specific assessment of post receptor signalling in neurons exposed
to insulin and related peptides.
8. Neuronal insulin and IGF1 receptors and Alzheimer’s disease
The studies on knockout mice have highlighted roles for
neuronal insulin in the control of body weight and glucose
homeostasis, with little evidence of cognitive deficits. However
high fat feeding of mouse models of AD (which overexpress a
mutant APP or PS1 leading to generation of amyloid pathology and
premature death) exacerbates the behavioural and pathological
phenotype [59,60]. Similarly crossing these AD models with mouse
models of obesity and diabetes also worsens cognitive impair-
ments . This is consistent with the concept that the generation
of insulin resistance (and subsequently T2DM) accelerates the
progression of AD. However, when the Tg2576 AD model was
crossed with the NIRKO mouse, or a mouse lacking the IGF1
receptor in neurons, there was no enhancement of the cognitive
deficits of the Tg2576 mouse . Indeed Tg2576 mice with
reduced IGF1 signalling in the brain were actually protected from
the premature death associated with this model of familial AD (as
well as having some reduction in amyloid production) .
Deletion of the IR from the neurons of this same mouse model of
AD had even greater benefits on development of amyloid
pathology yet did not counter the premature death of the model
. This clearly demonstrates different effects of the insulin and
IGF1 signalling processes on amyloid pathology and premature
mortality but questions the role of insulin and IGF1 in the cognitive
deficits of these mouse models. The detrimental effects of high fat
feeding on the Tg2576 and Triple Tg models, along with our own
studies demonstrating that high fat feeding promotes a very
specific cognitive deficit in rats , clearly suggest there is an
effect of poor diet on neuroendocrine or metabolic function that
influences behaviour. However whether this is due to a direct loss
of insulin action on the brain (or an alternative diet induced change
such as leptin or incretin resistance) requires further investigation.
9. Defective insulin signalling in Alzheimer’s disease
It appears that all of the components of the insulin-signalling
cascade are present within the CNS; however direct evidence that
insulin actually regulates key neuronal functions through the same
pathways across all brain regions as it does in the periphery is
comparatively weak. Insulin is a member of a small family of
polypeptides that includes (IGF)-1 and -2. The IR has high
homology with the IGF1 receptor and indeed each receptor will
bind and respond to both hormones although with an order of
magnitude greater affinity for the cognate hormone. In addition
the IGF1 receptor and IR can form hybrid receptors. The hybrid
receptor is much more responsive to IGF1 than to insulin, and it is
estimated that the majority of IR subunits in the brain are within
heterocomplexes with IGF1 receptors . This situation may be
even more complicated as recent evidence suggests that the IR
forms complexes with other growth factor receptors, such as the
hepatic growth factor (HGF) receptor in the liver . In this case
HGF is reported to modify the response of liver cells to insulin .
Therefore it is important to consider whether processes that
promote insulin resistance in neurons would affect the response of
cells to other growth factors and vice versa. For example, there is
compelling evidence that IGF1 is necessary for normal brain
function  and cognitive impairment is associated with an age-
related decline in serum IGF1 levels in rodents . Therefore, like
insulin, it seems that IGF1 has key beneficial effects on neuronal
function and survival. As insulin and IGF1 induce similar signalling
pathways it is likely that a molecular problem that generates
insulin resistance (although not yet characterised) could also alter
IGF1 signalling in the brain, hence IGF1 resistance as well as insulin
resistance in the brain could contribute to the association of T2DM
and cognitive decline.
All of the above data together demonstrates that simply
measuring IR expression in tissue is not an accurate approach to
assess the insulin sensitivity of a tissue. Steen and colleagues found
a significant reduction in many aspects (mRNA and protein
R. Williamson et al. / Biochemical Pharmacology 84 (2012) 737–745
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expression as well as post-translational modification) of the
insulin/IGF signalling cascade in a number of brain regions
associated with AD pathology when compared to control brain,
although the amount of reduction varied from region to region
. Interestingly, there was no reduction in these transcripts in
the cerebellum, a brain region relatively spared in AD pathology.
