Alternative Medicine Review Volume 14, Number 4 2009

The Relationship betweenAlzheimer's Disease and Diabetes:

Type 3 Diabetes^

Zina Kroner, DO

Abstract

In recent years. Alzheimer's disease (AD) has been considered

to be, in part, a neuroendocrine disorder, even referred to

by some as type 3 diabetes. Insuíin functions by controlling

neurotransmitter release processes at the synapses and

activating signaling pathways associated with learning and

long-term memory. Novel research demonstrates that impaired

insulin signaling may be implicated in AD. Post-mortem brain

studies show that insulin expression is inversely proportional

to the Braak stage of AD progression. It was also demonstrated

that neurotoxins, coined amyloid beta-derived diffusible

ligands (ADDLs), disrupt signal transducUon at synapses,

making the cell insulin resistant. ADDLs reduce plasticity of

the synapse, potentiate synapse loss, contribute to oxidative

damage, and cause AD-type tau hyperphosphorylation.

Diabetes and AD have signs of increased oxidative stress In

common, including advanced glycation end products (AGEs).

when compared to normal subjects. Diabetic patients appear

to have an increased risk for AD because AGEs accumulate in

neurofibrillary tangles and amyloid plaques in AD brains. This

research should encourage a more proactive approach to early

diagnosis of diabetes and nutritional counseling for AD patients.

(Altem Med Rev 2009;14(4):373-379)

IntroductionTlie epidemic of insulin resisrance/prcdiabetes

and type 2 diabetes may be associated with the emer-gence of highei- rates of Alzheimer's disease (AD). Newresearch delineates a direct correlation between sugarimbalance and AD.' AD is associated with consistentpathological Undings, including neurofibrillary tangles,amyloid-beta deposits, and signs of oxidative stress. No

common link among the proposed pathological pro-cesses has been identified. Novel evidence demonstratesthat impaired insulin signaling may significantly con-tribute to the pathogenesis of AD, contributing to theidea that it is actually a neuroendocrine disease.' Neu-rotoxins called amyloid beta-derived diffusible ligands(ADDLs) have been implicated as a cause of impairedinsulin signaling.' Advanced glycation end products(AGEs) are found in higher concentration in both hy-perglycemia and AD, contributing to oxidative stressand cell damage. Tliese AGEs are known to be furthermodified to reactive advanced glycation end products,(RAGEs), which can generate oxidative injury.

Understanding the mechanism ot action ofthis ncuroendocrine disorder, termed type 3 diabetes bysome, may shed light on new tools for diagnosing andtreating AD and for the need for early intervention inobese patients with insulin resistance.

The Clinical Link: Diabetes and ADThe research Unking diabetes and AD has its

roots in the groundbreaking Rotterdam study. Of 6,370elderly subjects studied ior 2.1 years, 126 developeddementia; 89 of these were specifically diagnosed withAD. Type 2 diabetes doubled the risk of a patient hav-ing dementia and patients on insulin had four times therisk.'' As rates of insulin resistance and diabetes in thesenior population are both increasing, this landmarkstudy, conducted almost a decade ago, has been gettingmore attention in recent years since further studies havesolidified the connection between diabetes and AD.

Zina Kroner, DO - Diplomate, American Board of Internal Medicine; completedresidency program at North Shore University Hospital, an NYU affiliate; medicaldirector of Advanced Medicine of New York. PLLC, New Yor1(. NY.Correspondence address: 121 East 60tti St, Suite 3C, New York. NY 10022www.advanced-medicine.comEmail: info@advanced-mediclne.com

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Alternative Medicine Review Volume 14, Number 4 2009

Since type 2 diabetes is reaching epidemicproportions and is under-diagnosed, and AD may beassociated with hyperglycemia, more attention shouldbe drawn to early diagnosis of diabetes. Tlie GertnerInstitute for Epidemiology and Health Policy Researchin Israel, in a recently published 25-year, cross-sectionalstudy of 623 adults, demonstrated that approximately13 percent ofthe studied population had undiagnosedtype 2 diabetes. This study reinforces the importance ofearly diagnosis of type 2 diabetes by identifyijig patientswith risk factors, including hypertension, hypertriglyc-eridemia, and a large waist circumference (males: >40inches [ 102 cmj, females: >35 inches [88 cm]) - factorsseen in metabolic syndrome. These results encourageearly detection via screening methods targeting thosewith traits of metabolic syndrome in otherwise healthyadults. '

Another study demonstrating the high preva-lence of diabetes showed almost one-third of elderlypatients in a sample of 7,267 subjects had diabetes, andthree-fourths had impaired fasting glucose (glucose lev-els >99 but < 126) or diabetes.''

