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BRAINA JOURNAL OF NEUROLOGY

REVIEW ARTICLE

Parkinsons disease, insulin resistance and novelagents of neuroprotectionIciar Aviles-Olmos,1 Patricia Limousin,1 Andrew Lees2 and Thomas Foltynie1

1 Sobell Department of Motor Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK

2 Reta Lila Weston Institute, 1 Wakefield Street, London WC1N 1PJ, UK

Correspondence to: Thomas Foltynie,

Box 146, National Hospital for Neurology and Neurosurgery,

Queen Square,

London WC1N 3BG, UK

E-mail: [email protected]

Multiple avenues of research including epidemiology, molecular genetics and cell biology have identified links between

Parkinsons disease and type 2 diabetes mellitus. Several recent discoveries have highlighted common cellular pathways that

potentially relate neurodegenerative processes with abnormal mitochondrial function and abnormal glucose metabolism. This

includes converging evidence identifying that peroxisome proliferator activated receptor gamma coactivator 1-a, a key regulator

of enzymes involved in mitochondrial respiration and insulin resistance, is potentially pivotal in the pathogenesis of neurode-

generation in Parkinsons disease. This evidence supports further study of these pathways, most importantly to identify neu-

roprotective agents for Parkinsons disease, and/or establish more effective prevention or treatment for type 2 diabetes mellitus.

In parallel with these advances, there are already randomized trials evaluating several established treatments for insulin resist-

ance (pioglitazone and exenatide) as possible disease modifying drugs in Parkinsons disease, with only preliminary insights

regarding their mechanisms of action in neurodegeneration, which may be effective in both disease processes through an action

on mitochondrial function. Furthermore, parallels are also emerging between these same pathways and neurodegeneration

associated with Alzheimers disease and Huntingtons disease. Our aim is to highlight this converging evidence and stimulate

further hypothesis-testing studies specifically with reference to the potential development of novel neuroprotective agents in

Parkinsons disease.

Keywords: Parkinsons disease; type 2 diabetes; neuroprotection; Alzheimers disease

Abbreviations: PGC1 = peroxisome proliferator activated receptor gamma coactivator 1 ; MPTP = 1-methyl 4-phenyl1,2,3,6-tetrahydropyridine; PINK1 = PTEN-induced putative kinase 1; PARIS = parkin interacting substrate

IntroductionThe pathogenesis of Parkinsons disease is gradually beingelucidated through the combined efforts of epidemiologists, gen-

eticists and molecular and cell biologists. Overlapping and inter-

related pathways involving mitochondrial turnover (mitophagy and

mitochondrial biogenesis), neuroinflammation and aggregation

and disaggregation of toxic protein oligomers, all appear to be

contributory. While these discoveries represent clear progress,

from the patients perspective, there remains a greater urgencyto search for and test potential neuroprotective or even neuror-

estorative treatments even prior to a definitive understanding of

disease pathogenesis.

Important steps in this neurodegenerative pathway have recently

been discovered highlighting links between Parkinsons disease

pathogenesis and the mechanisms underlying the development of

doi:10.1093/brain/aws009 Brain 2012: Page 1 of 11 | 1

Received August 18, 2011. Revised November 21, 2011. Accepted November 25, 2011.

The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

For Permissions, please email: [email protected]

Brain Advance Access published February 17, 2012


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insulin resistance. This is particularly noteworthy since several agents

used in the treatment of type 2 diabetes have been shown to be

neuroprotective in animal models of Parkinsons disease and are

now being evaluated in randomized controlled trials in patients with

Parkinsons disease. This review provides a synthesis of the emerging

links between Parkinsons diseasepathogenesis and insulin resistance

to generate hypotheses that can be further confirmed or refuted, and

to describe the basis for the investigation of anti-diabetes agents as

possible neuroprotective agents in Parkinsons disease.

Search strategyReferences for this review were identified through searches

of PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) with the

search terms: Parkinsons disease, neurodegeneration, diabetes,

insulin resistance, mitochondrial, PGC1, pioglitazone and exena-

tide from 1990 to May 2011. Articles were also obtained through

searches of the authors own files. Only papers published in

English were reviewed. The final reference list was generated on

the basis of relevance to the broad scope of this review.

Links between Parkinsons disease andtype 2 diabetes mellitus

Epidemiology

Evidence from prospective epidemiological studies has identified type

2 diabetes mellitus as an independent risk factor for multiple diseases

of the nervous system such as diabetic neuropathy (Boulton et al.,

2005), stroke (Tuomilehto et al., 1996; Hu et al., 2006) and more

recently Alzheimers disease (Leibson et al., 1997; Ott et al., 1999;

Peila et al., 2002). There are also reports of varying associations be-

tween diabetes or abnormal glucose tolerance and sporadic forms ofParkinsons disease from both cross-sectional and cohort studies.