More recent work investigated basal protein levels and post-
translational modification (an indirect marker of activity) of the
PI3K–PKB signalling pathway (Fig. 1) in tissue from AD, T2DM, or
AD with T2DM . Although this was only a small study they
found significant reductions in PDK1, PKB and GSK3b protein
expression in T2DM in comparison to control, and PI3K/p85, PDK1,
and PKB in AD brain compared to control. Interestingly, the deficits
were generally more severe in the brains of individuals presenting
with both AD and T2DM (reductions in IRb, IRS1, PI3K/p85, PDK1,
PKB and GSK3b). These reductions in protein correlated with
increased tau phosphorylation, down-regulation of O-GlcNAcyla-
tion of tau and enhanced calpain-I activation. Although correlative,
these preliminary data would suggest that common pathological
mechanisms occur in both T2DM and AD, and together they may
produce a more severe phenotype. However it may be dangerous
to extrapolate expression levels of signalling molecules to actual
cellular sensitivity to a specific hormone. All of the studies to date
examining insulin signalling in brain from AD patients have
focused on basal signalling status compared to age-matched
controls (due to the technical difficulty in obtaining samples before
and after insulin exposure). As mentioned earlier, all of the
proteins of the PI3K–PKB pathway (including the IR itself) can be
regulated by agents other than insulin. Therefore the basal
expression and activity of the pathway technically does not
provide specific assessment of insulin sensitivity of the tissue (e.g.
IGF1 induces the PKB pathway greater than insulin in neurons
(Fig. 3)). In addition isolated brain tissue contains more than
neurons. Indeed isolated astrocytes not only contain insulin (and
IGF1) receptors but also induce the PI3K–PKB pathway to a greater
extent in response to physiological insulin or IGF1 (Fig. 3). Finally,
the absolute level of expression of components of a pathway does
not always directly correlate with sensitivity of downstream
targets of the pathway to stimulation. For example, only 5% of
maximal PKB activation by insulin is required in liver cells to fully
repress the insulin target gene phosphoenolpyruvatecarboxyki-
nase , therefore this action of insulin can withstand a loss of
most of the cellular PKB without losing sensitivity to insulin, yet
requires PKB for response to insulin. Therefore new technology is
required to quantitatively assess key neuronal processes regulated
by insulin (before and after exposure to insulin at increasing
concentrations, or specific actions of insulin). Only then will it be
possible to fully assess the status of neuronal insulin sensitivity in
models of AD or in human AD brain.
Amyloid b (Ab) peptides are reported to regulate insulin
signalling in the brain. Soluble Abeta reduces insulin’s ability to
induce the PI3K–PKB pathway in cultured hippocampal neurons
, while soluble Ab oligomers reduce plasma membrane IR in
primary hippocampal neurons, promoting synaptic spine loss .
In both cases pretreatment with insulin protected against the
action of Ab suggesting a direct competition at the IR. It will be
interesting to determine if this is confirmed in intact tissue and in
Insulin can enhance survival of HT22 neuronal cultures through
a PI3K-mediated modulation of PKCdelta alternative splicing .
Insulin protects retinal neurons from stress-induced apoptosis,
possibly via the PI3K–PKB pathway  or the mTOR–p70S6K
pathway , both pathways harnessed by IGF1 and leptin
receptors as well. Therefore loss of neuronal responsiveness to
insulin, or insulin deficiency in the T2DM CNS, could render
neurons more susceptible to neurotoxic insults (e.g. Ab or
inflammation in AD), leading to decreased survival of neurons in
key areas of the brain associated with neurodegeneration in
The insulin-degrading enzyme (IDE) is a metalloprotease that
catabolises insulin and Ab, and may play a critical role in Ab
clearance in brain . Insulin can regulate IDE expression and
may directly compete with Ab for binding to IDE. Mice lacking IDE
have lower rates of Ab and insulin degradation and develop
hyperinsulinaemia and accumulate Ab species in the brain .
These data together propose that insulin deficiency in the CNS
could enhance Ab accumulation through loss of insulin inhibition
of IDE expression and reduced competition for IDE binding.
Finally, many of the protein kinases that can phosphorylate tau
on residues known to exhibit increased phosphorylation in AD are
regulated by insulin. The best example is GSK3, which phosphor-
ylates tau on several residues [77,78]. This enzyme is regulated by
insulin through the PI3K–PKB pathway in muscle cells , but it
should be kept in mind that GSK3 is regulated by many agents
using other signalling pathways.