Elevated body mass index (BMI), adiposity,impaired fasting glucose, and diabetes increase the riskof AD substantially. Tbe latest study, utilizing data on2,322 participants in the Baltimore Longitudinal Studyof Aging, shows the incidence oí AD increased in menwho gained weight between the ages of 30 and 45 andin women with a BMI >30 at ages 30, 40, and 45-'This suggests more emphasis should be placed on earlyweight-loss strategies for preventing AD.

A 2008 Swedish study showed a statisticallysignificant increase in the risk of developing AD in menwho develop type 2 diabetes in midlife.' Tlie researchersfollowed 2,269 men for 32 years and found that thosewith low insulin production at age 50 were líO-per-cent more likely to develop AD than those with ad-equate insulin production. This association was great-est in patients wlio did not have the apolipoprotein E4(ApoE4) genetic predisposition to AD (which rendersindividuals less efficient at breaking down beta-amyloidplaques), thereby making diabetes a possible indepen-dent risk factor for AD. Tliis study illustrates the im-portance of maintaining healthy blood glucose controlin middle-aged men as a possible means of preventingAD later in life.

A recent investigation suggests that AD is as-sociated with metabolic syndrome. After studying 50patients diagnosed with AD and comparing them to75 cognitiveiy normal controls, the AD patients had agreater waist circumference, higher triglycéride and glu-cose levels, and lower high-density lipoprotein choles-terol.** Patients with metabolic syndrome are diagnosedwith AD at a younger age than AD patients withoutmetabolic syndrome."

Type 3 Diabetesi Is It Actually a UniqueCondition?

The term type 3 diabetes was coined in 2005by Suzanne de la Monte, MD, MPH, Associate Profes-sor of Pathology and Medicine and neuropathologist atBrown Medical School. Her team, examining postmor-tem brain tissue of AD patients, found that AD maybe a neuroendocrine disease associated with insulin sig-naling. The team termed it type 3 diabetes because itharbors elements of both types I and 2 diabetes, sincethere is both a decrease in the production of insulin anda resistance to insulin receptors.^ '"

Tlie team analyzed 45 postmortem brains ofpatients of varying Braak stages of AD neurodegen-eration and found that insulin expression was inverselyproportional to the Braak stage, with an 80-percent de-crease in the number of insulin receptors in AD patientscompared to normal subjects. In addition, the ability ofinsulin to bind to the receptors was compromised. Therewas a reduced level of mRNA corresponding to insulin,insulin-like growth factor-l (IGF-1) and -2 polypep-tides, and their receptors. The research team also noteda reduction in the tau protein, which is regulated by in-sulin and IGF-1. '"" This phenomenon ultimately couldlead to neuronal cell death and AD exacerbation.

Tlie postmortem studies inspired a rat study Inwhich intracerebral injection of streptozotocin resultedin a chemical depletion of insulin and an alteration ofIGF-signaling mechanisms together with oxidative in-jury. Tlie combination of alterations resulted in neu-rodegeneration, including reduction in brain size andother neurological changes seen in AD.'"^

AD is characterized by a reduction in the uti-lization of glucose, and treatment with insulin has beenassociated with improved memory. Insulin, importantin memory processing, crosses the blood-brain barrierand is even produced in brain tissue itself. AD patients

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Alternative Medicine Review Volume 14, Number 4 2009

have less insulin and fewer insulin receptors than non-AD patients, and correction of insulin levels improvescognition. Insulin binds to insulin receptors in the brain,most of which are located in the cerebral cortex, olfacto-ry bulb, hippocampus, cerebellum, and hypothalamus.Since there are more insulin receptors in the cognition-pertinent areas of the brain, it is logical to consider theassociation between insulin and cognition.'^

Several studies utilizing intranasal, intrave-nous, and intracerebral administration of insulin dem-onstrate improved cognition. A study utilising intra-nasal insulin showed chat its administration enhancedverbal recall in normoglycemic adults with early ADor cognitive impairment.'' In the study, 25 partici-pants were randomly assigned to receive either placebo(n = 12) or 20 IU intranasal insulin (n=13) twice daily.After 21 days of treatment, changes in cognition weremeasured. The fasting plasma glucose and insulin lev-els were unchanged with treatment. However, whencompared with the placebo treated subjects, the insuHn-treated subjects retained more verbal information anddisplayed superior attention and functional status.