Survey data reveal that diabetes is established in 830% of patients

with Parkinsons disease, consistently in excess of the prevalence

found in non-Parkinsons disease individuals (Chalmanov and

Vurbanova, 1987; Pressley et al., 2003). This might be readily ex-

plained by increased detection of hyperglycaemia through additional

medical contact/urine/blood tests among individuals with

Parkinsons disease regularly attending hospital appointments. The

association is strengthened by reports suggesting that up to 5080%

of patients with Parkinsons disease haveabnormal glucose tolerance

when tested (although these figures are from non-contemporary

papers and we are unaware of confirmatory data from more recent

cohorts) (Barbeau etal., 1961; Elner and Kandel,1965; Lipman etal.,1974; Sandyk, 1993); however, in a series of 800 patients with

Parkinsons disease, concurrent diabetes was indeed shown to accel-

erate progression of both motor and cognitive symptoms (Schwab,

1960). In view of the possible confounding effects of Parkinsons

disease treatment, newly diagnosed, never-treated adults with

Parkinsons disease have also been studied and been shown to have

reduced insulin-mediated glucose uptake (Van Woert and Mueller,

1971), inhibition of early insulin secretion and long-term hyperinsu-

linaemia and hyperglycaemia after glucose loading (Boyd et al.,

1971). This takes into account the effects of some drugs used to

treat Parkinsons disease, such as levodopa, which induces both

hyperglycaemia and hyperinsulinaemia, whereas others (including

the ergot dopamine agonist bromocriptine) may increase insulin sen-

sitivity (Van Woert and Mueller, 1971; Sirtori et al., 1972).

Neuropathological studies of patients with Parkinsons disease

have shown that insulin receptors are densely represented on

the dopaminergic neurons of the substantia nigra pars compacta

(Unger et al., 1991) and loss of insulin receptor immunoreactivity

and messenger RNA in the substantia nigra pars compacta of pa-

tients with Parkinsons disease coincides with loss of tyrosine

hydroxylase messenger RNA (the rate-limiting enzyme in dopa-

mine synthesis) (Moroo et al., 1994; Takahashi et al., 1996).

Indeed abnormal glucose utilization has been specifically shown

in the brains of patients with Parkinsons disease undergoing

either magnetic resonance spectroscopy (Bowen et al., 1995) or

fluorodeoxyglucose-PET (Hu et al., 2000) demonstrating increased

lactate concentrations and glucose hypometabolism, supporting

the hypothesis that Parkinsons disease is a systemic disorder char-

acterized by a derangement of oxidative energy metabolism.

Further evidence for a positive association between Parkinsons

disease and type 2 diabetes mellitus has been obtained from pro-spective cohort studies. A statistically significant direct association

between triceps skinfold thickness and the risk of Parkinsons dis-

ease has been found in the Honolulu Heart Program (Abbott

et al., 2002) and both excess weight (Hu et al., 2006) and type

2 diabetes mellitus itself (Hu et al., 2007) were associated with an

increased risk of Parkinsons disease in a population-based pro-

spective cohort of Finnish males and females. This association

was independent of the known modifying factors such as smoking

status, coffee and alcohol consumption and body weight, tempt-

ing speculation regarding common pathways underlying the de-

velopment of these conditions. Nevertheless, a recent cohort study

could not replicate an association between either type 2 diabetes

mellitus or obesity and Parkinsons disease risk although the au-thors acknowledge that diagnosis of type 2 diabetes mellitus was

entirely based on self-report (Palacios et al., 2011).

Hyperglycaemia and dopamine

Any link between Parkinsons disease and type 2 diabetes mellitus

may relate to abnormalities in a common pathway or indirectly as

a consequence of chronic hyperglycaemia or hyperinsulinaemia.

Animal and in vitro studies have suggested a role for insulin in

the regulation of brain dopaminergic activity featuring a reciprocal

regulation between the two chemicals (Craft and Watson, 2004).

In the rat, elevation of glucose concentrations in the blood, to

levels equivalent to those produced by a meal or stress, suppresses

the firing of dopamine-containing neurons located within the sub-stantia nigra and prevents or reverses the increase in discharge

rates of dopaminergic cells normally elicited by the dopamine-

receptor antagonist haloperidol (Saller and Chiodo, 1980).

Administration of glucose to rats has also been shown to produce

a significant decrease of dopamine turnover in both striatum

and olfactory tubercle (Montefusco et al., 1983). Furthermore,

hyperglycaemia related to hypoinsulinaemia resulting from

streptozotocin-induced diabetes (which leads to toxicity to b islet

cells and is a model of type 1 diabetes mellitus) has been shown to

decrease basal dopamine concentrations and amphetamine-

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induced dopamine overflow in the mesolimbic cortex (Murzi et al.,

1996).

