Review

Insulin resistance in the nervous

system

Bhumsoo Kim and Eva L. Feldman

University of Michigan, Department of , Ann Arbor, MI 48109, USA

Metabolic syndrome is a cluster of cardiovascular risk fatty acids (FFAs) [4]. Inappropriate accumulations of

factors including , and dyslipidemia. In- in muscle and liver due to abnormal fatty acid

sulin resistance (IR) is at the core of metabolic syndrome. are the main features of IR. The resulting

In adipose tissue and muscle, IR results in decreased dyslipidemia is strongly correlated with increased CVD

signaling, primarily affecting downstream risk [5]. Visceral fat is also infiltrated with inflammatory

phosphatidylinositol 3-kinase (PI3K)/Akt signaling. It cells and secretes proinflammatory cytokines such as in-

was recently proposed that can develop hyper- terleukin 6 (IL-6) and tumor necrosis factor-a (TNF-a) [6],

insulinemia-induced IR, which in turn results in injury to which are implicated in the development of IR.

the peripheral and central nervous systems and is proba-

bly pathogenic in common neurological disorders such as Insulin signaling and molecular basis of IR

and Alzheimer’s (AD). This Insulin is a major anabolic that plays an essential

review presents evidence indicating that, similarly to role in homeostasis by regulating the balance

insulin-dependent metabolically active tissues such as between hepatic glucose production and glucose uptake

fat and muscle, neurons also develop IR and thus cannot by muscle and adipose tissue, the two major sites of glucose

respond to the neurotrophic properties of insulin, result- uptake in man. glucose levels are maintained by the

ing in neuronal injury, subsequent dysfunction and balance between lipolysis in adipocytes and skeletal mus-

disease states. cle and gluconeogenesis and glycogenolysis in liver. Insulin

also regulates glucose transport in adipocytes and myo-

Metabolic syndrome and cytes by controlling the translocation of glucose transport-

Metabolic syndrome (MetS) is a constellation of disorders er (Glut) 4 between intracellular pools and the plasma

related to an increased risk of cardiovascular disease membrane [7].

(CVD), and is the major contributor to the development Insulin binds to the extracellular a-subunit of the insu-

of diabetes [1]. The National Cholesterol Education Pro- lin receptor (InsR), which results in the autophosphoryla-

gram’s Adult Treatment Panel III (NCEP/ATP III) identi- tion and activation of the intracellular b-subunit [3]

fied six components of MetS that relate to CVD: (i) (Figure 1). Activated InsR phosphorylates several intracel-

abdominal obesity, (ii) atherogenic dyslipidemia, (iii) lular substrates including InsR substrate (IRS) family

raised blood pressure, (iv) IR with or without glucose members (IRS1–IRS4) and Shc, which subsequently

intolerance, (v) proinflammatory state, and (vi) prothrom- recruits downstream signaling molecules containing Src

botic state. A subject is diagnosed with MetS when homology 2 (SH2) domains including the p85 subunit of

he/she has central obesity plus any two of four additional PI3K and growth factor receptor-binding protein-2 (Grb-2)

factors (elevated triglycerides, reduced HDL-cholesterol, [8]. Activated PI3K phosphorylates phosphatidylinositol

or abnormal fasting plasma glucose). The 4,5-bisphosphate (PIP2) to generate phosphatidylinositol

National Health and Nutrition Examination Survey study 3,4,5-trisphosphate (PIP3). Increased PIP3 stimulates

found that MetS affects 34% of adults in the US [2]. The phosphoinositide-dependent protein kinase (PDK), result-

incidence increases with both higher body mass index and ing in the activation of Akt.

advancing age. In general, IRS serine phosphorylation inhibits insulin

IR is defined as a state of reduced responsiveness of target signaling even though it can act as a positive regulator

tissue(s) to normal circulating levels of insulin and is the depending on the environment [8] (Box 1). Increased IRS

central feature of (T2D) and MetS. Both serine phosphorylation prevents its interaction with the

genetic and environmental factors (lack of , obesity, InsR and downstream signaling molecules, induces mis-

smoking, and aging) affect the development of IR [3]. localization of IRS and enhances its degradation by the

ubiquitin–proteasome pathway. Enhanced proinflamma-

Pathophysiology of IR tory states during IR, due to increased release of FFAs and