A study utilizing intravenous (IV) insulin as-sessed cognitive performance in 22 adults with AD and15 normal adults receiving five consecutively higher IVdoses of insulin resulting in five plasma insulin levels(10, 25, 35, 85, and 135 microU/mL), while plasmaglucose levels of '^100 mg/dL were maintained. Cog-nitive performance was measured after 120 minutes ofinfusion. AD patients who were ApoE4-positive werefound to have improved memory at lower insulin levelsof 25 microU/mL, compared to their ApoE4-negativecounterparts, who required a higher blood insulin levelof 35 and 85 microU/mL before an improvement inmemory was noted. Interestingly, normal adults alsoshowed improved memory at insulin levels of 25 and85 microU/mL. This shows that AD patients who areApoE4-negative may not be as sensitive to insulin. '̂

A study utilizing intracerebroventricular insu-lin showed that its administration enhanced memoryformation in rodents undergoing a step-through passiveavoidance task."' Tliese studies suggest that insulin mayhave a role in enhancement of cognition and memory.Tlie other implication is that patients with the ApoE4genetic predisposition to AD may not reap the benefitsof improvement in AD by glycémie control.

Based on a recent epidemiological srudy, indi-viduals who are ApoE4-positive are not more likely tobe insulin resistant than those who are ApoE4-negative.Therefore, insulin resistance and being positive for theApoE4 alíele are independent risk factors ior AD; hav-ing both may pose an additive risk/^

Pathophysiological Connections betweenInsulin and AD

AD is characterized by both low insulin levelsand insulin resistance within the central nervous system(CNS), as opposed to type 2 diabetes, which is char-acterized by high insulin levels and insulin resistanceoutside of the CNS. Insulin resistance and hyperin-sulinemia cause a reduction in brain insulin.'^ Severalmechanisms might explain why insulin mediates mem-ory facilitation. As noted, insulin receptors are found inareas of the brain responsible for cognirion. Insulin ac-tivates signaling pathways associated with learning andlong-term memory.'^ According to de la Monte, insulinhelps to regulate processes such as neuronal survival,energy metabolism, and plasticity. These processes arerequired for learning and memory. Peripheral insulinresistance, therefore, affects cognition.''*'

In addition to regulating blood sugar levels,insulin iunctions as a growth factor for all cells, includ-ing neurons in the brain. Tlius, insulin resistance orlack of insulin, in addition to adversely affecting bloodsugar levels, contributes to degenerative processes in thebrain.2»

When insulin levels reach an exceedingly highlevel, the beta-amyloid peptide, the hallmark of ADthat accumulates in senile plaques, is modulated.^"'^Exaggerated elevation of plasma insulin levels causesamyloid peptide levels in the ccrebrospinal fluid to in-crease, resulting in memory insult.''

Amyloid beta-Derived Diffusible LigandsA group of researchers at Northwestern Uni-

versity studied why brains of AD patients are both lowin, and resistant to, insulin. According to William Klein,PhD, who led the research, amyloid beta-derived dif-fusible ligands may be responsible for the phenomenon.ADDLs are oligomers similar in morphology and sizeto prions chat have been linked to neu rodegenerativedisease. ADDLs may contribute to lowered insulin

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Figure 1. ADDLs and Alzheimer's Disease

Reduce plasticityCause oxidative of synapse

damage Bind tosynapse

Change shapeof synapse

Result inAD-type tau

hyperphosphorylation

ADDLs:neurotoxicoligomers

Synapsedysfunction

Inadequatestimulation of cholinea cety I transfera se

/^ \ Insulin

resistance

Insulin now cannotbind to synapse

1. ADDLs = amyloid beta-derived diffusible ligands2. Mechanism of action of ADDLs3. End-point of ADDLs

levels and insulin resistance in AD brains.' Because theADDLs are so small, they are more diffusible and there-fore more harmful than amyloid.

In healthy brains, insulin binds to a receptorat a synapse, resulting ultimately in memory forination.Klein's team found that ADDLs disrupt this mechanismof communication by binding to the synapse and chang-ing its shape, thereby causing dysfunction. Because theshape of the synapse is altered, insulin cannot effec-tively bind, disrupting signal transduction and result-ing in insulin resistance. ADDLs have been shown toreduce the plasticity ot the synapse, potentiate synapse

loss, cause oxidative damage, and result in AD-type tauhyperphosphorylation, mechanisms linked to AD.*'^'Since ADDLs have been shown to affect neuronal insu-lin receptor signaling, it has been suggested that insulinresistance in the AD brain is a response to ADDLs, in-ducing a neurological form of diabetes. Neurons withno ADDLs show an adequate number of insulin recep-tors.'^^' Figure 1 illustrates the mechanisms of action ofADDLs in Alzheimers disease.

