Does the association with diabetes say more about schizophrenia? - the GLUT theory prasanna de silva

sugar – some history

• initially from sugar cane (150 factories, 1750)

• new technology - sugar from beet (1799) causes ‘sugar mountain’

• tax on sugar removed (Gladstone, 1875)

• widespread reporting of adolescent decline ‘dementia praecox’ (Kreapelin, 1894)

dementia praecox (later schizophrenia)

• cognitive deficits seen as the core feature

• hallucinations, delusions, thought disorder

• self neglect due to inattention and apathy

• evidence of continuing deterioration and severe disability in ~20% (‘cure’ in 15 – 20%)

• needed an asylum network

epidemiology

• perinatal deficits (low birth weight, obstetric complications)

• teachers pick up ‘odd’ traits aged 7 – 11

• young (late adolescent / early adult) onset

• predominantly urban / inner city

• family history of psychosis, OCD and diabetes

• acute episodes associated with life events

findings in untreated patients• undirected / purposeless speech and

movements (stereotypies)

• apathy, inattention, poor planning can be seen also at an early stage

• higher rates (5%) of hyperglycaemia in drug naive subjects (1914, 2009)

• low dose Insulin / diet effective (1957) as are neuroleptics (1954 onwards)

• reducing stress beneficial (1977)

12

3

structural brain findings• reduced cortical volume with ventricular enlargement ~ 40%

• decreased size and poor connectivity of neurones in pre frontal cortex and hippocampus ( with reduced synaptic / dendritic markers)

• reduced cortical (mainly frontal) receptor load involving Dopamine1, Glutamate (non NMDA) and 5HT2A

• progressive gray matter loss on serial scanning of individuals

• in childhood schizophrenia x4 loss of frontal gray matter compared to control adolescents.

functional imaging• ‘hypofrontality’- with reduced DA input

• ‘hot spots’ of increased blood flow and metabolism in Broca’s area (motor speech producer) – sp. when hallucinating

• reduced activity in association areas

• increased DA supply to striatum and mesolimbic areas compared to frontal / pre frontal areas

• reduced frontal Glutamate supply to striatum (?causing increased DA input)

genetic findings• vast majority of cases unexplained

• however, 60% ‘familial’ (Schizophrenia, BPAD, OCD)

• no clear explanation for higher 1st degree relatives with DM (both type 1 and 2)

• recent interest in ‘single nucleotide polymorphisms’ (SNIPs)

• matching phenotypic features to genome (including common genetic loci between psychosis and diabetes @ 1q 21-25)

blue sky thinking

pathogenesis of schizophrenia

• prior to imaging findings, pharmacology based (Dopamine and Glutamate blockers)

• post mortem brain findings led to ‘neuro developmental’ theories (abnormal migration and maturation)

• imaging findings have modified above – how do you explain ‘hypofrontality’ and progressive cortical thinning?

• developmental versus degenerative debate

• or, both ( e.g. the GLUT theory)

what we know about GLUT

• Glucose transporter proteins, sited across membranes (500 amino acids, 7 sub types, funnel shaped) - think of a coin collecting funnel

• GLUT 4 (vast majority of GLUTs) present peripherally sp. muscle and fat – sensitive to Insulin and IGF

• GLUT 1 and 3, mainly in brain (also in placenta) – Insulin insensitive

more about GLUT!

• GLUT 3 neurones (mainly frontal / pre frontal brain), GLUT 1 endothelial cells

• GLUT 1 and 3 crucial to brain –fixed availability, Glucose being the only nutritional substrate

• GLUT 2 glucose sensors to detect hypoglycaemia present in hypothalamus, portal vain, kidneys

• in starvation, increased GLUT 1 and 3 production, and reduced GLUT 4 – brain needs to look for food (planning)

the GLUT hypothesis (McDermott

and de Silva, 2005)

• schizophrenia due to deficits in GLUT 1 and 3 (numbers or structural deficits)

• malnutrition of neurones (neuronal maturational problems and gradual loss of gray matter)

• particularly frontal lobe (contains most GLUT 3) and thalamus (GLUT 1)

• excess sugar intake may further down regulate GLUT 1 and 3 (GLUT 2 working in reverse)

evidenceZhao et al., Molecular Psychiatry, 2009

• GLUT 3 deficient (heterozygous) mice show perturbed social behaviour with reduced vocalisations (and evidence of stereotypies)

• abnormal spatial learning and working memory

• abnormal cognitive flexibility

• GLUT 1 deficient mice show much more neurological malformations and seizures

implications of neuronal glucose malnutrition

• frontal lobe under activity causing ‘negative symptoms’ (apathy, poor planning / executive function) Also liable to get disinhibition

• Dopamine diverted to anterior cingulate, mesolimbic and basal ganglia areas producing ‘positive symptoms’ (delusions / hallucinations) and movement disorders (stereotypies)