Abdominal fat accumulation is closely correlated to MetS proinflammatory cytokines from adipose tissue, also con-

and IR and increased risk of diabetes and CVD [1]. Visceral tribute to increased IRS serine phosphorylation by activat-

adipose tissue is a metabolically active endocrine organ ing IRS serine kinases [8].

whose dysfunction is responsible for increased plasma free In normal conditions, insulin stimulates Glut4 activity

in skeletal muscle via IRS tyrosine phosphorylation and

Corresponding author: Kim, B. ([email protected]). downstream PI3K activation (Figure 1). Glut4 is the major

1043-2760/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2011.12.004 Trends in Endocrinology and Metabolism, March 2012, Vol. 23, No. 3 133

Review Trends in Endocrinology and Metabolism March 2012, Vol. 23, No. 3

Glucose Insulin

InsR PIP3 PP2 Glut4 PIP3 PTEN p110 P P PIP2 Akt P P p85 PDK1 T308 P P P S473 P IRS P PI3-K P AS160 P P Glucose P Shc P Grb2 Glut4 mTORC2 SOS Glucose mTORC1 transport

GSK3β MAPK Bad pathway FoxO p70S6K caspase-9

Gene expression Protein Glycogen Survival Proliferation synthesis synthesis Differentiation growth Axon growth Development

TRENDS in Endocrinology & Metabolism

Figure 1. Insulin signaling pathways. The binding of insulin to InsR stimulates autophosphorylation of the receptor and recruits docking proteins Shc and IRS. IRS

phosphorylation stimulates PI3K activation, and this leads to the generation of phosphatidylinositol-3,4,5-triphosphate (PIP3) by phosphorylating phosphatidylinositol-4,5-

bisphosphate (PIP2). PDK1 and Akt are recruited to the plasma membrane by binding to PIP3 through their PH domains. PDK1 phosphorylates a threonine residue in the

catalytic domain of Akt. Full activation of Akt requires a second phosphorylation of a serine residue by the mTORC2 complex. Alternatively, phosphorylated Shc recruits

Grb2/SOS, which stimulates the MAPK signaling pathway. Substrates activated by the MAPK and PI3K/Akt pathways mediate various downstream biological responses of

insulin, including cell survival and glucose metabolism.

insulin-mediated glucose transporter in muscle and adi- uptake [10], possibly because of impaired insulin action in

pocytes [7]. Precise translocation of Glut4 from intracellu- liver and skeletal muscle. However some reports demon-

lar stores to the plasma membrane is crucial for insulin- strate a disparity between the activation of upstream

regulated glucose transport. The PI3K-dependent signal- signaling molecules (IRS–PI3K), Akt activation and glu-

ing pathway is crucial for the metabolic effects of insulin, cose tolerance, arguing against the crucial role of Akt in the

and this pathway is generally affected in individuals with development of IR [12].

the MetS and diabetes. Decreased association of the p85 Other downstream substrates involved in the develop-

subunit of PI3K and IRS is reported in obese and T2D ment of IR are the Akt substrate of 160 kDa (AS160, also

patients. Decreased expression of IRS and the association termed TCB1D4) and glycogen synthase kinase 3 (GSK3)

and activation of PI3K are also evident in genetically obese (Figure 1). Akt induces AS160 phosphorylation, which

and high-fat fed animals [9]. directly links insulin signaling to Glut4 trafficking [13].

Akt (Box 1) is a serine/threonine kinase activated by Insulin-stimulated AS160 phosphorylation is reduced in

PI3K and is responsible for glycogen, and protein T2D patients [14]. Insulin activates glycogen synthase,

synthesis, for cell survival and for the anti-inflammatory which is the rate-limiting enzyme in glycogen synthesis.