Measuring ADDL levels may potentially be anovel tool for diagnosing AD. In 2005, the ultrasensi-tive bio-barcode assay was used to measure ADDL con-

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centration in cerebrospinal fluid.Of 30 subjects, ADDL concentra-tions were found to be higher inthose diagnosed with AD com-pared to non-AD patients. Thistest is not readily available and lessinvasive testing is underway.''' AnADDL vaccine is being studiedand ADDL-blocking drugs arebeing considered by Klein et al."'

Insulin and theCholinergk Hypothesis

llic cholinergic hypo-thesis that suggests AD is causedby an inadequate production ofacetylcholine may also have linksto blood sugar abnormalities andinsulin resistance. Tlie researchersat Brown point out that insulinalso participates significantly inneurological function by stimu-lating the expression of cholineacetyltransferase (ChAT), the en-zyme responsible for acetylcbolinesynthesis (Figure 2). Therefore,suboptimal insulin levels as well as poor insulin recep-tor sensitivity can ultimately contribute to a decrease inacetylcholine, which further elucidates a possible bio-chemical link between diabetes and AD.-"

AGEs and Oxidation - Common Threadbetween Diabetes and AD

Another mechanism linking diabetes with ADis that both diseases, as mentioned previously, are as-sociated with increased oxidative stress and productionof AGEs. Although the association between vasculardementia and AGEs is well established, nevif researchpoints to a link between AGEs and AD. AGEs areformed by a sequence of events originally identified in1912 as the end-products of the Maillard reaction,^''during which reducing sugars can react with the aminogroups of proteins to produce cross-linked complexesand unstable compounds.

Figure 2. Insulin's Role in the Cholinergic Hypothesis: The Importanceof Insulin in Memory Formation

Cholineacetyltransferase

(enhanced by insulin)

Nerve Ending

AGEs have been found in retinal vessels, pe-ripheral nerves, kidneys, and the CNS of diabetics.AGEs couple with free radicals and create oxidativedamage, wbich in turn leads to cellular injury.'"" Dia-betic patients could have an increased risk of AD viaAGE production." Oxidative stress on its own alsocauses AGEs, creating a vicious cycle."

AGEs are also known to modify plaques andneurofibrillaty tangles, both implicated in AD.'* AGEshave been identified in neurofibrillary tangles (consist-ing of tau protein) and senile plaques (consisting ofbeta-amyloid protein). Since type 2 diabetes acceleratestbe production of AGEs, it may be another causativefactor in the development of AD.^ It has been pro-posed that a potential biomarker for early detection ofAD may be measurement of toxic AGEs in the serumor cerebrospinal fluid.'^ '

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ConclusionUnderstanding that AD has its foundation in

neuroendocrinology is persuasive evidence that there

should be greater emphasis on early diagnosis of meta-

bolic syndrome, insulin resistance, and type 2 diabetes.

Reterring to AD as type 3 diabetes has its foundation

in the fact that the CNS in AD is characterized by a

paucity of insulin and resistance of the insulin recep-

rors. This results in cognitive dysfiuiction, since insulin

is crucial tor neurological sign;üing processes to occur.

Insulin also participates in neurological function by

stimulating the expression of ChAT, the enzyme re-

sponsible for acetylcholine synthesis; acetylcholine is in

turn a necessary neurotransmitter for cognition. AGEs,

found in greater amounts in diabetic patients compared

to controls with normal glucose regulation, have also

been found in high concentration in AD brains.

The links between hyperglycémie states and

AD can allow for better future diagnostic strategies.

Since ADDLs may contribute to lowered insulin levels

and insulin resistance in AD brains, the future of di-

agnosis may entail the measurement of ADDLs. Mea-

surement of AGEs has also been proposed.

Treatment strategies utilizing this informa-

tion require more research. The knowledge that there is

a reduction of the sensitivity to insulin in AD patients

who are not ApoE4-positive suggests that optimization

of blood sugar levels may have therapeutic benefits. In-

sulin-sensitizing agents may potentially be used in the

setting of early AD.

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