• hyperactivity of Broca’s area (hallucinations) could also be a ‘distress’ phenomena

• excess / inappropriate use of memory stores and jumping to conclusions other distress signs (thought disorder and delusions)

also explains….• perinatal findings

(placenta only uses GLUT 1 and 3)

• adolescent onset (increased demand for Glucose followed by pruning)

• higher hyperglycaemia rates in drug free subjects (brain uses 20%-50% glucose, backlog producing insulin resistance)

• higher DM in 1st* relatives (GLUT gene deletions)

on pruning of the brain• think of gardening (flowering shrubs)

• mid winter, major prune (Feb)

• then, pruning newly grown shoots (May)

• finally, pruning first flowering buds (June)

• think of the difficulties after bitter winter

• liable to prune excessively causing reduced flowering, or, not prune at all.

GLUT deficit based neuronal pruning– stages 1 to 3

• Stage 1 (perinatal), GLUT 1 and 3 deficiency in placenta, causes low birth weight, prematurity and low fat stores in childhood (at risk children)

• Stage 2 (adolescence), GLUT 1 and 3 deficits with excessive pruning of gray matter, causes cognitive deficits, social anxiety and persecutory ideation, as seen in school children prior to schizophrenia (the ‘prodrome’)

• Stage 3 (early adulthood) GLUT deficits, excessive frontal pruning and Dopamine diversion to meso limbic / striatal areas, causes acute psychosis with hallucinations and delusions

how do anti psychotics really work?

Relevance of anti psychotics (Dwyer and Donohoe, 2003)

• all effective anti psychotics block GLUT

• strongest GLUT blocker is Clozepine

• followed by Olanzepine, Quetiapine, Risperidone

• Haloperidol weakest GLUT blocker

• most atypicals competitive (reversible) blockers, Risperidone not.

consequences of GLUT blockade in brain

• essentially, acts like a chemical pruner (equivalent to a pair of shears)

• useful if there has been limited or no pruning

• reduces metabolic activity in hot spots (Broca’s area, reducing hallucinations; hippocampus, reducing thought disorder)

• If already undergoing heavy pruning will make functioning worse (negative symptoms, psychomotor slowing)

consequences of GLUT blockade peripherally

• can cause / worsen hyperglycaemia (rat and human studies)

• excess appetite (GLUT 2 blockade will increase GLUT 4)

• Hyperlipidaemia (Glucose converted to lipids including Triglycerides)

• raised Leptin secondarily, then ‘Leptin resistance’ (fat stores saturated)

• eventually, metabolic syndrome

on anti psychotic selection• is it better to use moderate dose long term

treatment with additional means to deal with acute exacerbations?

(BZ, CBT and supportive counselling)

• or, selection on toxicity, tolerability and convenience? (Marie Stopes modal)

• how do we operationally define the threshold of relevant patient / carer information?

• how do we approach treatment of first episode illness? (information, depots)

clinical relevance of all this

• might need to learn from oncologists and their treatment models used in managing cancer

• need to clearly explain risks of the disease, risks / benefits of treatment and associated prognostic estimates to patients / carers

• need to be aware of potential problems with high sugar intake and metabolic syndrome, and consider preventative strategies

final thoughts• we need to think ‘outside the box’ on

schizophrenia

• theories such as GLUT offers a solution to the neuro developmental vs. neuro degenerative split , which can hinder further progress

• we need to look at the neuronal pruning process in more detail, including gene drivers

• we might need to think a bit more carefully about nutritional and metabolic problems in managing schizophrenia

selected references

• the history of sugar-http://www.britishsugar.co.uk/isolated storage/94175874-67b5-4c33-gf38-3802...25/08/2005

• Impaired glucose tolerance in drug naïve schizophrenics - Kirkpatric,B et al., Schizophrenia Research 2009; 107 (2-3): 122-127

• Anti psychotics and glucose intolerance – Smith et al., (meta analysis) BJPsych 2008, 192, 406-417

selected references• Progressive grey matter loss (MRI over 5 years)- Di Lisi, L.E.,

2008 Schizophrenia Bulletin 34, 312-321

• Childhood schizophrenia – Rapoport, J.L., Giedd, J.N. et al, 1999 Progressive cortical change in childhood schizophrenia Archives of General Psychiatry. 56(7), 649-654

• GLUT hypothesis – McDermott, E., de Silva, P., 2005, Medical Hypothesis 65, 1076 – 1081

• GLUT 3 deficient mice – Zhao, Y et al., 2009,Molecular Psychiatry, 1-14

• GLUT blockade by atypicals – Dwyer, D.S., Donohoe, D. 2003

Pharmacology, Biochemistry and Behaviour 75, 255-260

thank you