response (Figure 1) [3]. Akt plays crucial roles in IR by Glycogen synthase is inactivated by GSK3, which itself is

regulating insulin-stimulated transport of Glut4 in muscle phosphorylated and inactivated by insulin stimulation in a

and adipose tissue [3], and therefore it is not surprising PI3K/Akt-dependent manner [15]. An increase in the ac-

that alterations in Akt activity are found in various cells in tivity of GSK3 has been observed in diabetic animals and

diabetes and IR. Akt phosphorylation is reduced in adipo- patients, and GSK3 inhibitor treatment reverses diabetes

cytes and skeletal muscle of T2D patients [10] and Akt2 [16].

activation is closely correlated to Glut4 translocation By contrast, phosphorylation of Shc by InsR activates

through insulin-activated PI3K signals in adipocytes the mitogen-activated protein kinase (MAPK) branch of

[11]. Akt2 knockout mice, but not Akt1 or Akt3 knockout insulin signaling [3]. MAPK pathway activation by insulin

mice, develop diabetes with , hyperinsuli- signaling is responsible for expression, cell growth

nemia, glucose intolerance, and impaired muscle glucose and mitogenesis (Figure 1). In contrast to the decrease in

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Box 1. IRS and Akt signaling

Activation of InsR by insulin stimulation results in the binding and signaling are key therapeutic targets for various human

phosphorylation of IRS proteins (IRS1–IRS4) [74]. Phosphorylated including T2D and cancer. Akt1 and Akt2 are ubiquitously expressed,

tyrosine residues on IRS serve as docking sites for downstream even though Akt2 is more concentrated in insulin-sensitive tissues

signaling molecules with SH2 domains such as PI3K, which is crucial such as liver, muscle and adipose tissue. Akt3 expression is restricted

for Akt activation. In addition to over 20 tyrosine residues, IRS to the , testis, lung and pancreatic islets, with virtually no

proteins contain more than 50 potential serine/threonine phosphor- expression in visceral organs and muscle. Targeted deletion of Akt

À/À

ylation sites. Because serine phosphorylation of IRS1 triggers its demonstrates the unique roles of each isoform. Akt2 mice develop

degradation, this step is generally considered a negative regulator of IR and mild glucose intolerance, implying that Akt2 plays a crucial role

À/À

insulin signaling that contributes to the development of IR [8]. In an IR in energy homeostasis. Akt1 mice display mild growth retardation

state, there is abnormal activation of the kinases that phosphorylate and increased apoptosis, suggesting the important role of Akt in cell

À/À

multiple serine residues on IRS proteins, resulting in impaired insulin growth and survival. Interestingly, Akt1 mice display improved

À/À

signaling [8]. Multiple IRS serine kinases are activated during IR [8]. insulin sensitivity and reduced blood glucose levels. Akt3 mice

Increased IRS serine phosphorylation in IR states including obesity have smaller . Full activation of Akt requires the phosphoryla-

and T2D are reported in both animal and human studies [75]. tion of a threonine residue in the catalytic domain, and of a serine

Although IRS1 serine phosphorylation generally inhibits insulin residue in the hydrophobic motif by PDK1 and the mTORC2 complex,

signaling, recent reports suggest it may have positive roles for cell respectively (Figure 1). Once activated, Akt phosphorylates various

growth and mitogenesis [76]. substrates, leading to their activation or inactivation. These substrates

Akt (Akt1, Akt2 and Akt3), also known as PKB (PKBa, PKBb and contribute to the regulation of cellular processes such as cell cycle

PKBg), is a serine/threonine kinase activated downstream of growth control, growth and proliferation, survival, protein synthesis and

factors and various cellular stimuli. Many molecules involved in Akt glucose metabolism. Detailed reviews are given in [10,12].

PI3K/Akt activity, MAPK activity remains relatively nor- below). Intrathecal, but not subcutaneous, infusion of low-

mal in IR [17]. MAPK can phosphorylate IRS1 at specific dose insulin for 1 month significantly improves the function

serine residues and interfere with its signaling [8]; there- of motor and sensory nerves, measured by electrophysiolo-

fore, inappropriately high MAPK activity when IRS1 func- gy, in a (T1D) rat model [22]. Intrathecal

tion is already impaired could lead to worsening of IR. insulin infusion also prevents axonal atrophy of sensory