Chronic hyperglycaemia leads to oxidative stress and the pro-

duction of reactive oxygen species, which has been implicated in

the ongoing b cell death in type 2 diabetes mellitus (Evans et al.,

2002). While production of reactive oxygen species may also be a

mechanism underlying dopaminergic cell loss in hyperglycaemic

animals, this remains speculative, and a further possibility emerges

from work demonstrating that in both insulin-deficient rats and

insulin-resistant mice, diabetes impairs hippocampus-dependent

memory, synaptic plasticity and adult neurogenesis (Stranahan

et al., 2008, 2010). However, given that any epidemiological

association between Parkinsons disease and dopamine appears

restricted to type 2 diabetes mellitus, it is likely that chronic hyper-

glycaemia per se, is only a minor risk factor for Parkinsons disease

in humans.

Insulin resistance and mitochondrialdysfunction

The development of insulin resistance in humans is closely corre-

lated with immune cell infiltration and inflammation, with clear

links between the development of obesity, type 2 diabetes mellitus

and cardiovascular disease (Hotamisligil, 2006). Unambiguous links

have also been established between exercise, obesity, insulin

resistance and levels of interleukin-6 (Kern et al., 2001).

Evidence for mitochondrial dysfunction in the development of in-

sulin resistance has been obtained through measuring rates of

in vivo mitochondrial phosphorylation using proton 1(H) magnetic

resonance spectroscopy in the relatives of patients with type 2

diabetes mellitus, finding that rates of mitochondrial ATP produc-

tion are reduced by 30% in the muscle of lean, pre-diabetic insulin

resistant subjects (Petersen et al., 2004). In addition, there aremany specific examples of insulin resistance occurring due to

mitochondrial mutations; it has been estimated that $1.5% of

type 2 diabetes mellitus is attributable to the mitochondrial

A3243G mutation [the cause of mitochondrial encephalopathy,

lactic acidosis and stroke-like episodes (MELAS; Gerbitz et al.,

1995)].

The more widespread development of insulin resistance has also

been proposed to be mediated through mitochondrial dysfunction

(Stark and Roden, 2007) at least to a partial extent through

muscle expression of transcriptional regulators including PGC1,

an important regulator of enzymes involved in mitochondrial

respiration. Expression of PGC1 is rapidly induced following

even a single bout of exercise, which then reverts to baselineafter cessation of exercise to enable fine control of the energy

demands of skeletal muscle (Handschin and Spiegelman, 2008).

Individuals that undergo regular exercise have chronically elevated

levels of PGC1, in association with a switch in muscle fibre type

characterized by increased mitochondrial density and function

(Lin et al., 2002).

Direct exploration of patterns of gene expression associated

with insulin resistance has been studied in skeletal muscle in

patients with type 2 diabetes mellitus as well as non-diabetic in-

dividuals with and without a family history of type 2 diabetes

mellitus. The earliest sign of insulin resistance was shown to be

reduction in expression of PGC1 and the mitochondrial gene

nuclear respiratory factor 1 (NRF1) (Patti et al., 2003) . I n a

whole genome methylation analysis of skeletal muscle from type

2 diabetes mellitus and control subjects, hypermethylation of

PGC1 was found in association with reduced PGC1 messenger

RNA and reduced mitochondrial DNA levels in subjects with type 2

diabetes mellitus. Hypermethylation of PGC1 can be induced by

dietary factors such as fatty acids, as well as cytokines such as

tumour necrosis factor- (TNF-), suggesting a potential mechan-

ism underlying the geneenvironment interaction in type 2 dia-

betes mellitus risk (Barres et al., 2009).

Parkinsons disease and mitochondrialdysfunction

The earliest link between Parkinsons disease and mitochondrial

dysfunction followed the observation that individuals injected

with heroin contaminated with MPTP (1-methyl 4-phenyl

1,2,3,6-tetrahydropyridine) acutely developed parkinsonism

(Langston et al., 1983). Both MPTP and another environmental

toxin, rotenone, were subsequently shown to cause degeneration

of dopaminergic neurons in animal models by selective inhibition

of complex I (Gerlach et al., 1991) suggesting that in humans,

complex I impairment may itself be sufficient to cause the disease.

Complex I (NADH CoQ dehydrogenase) is the first enzyme of the

mitochondrial respiratory chain, playing a crucial role in ATP gen-

eration. Complex I dysfunction decreases ATP production, gener-

ates free radicals and sensitizes cells to the pro-apoptotic protein

Bax thus leading to apoptosis (Perier et al., 2005). A direct relation

between mitochondrial dysfunction and sporadic Parkinsons dis-

ease has been demonstrated in post-mortem tissue, revealing

complex I deficiency (Schapira et al., 1989; Mann et al., 1994)and damage (Keeney et al., 2006) in the substantia nigra of pa-

tients with Parkinsons disease. However, it is likely that neurode-

generation provoked by complex I inhibitors alone is rare.

