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U

ntil recently, it was the view that insulin had little effect on

the energy metabolism of the brain. It was thought illogical

that something as important as the brain would be

dependent in any way on when a person last ate a meal. This was

because the brain is a particularly energy intensive organ,

consuming approximately 25% of the body’s total glucose.

However, it was first discovered that astrocytes and microglial cells,

which are major communicating cells in the brain, are insulin sensitive

and later that the insulin receptor had a wide distribution in the brain.

Fluorodeoxy-glucose positron emission tomography studies

demonstrated that insulin had a role in regulating global brain

glucose utilisation in humans, most markedly in the cortical regions.

Other studies have demonstrated that insulin plays a key role in

neuroplasticity, neuromodulation and neurotrophism – the process of

neuronal growth, stimulated by neuronal differentiation and survival.

Epidemiology studies demonstrate that the risk of developing

Alzheimer’s disease is increased by 50% in subjects with diabetes.

Type 2 diabetes, which accounts for 90% of all diabetes, is due to

both insulin resistance and decreased pancreatic

β

-cell function.

In the early stages, insulin resistance results in the pancreatic

islets secreting more insulin in an attempt to overcome the

resistance. Over time, this leads to an increasing failure of the islet

to produce enough insulin and ultimately hypoinsulinaemia so that

the patient requires insulin injections.

Insulin resistance

A key question is whether the brain develops insulin resistance.

Recent studies using

post-mortem

brains from patients with

Alzheimer’s, but without diabetes, showed markedly reduced

responses to insulin in the insulin receptor

insulin receptor

substrate-1

phosphoinositol-3 kinase signalling pathway in the

hippocampus and to a lesser degree in the cerebellar cortex.

In the hippocampus, the biomarkers of insulin resistance

increased progressively from normal cases through mild cognitive

impairment cases to Alzheimer’s disease regardless of diabetes.

However, there is no evidence that the brain in Alzheimer’s disease

is hyperglycaemic, unlike peripheral tissues in diabetes. Thus an

appropriate term to describe the state of Alzheimer’s disease brain

is ‘insulin-resistant brain’. This is analogous to insulin resistance

syndrome, which is a feature of several peripheral tissue disorders.

Insulin resistance in peripheral tissues could promote insulin

resistance in the brain by reducing brain insulin uptake and by

raising brain levels of A

β

.

A second reason why peripheral resistance to insulin may affect

the brain has now been proposed. This is that toxic ceramides

generated by the disturbed lipid metabolism in insulin-resistant

liver pass into the circulation and transit across the blood brain

barrier into the brain. There they induce inflammation, leading to a

second-pronged attack on central insulin action.

These studies lead to the view that drug treatments that improve

either or both central and peripheral insulin resistance are

potential treatments, or at least agents, to delay the progression

of mild cognitive impairment to Alzheimer’s disease. In fact, two

anti-diabetes drugs have already been shown to have some

beneficial effects. They are metformin and thiazolidinedione

rosiglitazone, and a third drug, pioglitazone, has been proposed

for a large clinical trial.

Potential treatment

However, none of these drugs are a perfect treatment. Many

patients do not easily tolerate metformin as a result of

gastrointestinal side effects and the thiazolidinedione insulin

sensitiser drugs produce weight gain and water retention. There is,

therefore, a need for a concerted effort to discover drugs that act

to cause insulin sensitisation in the brain and liver. Such drugs are

a potential treatment for Alzheimer’s patients possibly when

coupled with nasal delivery of insulin, which has been shown to

improve learning and memory in clinical trials. The greater need,

however, is to develop strategies that will delay the onset and

progression of mild cognitive impairment towards Alzheimer’s.

For this, drugs are not the answer, unless one had diagnostic

assays that were highly predictive, since it would be unethical to

give drugs with inherent risks to people who might not develop the

disease. However, if non-toxic plant extracts with similar insulin

sensitiser action could be identified, these could be made

available to the public.

Mike Cawthorne

Clore Laboratory

University of Buckingham

te l :

+44 (0)1280 820309

mike.cawthorne@buckingham.ac.uk www.buckingham.ac.uk/clore/

Several lines of evidence suggest that Alzheimer’s disease has strong links with

insulin action and that the condition could be described as ‘diabetes of the brain’

Alzheimer’s and diabetes

The Buckingham Institute of Translational Medicine

The University of Buckingham