Proper insulin signaling is crucial to maintaining glu- nerves. These results suggest that lack of proper trophic

cose homeostasis. In IR, insulin signaling is impaired at support by insulin on peripheral neurons might be one

multiple levels, resulting in imbalance between glucose mechanism for the development of PNS dysfunction, espe-

uptake and production in peripheral tissues. Most studies cially neuropathy. Unfortunately, there is very little knowl-

of IR, however, have focused on metabolically active tissues edge about the neuronal signaling mechanisms downstream

such as muscle or adipocytes, and there is surprisingly of InsR in the PNS (Figure 2). It was only recently reported

little knowledge about IR in neurons. In the following that DRG neurons predominantly express IRS2 [23]. IRS2

sections we discuss insulin signaling in neurons and neu- serine phosphorylation is significantly increased in DRG

ronal IR as a potential contributor to the development of neurons from both type 1 and 2 diabetic mice with neuropa-

neurodegenerative diseases. thy. In addition, insulin-stimulated Akt phosphorylation

and neurite outgrowth are decreased in DRG neurons from

The role of insulin receptor signaling in neurons a model of T2D and neuropathy, the ob/ob mouse [23].

Although neurons are not insulin-dependent, they are InsRs are widely expressed in the brain, including the

insulin-responsive [18]. The InsR and downstream signal- olfactory bulb, , , hypothala-

ing molecules including IRS are expressed throughout the mus and amygdala [24]. InsRs are more concentrated in

peripheral and central nervous systems (PNS and CNS) neurons compared to glial cells and are especially high in

(Figure 2). Both InsR mRNA and protein are detected in postsynaptic densities [25]. Along with leptin, insulin in

peripheral sensory neurons of dorsal root ganglion (DRG) the brain is best known for its role in the control of energy

neurons [19]. InsR expression is especially high in small- homeostasis [26]. Direct administration of insulin to the

diameter sensory DRG neurons and lateral laminae V and brain reduces food intake and body weight. By contrast,

X of the spinal cord, suggesting the involvement of insulin both insulin antibody infusion to hypothalamus [27] and

signaling in nociceptive pathways. Immunohistochemistry -specific deletion of InsR (NIRKO) in mice [28] give

demonstrates preferential expression of InsRs at the peri- rise to hyperphagia and obesity. Insulin also regulates

karya of DRG neurons [20]. Intrathecal injection of insulin peripheral glucose metabolism and increases insulin sen-

rescues and regenerates sural nerves after crush injury, sitivity by reducing hepatic glucose production. This effect

demonstrating a direct neurotrophic effect of insulin in is mainly regulated through InsR signaling in the ventro-

peripheral neurons [20]. Systemic insulin injection also medial portion of the hypothalamus [26].

accelerates reinnervation of motor axons after sciatic nerve Although controversial, there is evidence that insulin

transection [21]. With direct injury to the PNS, neuronal may play important roles in learning and . Intrana-

regeneration or reinnervation is associated with increased sal insulin administration improved working memory in

InsR expression. both human and animal studies [29]. Intrahippocampal

A common problem in the PNS is distal-to-proximal loss delivery of insulin, but not IGF-I, improves hippocampus-

of nerve function, a condition known as neuropathy. The dependent spatial working memory [30]. InsR mRNA and

most common cause of neuropathy in the Western world is protein levels are upregulated in the hippocampus in asso-

diabetes, with an estimated 60% of patients with diabetes ciation with short-term memory formation after a spatial

afflicted with diabetic neuropathy (DN) (discussed in detail learning experience [31]. Furthermore, poor cognitive

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Insulin InsR

Energy homeostasis IRS p110 Learning and memory P P P p85 Peripheral glucose metabolism

P Akt P

Downstream CNS signaling pathways

Regeneration Reinnervation PNS Survival

TRENDS in Endocrinology & Metabolism

Figure 2. Insulin action in the CNS and PNS. Even though neurons are generally not considered to be insulin-dependent, they are responsive to insulin, and InRs are widely

distributed in both the PNS and CNS. Insulin signaling is important for various aspects of neuronal functions including energy homeostasis, learning and memory,

peripheral glucose metabolism (PNS), and regeneration, reinnervation and survival (CNS).