Complex I toxins may, however, contribute to the pathogenesis

of Parkinsons disease acting in tandem with other environmental

influences and genetic causes (Schapira, 2010). Although also rare,

there are numerous reports of parkinsonism occurring in associ-

ation with mitochondrial mutations including the G11778A muta-

tion associated with Lebers hereditary optic neuropathy (Simon

et al., 1999), polymerase- mutations (Luoma et al., 2007) and

more commonly in association with somatic mitochondrial dele-

tions (Bender et al., 2006). A common mitochondrial haplotype

has also been associated with sporadic Parkinsons disease(Pyle et al., 2005).

Converging evidence suggests that both environmental and

genetic factors can interfere with normal processes of the removal

of damaged or dysfunctional mitochondria known as mitophagy.

Healthy mitochondrial turnover through mitophagy and mitochon-

drial biogenesis as well as ongoing processes of fission, fusion and

mitochondrial budding are all essential to maintain normal cellular

bioenergetic function. This relies on intact mitochondrial DNA,

which is particularly vulnerable to damage by free radicals due

to its lack of a histone coat and limited facilities for repair.

Parkinsons disease and insulin resistance Brain 2012: Page 3 of 11 | 3


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Furthermore mitochondrial DNA mutations, whether induced by

oxidative stress or ageing, have a further effect on complex I and

respiratory chain function leading to increased damage again

through the production of reactive oxygen species (Cooper

et al., 1992). Normal human substantia nigra and striatum exhibit

the greatest free radical-mediated mitochondrial damage with age

(Kraytsberg et al., 2006). Other cellular pathways essential for

normal mitochondrial turnover have been identified directly as a

result of the identification of specific gene mutations causing

Mendelian forms of Parkinsons disease (Schapira, 2008).

Parkin mutations cause autosomal recessive juvenile parkinson-

ism. Intracellular localization studies have reported the association

of parkin and mitochondria (Stichel et al., 2000). The function of

parkin is not completely clear but the protein has E3 ligase activity,

and is thought to monitor the quality of mitochondria and trigger

mitophagy of dysfunctional mitochondria (Rakovic et al., 2010),

by triggering the ubiquitinproteasome system (Chan et al.,

2011). Parkin knockout mice have demonstrated alterations in

abundance and/or modification of a number of proteins involved

in mitochondrial function or oxidative stress, with reductions in

several subunits of complexes I and IV, and functional assaysshowing reductions in respiratory capacity of striatal mitochondria

isolated from parkin/ mice. Furthermore, these mice show a

delayed rate of weight gain, suggesting broader metabolic

abnormalities (Palacino et al., 2004). Mitochondrial function has

also been shown to be decreased (complex I and IV activities) in

peripheral blood from patients with parkin mutations (Muftuoglu

et al., 2004).

PINK1 (PTEN-induced putative kinase 1) mutations also cause

autosomal recessive juvenile parkinsonism. The gene encoding

PINK1 encodes a 63-kDa protein with an 8-kDa mitochondrial

targeting sequence. In health, this protein is imported intact into

the mitochondria, where it has been suggested that PINK 1 re-

cruits parkin from the cytoplasm to the mitochondria to initiate theprocess of mitophagy (Vives-Bauza and Przedborski, 2011).

DJ-1 is a 23-kDa protein that is expressed in peripheral tissues

and parts of the brain, including the hippocampus, cerebellum,

olfactory bulb, striatum, substantia nigra pars compacta and sub-

stantia nigra pars reticulata, both in cells bodies and dendrites,

localized to the mitochondrial matrix and intermembrane space

(Zhang et al., 2005). The deletion or silencing of DJ-1 causes

parkinsonism possibly by sensitising cells to oxidative stress,

while over-expression of DJ-1 protects cells implying a protective

role for the protein (Yokota et al., 2003). Substantia nigra neurons

from DJ-1 knockout mice have increased sensitivity to MPTP

and oxidative stress (Kim et al., 2005), while cells derived from

patients with DJ-1 mutations have abnormal mitochondrial morph-ology (Irrcheret al., 2010). DJ-1 has been shown to associate with

the mitochondrial Bcl-XL, an anti-apoptotic protein (Ren et al.,

2011).