10. Loss of metabolic control and cognition
Loss of insulin action on the brain is not the only mechanism by
which dementia can be linked to diabetes. There is evidence that
simple short-term alterations in glycaemic control may affect
cognitive performance. Two large clinical trials reported an
association between deficits in motor speed and psychomotor
efficiency and mean glycated haemoglobin concentrations (an
assessment of glucose control) in people with type 1 diabetes
[79,80]. In addition cognitive impairments have been reported in
T2DM associated with single measures of glycated haemoglobin
. It is possible that long-term hyperglycaemia may alter
microvascular structure in the brain leading to the development of
cognitive impairment. Meanwhile deliberate acute elevation of
blood glucose induced specific decrements in working memory,
attention and mood (although this was in people already
diagnosed with T2DM) . This may suggest that a more acute
alteration in cerebral blood flow or osmotic effects on the brain
may promote impaired cognition in diabetes. In contrast others
have reported that intensive glucose lowering regimens have little
effect on cognitive measures , suggesting that improving
glucose control alone may not be sufficient to reverse the effects of
diabetes on dementia. It seems likely that the role of glycaemic
PKB activity (Units per mg)
Fig. 3. Primary cells were incubated with insulin (100 nM) or IGF1 (100 ng/ml) for
15 min prior to lysis. PKB was immunoprecipitated from 100 mg of total cellular
protein and incubated with crosstide and Mg[g-32P]ATP for 10 min. One unit of
kinase activity is defined as that amount catalysing the incorporation of 1 nmol of
phosphate into substrate in 1 h.
R. Williamson et al. / Biochemical Pharmacology 84 (2012) 737–745
Author's personal copy
control and hormone responsiveness in cognition and neurode-
generation will be complex. Associations may well depend on
other clinical features (e.g. inflammation, infection, steroids, body
composition etc), as well as the precise measure of cognition and
11. Inflammation and cognition
Microglial activation and inflammation within the CNS are
linked to a number of neuropathological conditions including AD
and Parkinson’s disease , and increasing levels of inflammatory
cytokines, e.g. IL-1b and IL-6 can disrupt hippocampal synaptic
plasticity and elements of spatial learning. Obesity induced
peripheral insulin resistance is associated with a marked increase
in the production of pro-inflammatory cytokines and plasma levels
of free fatty acids. Indeed chronic activation of the innate immune
system in response to stress such as excessive or inappropriate fat
deposition may contribute to the development of insulin resis-
tance and T2DM . Mice maintained on a diet rich in saturated
fat for 16 weeks were found to be impaired in the Morris water
maze, a test of spatial memory. Moreover, increased expression of
various markers of neuroinflammation including TNF-a, IL-6 and
the chemokine MCP-1 were observed in the brains of animals fed
the high fat diet . Therefore chronic inflammation could
represent a common underlying condition promoting the associa-
tion of AD with diabetes. Alternatively, hyperinsulinaemia
associated with insulin resistance may promote CNS production
of cytokines. Fishel et al. induced hyperinsulinaemia in healthy
elderly men and observed a marked increase in the levels of pro-
inflammatory cytokines (IL-1b. IL-6 and TNFa), F2-isoprostane, a
brain derived marker of lipid peroxidation and Ab42 within the
cerebral spinal fluid . Interestingly, those with the greatest BMI
had the highest levels of TNFa, a cytokine that inhibits Abeta
transport from the brain to the periphery. This may lead to a
vicious cycle of increasing levels of TNFa and Abeta within the
brain of obese hyperinsulinaemic individuals facilitating the
formation of amyloid plaques. Furthermore, TNFa and IL-6 are
known to induce activation of NFkB and subsequent transcription
of the pro-inflammatory genes TNFa, IL-6 and IL-1b and the
chemokines CRP and monocyte chemo-attractant protein-1. Thus
induction of the innate immune system has the potential to have
major implications on neural and cognitive function and worsen-
ing of pathology associated with AD.
Oxidative stress, the accumulation of advanced glycation end
products (AGE) and the resulting CNS cellular and molecular
damage may contribute to diabetes induced brain ageing . The
generation of AGE products increases pro-inflammatory mecha-
nism within the brain that enhances oxidative stress and vice
versa. The anti-oxidant capacity of the brain decreases with age but
appears to decline faster in diabetes providing another mechanism
by which diabetes could increase brain ageing leading to cognitive
12. Perspectives for intervention in AD with insulin or insulin
Trials to improve insulin resistance or insufficiency in the CNS
are only just starting. The main therapeutics available for treating
insulin resistance include the biguanide metformin, the peroxi-
some proliferator activated receptor gamma (PPAR-g) agonists and
incretins. These are all being investigated for beneficial effects on
cognitive performance in populations with diabetes and without.