performance in diabetes or AD is associated with IR and/or DN is the most common and costly complication of both

decreased InsR signaling [26]. Similarly, the anti-diabetic T1D and T2D. It is defined as ‘the presence of symptoms

drugs and peroxisome proliferator-activated receptor gam- and/or signs of peripheral nerve dysfunction in people with

ma (PPARg) agonists, pioglitazone and rosiglitazone, dem- diabetes after exclusion of other causes’ [35]. The onset of

onstrate mixed results for improvements in memory in both DN correlates with the duration of diabetes; 50% of

human and animal studies [32]. However, NIRKO mice, patients develop DN after 25 years of diabetes [35]. In a

despite the complete loss of neuronal InsRs and signaling, cross-sectional study in the UK the overall prevalence of

demonstrate little alteration in spatial learning [33]. A DN was 28.5% of diabetic patients, which increased to 44%

recent report demonstrates that brain-specific IRS2 knock- in patients over 70 years of age [36]. DN is the leading

out mice have enhanced hippocampal spatial memory, sug- cause of non-traumatic lower limb amputations and costs

gesting that IRS2 acts as a negative regulator of memory for the treatment of DN and associated morbidities in the

formation [34]. US exceed $11 billion annually (up to 27% of the direct

As discussed above, the important role of insulin in medical cost of diabetes).

many aspects of neuronal function in both the PNS and Studies by the Diabetes Control and Complications

CNS suggests that the development of IR may play a role in Trial (DCCT) research group provide a clear connection

the pathogenesis of neurological diseases [21]. The follow- between chronic hyperglycemia and the development of

ing sections summarize current evidence indicating that DN [37]. Currently, strict glycemic control is one of the very

IR is instrumental in the development of diseases of the few available treatment options for DN. Studies focused on

PNS and CNS, using DN and AD, respectively, as the best- the glucose metabolic pathway suggest that overproduc-

studied examples. tion of sorbitol and amino sugars due to activation of the

polyol and hexosamine pathways, excess or inappropriate

Diabetic neuropathy activation of protein kinase C (PKC) and accumulation of

Diabetes is a complex metabolic disorder characterized by advanced glycation endproducts, among others, contribute

hyperglycemia and associated microvascular and macro- to the pathogenesis of DN. All of these pathways are

vascular complications, including retinopathy, nephropa- related to the metabolic and/or redox state of the cells.

thy, neuropathy and CVD. According to recent data from Readers are encouraged to refer to recent reviews for more

the Centers for Disease Control and Prevention (http:// detailed biochemical and molecular , and

www.cdc.gov/diabetes/pubs/), 25.8 million people (8.3% of their application to therapeutic strategies for DN [38,39].

the US population) are diagnosed with diabetes, with

another 79 million adults with . Diabetes costs IR and DN

$174 billion in direct and indirect expenses (22% of total Studies in the last 10 years clearly suggest that insulin is a

medical expenses). Diabetes is the leading cause of kidney neurotrophic factor responsible for regulating neuronal

failure and new cases of blindness among adults and is a growth, survival and differentiation [20,21]. As discussed

major cause of heart disease and stroke in the USA. above, InsR and IRS are widely expressed in peripheral

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neurons in both the cell body and axons [19,20,23]. There of AD are the appearance of senile plaques composed of

are a variety of opinions concerning the pathogenesis of DN amyloid b (Ab) peptides and neurofibrillary tangles (NFTs)

[39]. Considering the important neurotrophic role of insu- derived from the aggregation of microtubule-associated pro-

lin, it is possible that perturbation of insulin signaling tein tau (Box 2). Aging is the most definitive for

during IR (both insulin deficiency in T1D and hyperinsu- AD, with the incidence doubling every 5 years in the popu-

linemia in T2D) result in neurodegeneration and contrib- lation over 65 years of age; 50% of people over 85 years of age

ute to the pathogenesis of DN. Insulin administration are affected by various degrees of AD. AD currently affects

relieves painful DN [40] and reverses slowing of motor 5.4 million Americans and the incidence is expected to reach

and sensory conduction velocities [22] in animal models of over 16 million by 2050 (http://www.alz.org/downloads/

T1D, suggesting a direct role of insulin on neurons. Facts_Figures_2011.pdf). It is estimated to cost $183 billion