-Synuclein (SNCA) mutations can cause autosomal dominant

Parkinsons disease, and -synuclein is the main component of the

pathological feature of Parkinsons diseasethe Lewy body. The

pathological features of Parkinsons disease, can be replicated

by simply over-expressing SNCA in transgenic flies (Feany and

Bender, 2000) suggesting that one mechanism by which neurode-

generation occurs is through a toxic gain-of-function. The exact

function of -synuclein remains unknown, and the relationship

between SNCA oligomers and aggregates, their degradation by

the ubiquitinproteasome and lysosomal systems and neuronal

toxicity requires further work (Wong and Cuervo, 2010). There

are nevertheless indications that SNCA affects various mitochon-

drial pathways (Poon et al., 2005). SNCA co-localizes with cyto-

chrome c forming hetero-oligomers, which can prevent apoptosis,

but in the process forms complexes with prolonged peroxidase

activity that induces protracted oxidative stress (Bayir et al.,

2009). It has also been shown that phosphorylated SNCA (the

dominant form in Parkinsons disease) influences the normal pro-

teinprotein interactions including the pull down of protein com-

plexes involved in mitochondrial electron transport (McFarland

et al., 2008), while over-expression of SNCA leads to the protein

entering mitochondria and interfering with mitochondrial function

(Devi et al., 2008; Chinta et al., 2010).

Leucine-rich repeat kinase (LRRK-2) mutations can also cause

autosomal dominant Parkinsons disease. This protein has GTPase

and kinase domains and study of its interaction with SNCA is on-

going (Greggio et al., 2011). Whether LRRK-2 plays a critical role

in determining the phosphorylation status of SNCA remains to bedetermined, however, it has recently been demonstrated that

in the transgenic G2019S mutant LRRK2 mouse, there is age-

dependent degeneration of dopamine nigrostriatal neurons to-

gether with damaged mitochondria and an increase in mitophagy

(Ramonet et al., 2011).

Glucocerebrosidase (GBA) mutations cause Gauchers disease

and have been identified as a risk factor for Parkinsons disease

even in the heterozygous state (Sidransky et al., 2009). There has

been shown to be a bidirectional link such that SNCA inhibits the

lysosomal activity of GBA and functional loss of GBA leads to

accumulation of SNCA (Mazzulli et al., 2011), potentially explain-

ing the risk of Parkinsons disease through a positive feedback

loop. Other potential mechanisms also include lipid accumulationand impaired mitophagy or mitochondrial trafficking (Westbroek

et al., 2011).

In Parkinsons disease there is therefore ample evidence of mito-

chondrial dysfunction that includes complex I inhibition, oxidative

stress, PINK1 and DJ-1 dysfunction, and an interaction between

parkin and PINK1 that influences mitophagy and mitochondrial

biogenesis. Complex I inhibition initiated by any of a range of

environmental toxins will increase free radical generation, and

thus initiate a vicious cycle of events that further impairs mito-

chondrial function and may enhance any underlying genetic

defects and further impair neuronal activity. Neuroinflammation

undoubtedly leads to further mitochondrial stress through the pro-

duction of reactive oxygen species as well as through the activa-tion of microglia and subsequent release of pro-inflammatory

cytokines such as nitric oxide and TNF- (Whitton, 2007; Tansey

et al., 2008). This can be readily detected through the identifica-

tion of activated microglia on imaging (Gerhard et al., 2006) and

neuropathology (McGeer et al., 1988). The role of a neuroinflam-

matory process in Parkinsons disease is further supported by the

association between the human leukocyte antigen locus and

Parkinsons disease risk in a meta-analysis of genome wide studies

(Nalls et al., 2011) and the reported beneficial effects of

anti-inflammatory agents on risk of Parkinsons disease (Wahner



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et al., 2007). It is likely that multiple pathways remain relevant in

Parkinsons disease pathogenesis with interrelated aspects that

impact on mitochondrial function.

Converging evidence implicatingPGC1a

Converging evidence suggests that cellular pathways leading toeither insulin resistance or neurodegeneration involve mitochon-

drial mechanisms. It is well known that mutations in mitochondrial

DNA can lead to a wide variety of phenotypes that commonly

involve neurodegeneration and diabetes (Hara et al., 1994;

Finsterer et al., 2008). However, these mutations do not account

for a significant proportion of cases of sporadic Parkinsons dis-

ease. Normal mitochondrial biogenesis, respiration and metabolism

of reactive oxygen species requires intact expression of both

nuclear and mitochondrial encoded genomes now recognized as

being regulated by PGC1 (Lin et al., 2005; Finck and Kelly, 2006;

St-Pierre et al., 2006). It has previously been shown that PGC1

has a powerful suppressive effect on reactive oxygen species pro-

duction, in parallel to its effects in elevating mitochondrial respir-

ation. This occurs through the PGC1-mediated expression of

genes involved in reactive oxygen species detoxification, as well

as PGC1 expression that is rapidly induced by these proteins

following a single bout of endurance exercise in vivo (Handschin

and Spiegelman, 2008). Insulin resistant patients show reduced

expression of PGC1 and the mitochondrial encoded gene

COX1 (Heilbronn et al., 2007), while reduction in PGC1-

responsive genes has been shown among patients with type 2

diabetes mellitus and their asymptomatic relatives compared with

healthy controls (Petersen et al., 2004). Indeed polymorphisms in

PGC1 have been associated with an increased risk for type 2

diabetes mellitus in diverse populations (Ek et al., 2001; Haraet al., 2002; Bhat et al., 2007).