The PPAR-g agonists have been used in the treatment of T2DM
for many years and are thought to improve insulin sensitivity
through enhancing the deposition and function of adipose tissue,
moving triglycerides and fatty acids away from liver and muscle,
thereby improving response to insulin . Interestingly induc-
tion of PPAR-g activity may also reduce both Ab accumulation and
neuroinflammation [90,91]. Therefore PPAR-g agonists have the
potential to improve several molecular pathologies associated
with both T2DM and AD making them potential therapeutics for
the treatment of MCI associated with insulin resistance and
neuroinflammation. Indeed the PPAR-g agonist rosiglitazone
protected the Tg2756 AD mouse model from corticosterone stress
. In addition, 6-month treatment with rosiglitazone improved
attention and preserved memory in patients with amnestic mild
cognitive impairment and early AD . A correlation was
observed between improvement in fasting plasma insulin and
memory preservation, consistent with a mechanistic connection
between insulin resistance and memory deficits. However a
subsequent Phase III trial with rosiglitazone did not detect any
benefit of the drug over placebo , while the recent evidence of
increased heart failure associated with PPAR-g agonists have
reduced their use in diabetes therapy and may prevent further
investigations of this class of insulin sensitising agent in
Metformin (in combination with weight control) remains the
initial treatment of choice for T2DM, even though its precise
mechanism of action remains unclear and controversial. It
improves fasting insulin levels and enhances insulin regulation
of hepatic glucose production. Therefore it is has always been
considered an insulin sensitising agent, with its major actions on
the liver. However more recent work has suggested it can cross the
blood–brain barrier and regulate tau phosphorylation in a mouse
model of AD . Conversely it has been linked to enhanced
amyloid production in cells . However its insulin sensitising
properties make it an ideal tool to establish the potential
mechanistic link between insulin resistance and dementia,
including AD, and as such several clinical trials are ongoing at
the time of writing. A retrospective Taiwanese study provided the
first epidemiological evidence that intervention with metformin
could reduce the incidence of dementia in people with diabetes
Glucagon-like peptide-1 and gastric inhibitory peptide are
peptides made in the gut that induce insulin secretion from the
pancreatic beta cells in a glucose dependent manner. Therefore
they are technically insulin secretagogues rather than insulin
sensitisers. Drugs that prevent degradation of these peptides
(gliptins), or more stable forms of these peptides (exenatide and
liraglutide) are now in clinical use as adjunct therapy in diabetes.
Receptors for both peptides have been found in other areas of the
body including the brain and additional biological actions are
being discovered. Recently liraglutide and exenatide were found
to antagonise processes linked to neurodegeneration and AD
progression in mouse models, even in the absence of diabetes
[98,99]. These incretins prevented the damaging effect of Ab
oligomers on CNS insulin signalling (in particular IRS1 regula-
tion). This raises the exciting possibility that they could be a
novel treatment for dementia irrespective of the presence of
With some preliminary evidence that insulin may be reduced in
AD brains (see earlier), studies are underway to investigate the
therapeutic benefit of administration of insulin through the nose to
patients with MCI and T2DM, bypassing any defects in blood–brain
barrier insulin transport and the obvious concern of hypoglycae-
mia subsequent to peripheral administration . Despite the
disappointment of the human trials with rosiglitazone it remains
quite possible that direct application of insulin to the CNS will have
benefits even if the cognitive decline in the subjects is not due to
insulin resistance. This approach plus the investigation of
metformin therapy in patients with MCI remain worthwhile
approaches in a condition with very few therapeutic options.
R. Williamson et al. / Biochemical Pharmacology 84 (2012) 737–745
Author's personal copy
The relationship between insulin resistance and cognitive
function is complex and while it is clear that insulin has important
effects on neurobiology and potentially beneficial actions on
neurodegenerative processes, there is still only indirect evidence
that neurons (or astrocytes) develop defects in insulin action in line
with peripheral insulin resistance. Although the epidemiological
evidence that insulin resistance associates with cognitive impair-
ments continues to accumulate most of the data remains
correlative with little convincing detailed mechanistic proof that
neuronal insulin resistance enhances the development of demen-
tia. Indeed mouse knockout studies seem to suggest that the
connection is not a simple loss of post-receptor signalling. We
urgently require more accurate methodology to assess the insulin
sensitivity of neuronal populations in vivo. This does not negate
the importance of investigating whether insulin-sensitising drugs
(or insulin itself) slow down cognitive decline in at risk groups, and
we await the outcome of these trials with great hope. What is
without doubt is the damaging effects of high fat diets and lifestyle
on cognitive function and if this increase in ‘New-Age’ dementia is
not addressed quickly there will be a health care crisis within a
generation in most developed countries.
The work of the authors is supported by Alzheimer’s Research
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