Nevertheless, the direct effect of IR on the development in direct medical expenses, with another $202.6 billion

of DN remains poorly understood. It was recently demon- accounting for unpaid economic expenses for care-givers;

strated that neurons indeed develop IR following hyper- the medical expense is estimated to increase to $1.1 trillion

insulinemia in a manner similar to that in metabolic by 2050.

tissues [41]. Development of IR on chronic insulin treat-

ment is accompanied by a decrease in insulin stimulation MetS and AD

of Akt, p70S6K and GSK3b, but does not affect MAPK- Multiple studies report that patients with MetS have an

mediated signaling pathways, a result mimicking that increased risk of developing AD compared to age- and

seen in muscle and adipocytes [17,42]. Similarly, insu- gender-matched controls. Accumulating evidence suggests

lin-induced Akt stimulation is also reduced in DRG neu- that AD is closely related to dysfunction of both insulin

rons from animal models of T2D that develop DN: db/db signaling and glucose metabolism in the brain, prompting

and ob/ob mice [23,41]. Interestingly, hyperinsulinemia- some investigators to refer to AD as type 3 diabetes or an

mediated decreases in Akt phosphorylation are reversed insulin-resistant brain state [51,52]. The Rotterdam study

by PI3K, but not MAPK, inhibition [41]. However, there suggests that IR, but not blood glucose, is associated with a

are conflicting reports on the roles of IRS proteins in higher risk of AD [53]. Another study demonstrates that

decreased Akt phosphorylation in neurons [23,41].

One of the key pathological features of diabetes and IR

in metabolic tissues is increased due to Box 2. Ab and tau

mitochondrial dysfunction, and this is characterized by

Two of the most prominent pathological characteristics of AD are

smaller mitochondrial size and decreased mitochondrial amyloid plaques and NFTs [50]. Amyloid plaques are composed of

Ab produced by the proteolytic cleavage of APP, whereas the major

DNA content [43]. Similar disruption of mitochondrial

component of NFTs is aggregated tau. Ab species that are 39–42

fission–fusion machinery is present in several neurological

amino acids long are generated by sequential cleavage of APP by b-

disorders [44,45]. In addition to a role in cellular energy

site APP-cleaving enzyme 1 (BACE-1), and g-secretase, a complex of

(ATP) production, mitochondria are important mediators at least five different proteases. Oligomeric aggregates of Ab42 are

of cellular function by integrating glucose and lipid metab- the most neurotoxic intermediate. By contrast, when APP is cleaved

by a-secretase, this leads to the production of a non-amyloidogenic

olism [43]. Insulin regulates mitochondrial metabolism

peptide that is not toxic to cells. An imbalance between production,

and oxidative capacity through PI3K/Akt signaling

accumulation and clearance of Ab results in the deposition of

[43,46]. Therefore, decreased Akt signaling by hyperinsu-

plaques and initiation or progression of AD (amyloid hypothesis).

linemia-mediated IR may have profound effects on mito- Under normal conditions, the main function of tau is in the

chondrial function in neurons and result in subsequent stabilization of neuronal microtubules, especially in axons, the

maintenance of cellular morphology and the transport of molecules

increased oxidative stress. It was recently demonstrated

and organelles. Tau is regulated by post-translational modifications

that glucose-mediated oxidative stress contributes to the

including phosphorylation, glycation, glycosylation, sumoylation,

development and progression of DN by inducing an imbal-

O-GlcNAcylation and cleavage [77]. In AD, tau is abnormally

ance in mitochondrial biogenesis and fission [47,48]. Simi- phosphorylated at its over 80 serine/threonine residues, followed

larly, chronic insulin treatment induces mitochondrial by aggregation of tau filaments appearing as NFTs in cell bodies

and proximal dendrites. Several kinases (GSK3b, cyclin-dependent

dysfunction by increasing expression of the fission protein

kinase 5, extracellular signal-regulated kinase, microtubule affinity-

Drp1 in adult DRG neurons [41]. These studies suggest

regulating kinases) and phosphatases (protein phosphatase 2A) are

that chronic insulin stimulation in vivo and in vitro results

responsible for tau phosphorylation. The evidence indicates that

in the disruption of Akt signaling and mitochondrial bio- both hyperphosphorylation and tau cleavage play an important role

in the progression of AD. Tau truncations enhance its capacity to

genesis, a result of IR in DRG neurons. We contend that

aggregate and serve as a nucleation center, promoting the

disruption of insulin signaling due to IR makes PNS

pathologic assembly of tau filaments. Truncated tau induces

neurons more vulnerable to metabolic insults such as

apoptosis of cortical neurons in vitro and when expressed in

hyperglycemia and contributes to the development of transgenic animals results in reduced spatial memory and impaired