PGC1 has also been implicated as having a major role in

Parkinsons disease pathogenesis. Meta-analysis of gene expres-

sion data using microarrays has utilized post-mortem brain hom-

ogenates to look at gene expression in the substantia nigra pars

compacta of patients with confirmed SNCA-positive Lewy body

Parkinsons disease. Robust three tiered analysis from separate

genome wide datasets have indicated that gene sets involved

in mitochondrial electron transport, mitochondrial biogenesis,

glucose utilization and glucose sensing were strongly associated

with Parkinsons disease. Included amongst these gene sets were

10 PGC1 responsive genes. Furthermore it was shown that

over-expression of PGC1 was able to protect dopaminecell loss induced by the mitochondrial toxin rotenone (Zheng

et al., 2010).

In parallel with these discoveries was the identification of a

zinc-finger protein, parkin interacting substrate (PARIS), which is

up-regulated 3-fold in the nigra of patients with not only

parkin-related parkinsonism but also sporadic Parkinsons disease,

and is both necessary and sufficient for the neurodegeneration

associated with parkin animal models (Shin et al., 2011). The

same group further identified that PARIS represses the expression

of PGC1 and PGC1 target genes playing an important role in

mitochondrial function including NRF1, and the oxidative

phosphorylation regulator ATP5b. The site of interaction between

PARIS and PGC1 is a sequence that is involved in the regulation

of transcripts involved in insulin responsiveness and energy metab-

olism (Mounier and Posner, 2006). Although other pathways are

undoubtedly also relevant, it is clear that parkin, PARIS, PGC1

and NRF1 contribute to the pathogenesis of Parkinsons disease.

Loss of expression of PGC1 controlled genes may therefore be a

key link between abnormal mitochondrial function, abnormal glu-

cose utilization and Parkinsons disease. Hypermethylation of

PGC1 during life may follow either genetic or environmental in-

fluences that promote accumulation of free fatty acids, TNF- and

ceramides (Summers and Nelson, 2005; Staiger et al., 2006; Barres

et al., 2009), which might then lead to decompensation of mito-

chondrial bioenergetics and the onset of Parkinsons disease

(Figure 1).

Tissue specificity of mitochondrialdysfunction: parallels between insulin

resistance, Parkinsons disease andother neurodegenerative diseases

There has been considerable speculation regarding the (initially)

selective degeneration of dopaminergic neurons in Parkinsons dis-

ease. Dopaminergic neurons in the substantia nigra pars compacta

have an incredibly complex structure in terms of axon length and

number of synapses (4100 000). Mathematical modelling has

shown that neuronal energetic demand rises exponentially with

axon structure and arbour complexity. This potentially makes

dopaminergic neurons of the substantia nigra pars compacta

more sensitive to energetic stress than other types of dopamine

or indeed non-dopaminergic neurons (Matsuda et al., 2009; Moss

and Bolam, 2010).There is considerable evidence from epidemiology, neuropath-

ology and functional neuroimaging that also implicates diabetes as

a risk factor for cognitive impairment and Alzheimers disease

(Janson et al, 2004; Luchsinger et al., 2007; Toro et al., 2009).

In a study of animal models of double-mutant Alzheimer and dia-

betic transgenic mice, the onset of diabetes has been shown to

exacerbate Alzheimers disease-like cognitive dysfunction (Takeda

et al., 2010). Excessive energy intake appears to affect cognitive

function adversely though oxidative stress, inflammation and im-

paired cellular stress responses (Pistell et al., 2010; Kapogiannis

and Mattson, 2011), mediated via reduced expression and/or ac-

tivity of mitochondrial proteins and oxidative genomic damage

(Bishop et al., 2010). In animal models in which neurotoxicity ismediated by oxidative stress, dietary energy restriction has been

shown to protect neurons and synapses (Guo et al., 2000), while

exercise has been shown to enhance hippocampal neurogenesis

and reduce glucocorticoid levels (Kannangara et al., 2010).

Ageing and chronic hyperinsulinaemia both upregulate genes

for inflammatory/immune pathways and downregulate insulin sig-

nalling genes, blocking glucose utilization and decreasing mito-

chondrial function in hippocampal neurons (Blalock et al., 2010).

This is reflected in the reduction in the activity of several mito-

chondrial enzymes (e.g. pyruvate and isocitrate dehydrogenases,



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-ketoglutarate dehydrogenase complex) in brain tissue samples

from patients with Alzheimers disease (Bubber et al., 2005).

Abnormal distribution of mitochondria in fibroblasts taken from

subjects with Alzheimers disease has been proposed as evidence

that mitochondrial fission/fusion processes may have relevance in

Alzheimers pathogenesis (Wang et al., 2008). Furthermore, there

are data to show an association between reduced PGC1 levels

and Alzheimer pathology in post-mortem human brains, and that

PGC1 over-expression can reduce hyperglycaemia-mediated

b amyloidogenesis (Qin et al., 2009).

In parallel with the complexity of nigro-striatal neurons, hippo-

campal pyramidal neurons have the highest energy requirements

of any neurons in the brain (LaManna and Harik, 1985) and this

may also contribute to their vulnerability to neurotoxicity mediatedvia mitochondrial dysfunction in Alzheimers disease. Analogous

with Parkinsons disease pathogenesis, it is likely that a combin-

ation of factors including amyloid-b oligomer accumulation, oxi-

dative stress as well as a deficit in neurotrophic factor signalling all

play a role in mitochondrial dysfunction in vulnerable neurons

producing mild cognitive impairment and Alzheimers disease

(Mattson et al., 2008). The association of molecular alterations

in Alzheimers disease with perturbed neuronal energy metabolism

and the impact of energy intake and expenditure on cognition and

ageing suggest an important link between Alzheimers disease

pathogenesis and brain energy metabolism that may be amenable

to pharmacological interventions.

Other neurodegenerative diseases also share links with type 2

diabetes mellitus. Patients with Huntingtons disease develop type

2 diabetes mellitus about seven times more often than matched

healthy controls (Podolsky, 1972), and this is a consistent feature

in the mouse models of Huntingtons disease (Hurlbert et al.,

1999), with ensuing demonstrations that the mutant huntingtin

protein has a direct effect on mitochondrial function and traffick-

ing (Orr et al., 2008) and inhibits expression of PGC1 (Cui et al.,

2006). In addition, type 2 diabetes mellitus is a common feature of

Friedreichs ataxia, aceruloplasminaemia and ataxia telangiectasia,

as well as a range of more esoteric disorders featuring neurode-

generation, reviewed in Ristow et al. (2004).

Therapeutic implications

The converging evidence implicating the PARIS/PGC1 pathway

in the neurodegenerative process associated with Parkinsons dis-

ease highlights the need for further study of the therapeutic

effects of PARIS inhibition, and/or PGC1 stimulation as potential

neuroprotective treatments. High-throughput screens can identify

potential compounds for in vitro and in vivo testing ahead of

human trials. Particularly exciting is the realization that some of

Figure 1 Schematic overview of emerging pathways linking insulin resistance and neurodegeneration. FFAS = free fatty acids;HLA = human leucocyte antigen; IL-6 = interleukin 6; LRRK-2 = leucine-rich repeat kinase 2; NO = nitric oxide; PGCI = ppar receptor

coactivator; ROS = reactive oxygen species; UPS = ubiquitin proteasome system; SNCA = synuclein.



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the existing licensed treatments for type 2 diabetes mellitus po-

tentially have beneficial effects on related pathways of mitochon-

drial function, directly or indirectly through an influence on PGC1

activity, and trials have already been initiated to evaluate effects

on patients with Parkinsons disease and/or other neurodegenera-

tive diseases.

Pioglitazone

Pioglitazone is a licensed treatment for patients with type 2 dia-

betes mellitus, and reduces insulin resistance via its action on the

nuclear receptor peroxisome proliferator-activated receptor

gamma (PPAR-). It modulates the transcription of genes involved

in insulin sensitivity. Of major interest is the recent observation

that pioglitazone and other active thiazolidinedione compounds

bind to the outer mitochondrial membrane protein (mitoNEET)

with an affinity comparable to its binding to PPAR- and there

has been a suggestion that many of the clinical effects of

pioglitazone are mediated by binding to mitoNEET (Colca et al.,

2004; Paddock et al., 2007; Wiley et al., 2007). MitoNEET plays a

key role in electron transport and oxidative phosphorylation, and

pioglitazone binding to MitoNeet has been shown to have positiveregulatory effects on complex I activity in neuronal cells (Ghosh

et al., 2007).

Pioglitazone has been shown to be protective against neurode-

generation in MPTP mouse models of Parkinsons disease (Breidert

et al., 2002; Dehmer et al., 2004). The neuroprotective properties

of pioglitazone have been suggested to be mediated via a sequen-

tial action through PPAR activation, inducible nitric oxide synthase

induction and nitric oxide-mediated toxicity (Dehmer et al., 2004).