DN [41,49]. reflexes. Similar to Ab, the intermediate oligomeric form of tau is

more neurotoxic than helical filaments. NFTs are more closely

AD related to the severity of cognitive impairment than amyloid

pathology. Studies suggest that tau is required for Ab toxicity and

AD is a progressive neurodegenerative disease character-

blocking of tau expression with antisense oligonucleotides com-

ized by loss of memory and other cognitive functions nec- pletely blocks Ab toxicity in rat embryonic cortical neuron cultures

essary to perform complex daily activities [50]. It is the [78]. However, there is also a view that amyloid plaques and NFT

formation are protective responses against more toxic oligomeric

most common form of dementia, accounting for over 70% of

forms of Ab and tau [79,80].

all cases. The most prominent neuropathological features

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both hyperinsulinemia and hyperglycemia are associated of NFT [68] (Box 2). Impaired insulin signaling reduces

with an increased risk of senile plaque formation, but not GSK3a/b phosphorylation, and thus constitutively activates

NFTs, after adjustment for age, sex, systolic blood pres- these molecules, which affects both Ab and tau accumula-

sure, total cholesterol, body mass index, habitual smoking, tion. It is also reported that decreased insulin-stimulated

regular exercise and CVD [54]. IR is associated with re- Akt phosphorylation resulting from chronic hyperinsuline-

duced cerebral glucose metabolism (CMRglu) in various mia reduces GSK3b phosphorylation, in other words, acti-

brain regions in cognitively normal adults with prediabe- vation [49]. In addition, constitutively active Akt inhibits

tes and T2D, and is suggested as a marker for AD even APP trafficking and Ab secretion through feedback inhibi-

before the onset of mild cognitive impairment [55]. A tion of IRS and PI3K [69]. Therefore, precise regulation of

detailed analysis of 14 high-quality longitudinal studies Akt signaling is crucial for both amyloid and tau neuropa-

from MEDLINE and EMBASE searches [56] demonstrates thology in AD.

that individuals with T2D have a greater than twofold Impaired glucose metabolism due to IR affects AD

increased risk of developing AD compared to individuals neuropathology by dysregulation of O-GlcNAcylation, a

without T2D, adjusted for age and sex, education and protein modification by O-linked N-acetyl-D-glucosamine

vascular risk factors (including a history of stroke, hyper- (GlcNAc). Similar to phosphorylation, O-GlcNAcylation is

tension, and heart disease). a dynamic post-translational modification involving the

The role of MetS and IR in AD is also evident from attachment of GlcNAc moieties to the hydroxyl groups of

animal studies. Control animals fed with a high-fat diet serine and threonine residues [70]. In some cases O-

performed poorly in a cognitive test, which correlated well GlcNAc may occur at or near residues that can also be

with the development of IR but not with weight gain [57]. phosphorylated, thereby modulating each other. APP is

Similarly, development of IR on drinking fructose water is modified by O-GlcNAc in a region that may affect its

correlated with increased Ab production, which is pre- degradation, and a recent report demonstrates that O-

vented by treatment with the insulin sensitizer pioglita- GlcNAcylation of APP encourages non-amyloidogenic pro-

zone [58]. Age-dependent increases in tau phosphorylation cessing of APP, thus decreasing Ab production and secre-

and cleavage are observed in the best-characterized T2D tion [71]. Tau has at least 12 O-GlcNAcylation sites, which

mouse model, the db/db mouse [59]. Furthermore, induc- are mostly inversely correlated with phosphorylation sta-

ing diabetes and IR by streptozotocin (STZ) or a high-fat tus [70]. Recent reports demonstrate that reduced brain

diet in AD animal models exacerbates both amyloid and glucose metabolism and O-GlcNAcylation result in in-

tau accumulation [60,61]. creased tau phosphorylation in both in vivo and in vitro

The converse is also true, because patients with AD are models [72]. Therefore, disruption of glucose metabolism

also more likely to develop diabetes. The Mayo Clinic AD due to IR may affect both amyloid and tau pathology.

Patient Registry reveals that 80% of AD patients have Conversely, Ab can inhibit insulin signaling. All forms

either T2D or an level [62]. Many of Ab, including monomers, oligomers and Ab-derived

features of MetS, including obesity, dyslipidemia and IR, diffusible ligands (ADDLs), directly bind to InsR and pre-

are risk factors not only for diabetes and CVD but also for vent insulin signaling [73]. Intracellularly, Ab prevents the

AD [63]. interaction of PDK1 with Akt and inhibits Akt activation

[51]. Therefore, there may be a feed-forward mechanism

Molecular mechanism for the role of IR in AD between impaired insulin signaling and increased Ab pro-

Brain insulin signaling plays crucial roles in the regulation duction to further exacerbate AD pathology in the presence

of food intake, body weight and reproduction, as well as in of IR.

learning and memory [64]. Defective insulin signaling is

associated with decreased cognitive ability and develop- Concluding remarks and future perspectives

ment of dementia, including AD [65]. A recent study dem- IR is the core pathogenic feature of MetS, a cluster of

onstrated a decrease in the phosphorylation of similar disorders including diabetes, obesity, dyslipidemia and

insulin signaling molecules in both AD and T2D patient hypertension, all of which lead to increased CVD. Until

brains. The decrease was more severe in the brains of recently, the study of IR was mainly focused on metabolic

patients with both AD and T2D [66]. Disruption of insulin tissues such as muscle and adipose tissue; recent data,

signaling makes neurons more vulnerable to metabolic however, suggest that IR also develops in the nervous

stress, thus accelerating neuronal dysfunction. system. IR in sensory neurons makes cells respond inap-

As in peripheral tissues, IR predominantly affects PI3K/ propriately to growth factor signals, and this impairment

Akt signaling in the brain. It was demonstrated that insulin- may contribute to the development of neurodegeneration

stimulated Akt phosphorylation is decreased in hyperinsu- and subsequent DN. IR in diabetes is tightly correlated

linemic conditions in cortical neuron cultures [49]. Further- with the increased risk of AD by making cortical and

more, db/db cortical slice cultures display increased basal hippocampal neurons more vulnerable to Ab and tau

Akt phosphorylation and insulin cannot further stimulate toxicity. In both systems, decreased Akt signaling is the

+

Akt phosphorylation as it does in non-diabetic control (db ) common feature of neuronal dysfunction. Akt signaling is

cortex. One of the key signaling molecules activated down- crucial for cell survival and normal cell function. We

stream of Akt is GSK3ab [67]. GSK3a increases Ab produc- speculate that IR accelerates neuronal dysfunction by

tion by stimulating amyloid precursor protein (APP) preventing neurons from responding to the neurotrophic

g-secretase activity, whereas GSK3b is the major tau kinase properties of insulin and rendering them more susceptible

responsible for its hyperphosphorylation and the formation to a variety of injurious stimuli (Figure 3).

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Metabolic syndrome (a) (b) Insulin Insulin

InsR Neuronal insulin resistance

P P IRS P P IRS

P Akt P Akt

Loss of insulin-mediated neurotrophism increases neuronal susceptibility to toxic/ Normal metabolic injury neuronal function Neuronal

dysfunction Diabetic Alzheimer’s neuropathy disease

TRENDS in Endocrinology & Metabolism

Figure 3. Model of the development of neuronal IR. (a) Insulin-mediated signaling activates Akt and maintains normal neuronal function. (b) In the presence of MetS, as in

insulin-dependent tissues, neurons develop IR, and in turn cannot respond to the neurotrophic properties of insulin. Neurons become more susceptible to neurotoxic

stimuli, resulting in neuronal dysfunction and the onset and progression of neurologic disease states.

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