Pioglitazone has also been shown to be neuroprotective against

the lipopolysaccharide model of Parkinsons disease through

reduction of microglial activation and reduction of oxidative

stress, enabling restoration of mitochondrial function (Hunter

et al., 2007).Conflicting data have, however, suggested that the mechanism

of action of pioglitazone in protection against MPTP induced

neurodegeneration is solely mediated through the inhibition of

monamine oxidase B (MAO-B), which prevents metabolism of

MPTP to the toxic MPP+ (Quinn et al., 2008). In view of this

uncertainty, but responding to the pressing need to evaluate this

agent in patients with Parkinsons disease, a randomized trial has

been initiated to explore possible neuroprotective effects of

pioglitazone among patients already on MAO-B inhibitors

(Clinical Trials.gov Identifier NCT01280123). Pioglitazone is also

being trialled as a treatment for Alzheimers disease (Clinical

Trials Identifier NCT00982202) and Friedreichs ataxia (Clinical

Trials Identifier NCT00811681).

Exenatide

Glucagon-like peptide 1 (GLP-1) is a naturally occurring hormone

that has an important role in insulin and glucose homeostasis but

has a circulating half-life of only 12 min. Exenatide is a synthetic

agonist for the GLP-1 receptor and has been granted a license for

the treatment of type 2 diabetes with confirmed beneficial effects

on glucose control, thought to be mediated by b-cell proliferation,

increased insulin production, decreased gluconeogenesis and

weight loss that follows chronic GLP-1 receptor stimulation in

the gastrointestinal tract (Buse et al., 2004; DeFronzo et al.,

2005; Kendall et al., 2005; Drucker et al., 2008). GLP-1 receptors

are also distributed throughout the brain and stimulation of central

receptors in the hypothalamus is responsible for early satiety.

Further effects from central GLP-1 stimulation are as yet unclear,

but neurotrophic and neuroprotective properties have been iden-

tified in vitro (Perry et al., 2002). Exenatide has been evaluated as

a neuroprotective agent in multiple animal models of Parkinsons

disease (Bertilsson et al., 2008; Harkavyi et al., 2008; Kim et al.,

2009; Li et al., 2009), demonstrating consistent benefits but again

with inconsistent conclusions regarding mechanism of action

whether anti-inflammatory (Harkavyi et al., 2008; Kim Chung

et al., 2009; Kim et al., 2009) or related to stimulation of neuro-

genesis (Bertilsson et al., 2008; Belsham et al., 2009; Li et al.,

2010). More recently, exenatide has been shown to protect

b islet cells from apoptosis, prevent damage to mitochondrial

DNA encoded genes and stimulate mitochondrial biogenesis

(Fan et al., 2010).

Despite this mechanistic uncertainty (and even encouraged by

the potential multiple effects on cell biology) and based on the

encouraging data from the animal Parkinsons disease models, andthe excellent safety profile in patients with type 2 diabetes melli-

tus, recruitment has been completed of patients to a randomized

controlled trial at the UCL Institute of Neurology in Queen Square,

London evaluating the effects of exenatide on Parkinsons disease

(Clinical trials.gov Identifier NCT01174810).

Scientists and physicians interested in Alzheimers disease are

also studying the GLP-1 receptor agonists. Exenatide has been

shown in animals to promote neuronal activity, enhance synaptic

plasticity and cognitive performance (Perry and Greig, 2004).

A randomized clinical trial to assess the safety and efficacy of

exenatide treatment in participants with early Alzheimers disease

is currently recruiting participants at NIA (Clinical trials.gov

Identifier NCT01255163).

ConclusionsA great deal of research has informed on the precise relationships

between exercise, obesity, insulin resistance and cardiovascular

risk. Links between type 2 diabetes mellitus and widely differing

diseases are the subject of increasing interest, aside from the cur-

rent hypothesis regarding Parkinsons disease, including possible

relationships between diabetes and cancer (Giovannucci et al.,

2010). Relationships between insulin, ageing and neurodegenera-

tion have been considered in relation to toxic protein aggregation

and the insulin-like growth factor-1 (IGF-1) signalling pathway(Cohen and Dillin, 2008). Alongside the undoubted importance

of proteo-toxicity in neurodegeneration, the weight of converging

evidence is highlighting the role of impaired mitochondrial func-

tion in both Parkinsons disease and diabetes mellitus, mediated

through PGC1. Therapeutic agents licensed for the treatment of

type 2 diabetes mellitus and potentially having an impact on this

pathway are already being evaluated in randomized controlled

trials of patients with Parkinsons disease. Further identification

of inhibitors and stimulators of the PGC1 pathway in neuronal

cells will undoubtedly follow.



8/11

FundingParkinsons Appeal, the Cure Parkinsons Trust and Parkinsons UK

to T.F. None of these funding institutions had any influence or

involvement in the writing of this article. The authors research

into exenatide is being funded in its entirety by the Cure

Parkinsons Trust.

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