Re: High insulin levels correlated to Alzheimer's

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--- Diane Walter <dianepwalter@...> wrote:

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> http://www1.excite.com/home/health/health_article/

> 0,11720,527298|08-09-2005%3A%3A06%3A00,00.html

Hi All,

See the pdf-available below paper.

Arch Neurol. 2005 Aug 8; [Epub ahead of print] Related Articles, Links

Hyperinsulinemia Provokes Synchronous Increases in Central Inflammation and

{beta}-Amyloid in Normal Adults.

Fishel MA, GS, Montine TJ, Wang Q, Green PS, Kulstad JJ, Cook DG, Peskind

ER,

Baker LD, Goldgaber D, Nie W, Asthana S, Plymate SR, Schwartz MW, Craft S.

CONTEXT: Inflammation has been implicated as a pathogenetic factor in

Alzheimer

disease, possibly via effects on beta-amyloid (Abeta). Hyperinsulinemia induces

inflammation and is a risk factor for Alzheimer disease. Thus, insulin

abnormalities

may contribute to Alzheimer disease pathophysiology through effects on the

inflammatory network. OBJECTIVES: To determine the effects of induced

hyperinsulinemia with euglycemia on Abeta, transthyretin, and inflammatory

markers

and modulators in plasma and cerebrospinal fluid (CSF). DESIGN: Randomized

crossover

trial. SETTING: Veterans Affairs hospital clinical research unit. PARTICIPANTS:

Sixteen healthy adults ranging from 55 to 81 years of age (mean age, 68.2

years).

INTERVENTIONS: On separate mornings, fasting participants received randomized

infusions of saline or insulin (1.0 mU . kg(-1) . min(-1)) with variable

dextrose

levels to maintain euglycemia, achieving plasma insulin levels typical of

insulin

resistance. Plasma and CSF were collected after an approximately 105-minute

infusion. MAIN OUTCOME MEASURES: Plasma and CSF levels of interleukin 1alpha,

interleukin 1beta, interleukin 6, tumor necrosis factor alpha, F(2)-isoprostane

(CSF

only), Abeta, norepinephrine, transthyretin, and apolipoprotein E. RESULTS:

Insulin

increased CSF levels of F(2)-isoprostane and cytokines (both P<.01), as well as

plasma and CSF levels of Abeta42 (both P<.05). The changes in CSF levels of

Abeta42

were predicted by increased F(2)-isoprostane and cytokine levels (both P<.01)

and

reduced transthyretin levels (P = .02). Increased inflammation was modulated by

insulin-induced changes in CSF levels of norepinephrine and apolipoprotein E

(both

P<.05). CONCLUSIONS: Moderate hyperinsulinemia can elevate inflammatory markers

and

Abeta42 in the periphery and the brain, thereby potentially increasing the risk

of

Alzheimer disease.

PMID: 16087755

RESULTS

INSULIN, CYTOKINES, AND F2-ISOPROSTANE

Intravenous insulin administration produced reliable el-evations

in CSF insulin levels, which is consistent with

animal models showing insulin transport into the brain

and subsequent egress into CSF 22 (mean [sEM] saline and

insulin infusions were 1.44 [0.20] µU/mL and 2.22 [0.35]

µU/mL, respectively; P=.02).18

We then examined changes in cytokine and F2-isoprostane

levels during hyperinsulinemia. Insulin in-creased

CSF levels of all 4 cytokines (Figure 1A-D; IL-1á

[P<.001], IL-1ß [P<.001], IL-6 [P=.007], and TNF-á

[P=.002]) and F2-isoprostane (Figure 1E; P=.01). Adults

with greater BMIs tended to have higher CSF TNF-á lev-els

in response to insulin (r =0.49, P=.06). In contrast,

plasma cytokine levels did not change reliably in re-sponse

to insulin. Plasma and CSF cytokine levels were

uncorrelated, as were insulin-induced changes. Insulin

did not affect CSF protein, suggesting that changes in in-flammatory

reactants were not due to nonspecific ef-fects

on CSF turnover (P=.33).

INSULIN AND Aß

Plasma Aß42 increased with insulin, an effect that was

associated with BMI (Figure 2A; P=.046). Adults with

greater BMIs showed greater plasma Aß42 elevations with

insulin (r =0.49, P=.047) (Figure 2B). Consistent with

the observation that TNF-á modulates Aß transport be-tween

the CNS and the periphery,13 insulin-induced

changes in CSF TNF-á levels predicted changes in plasma

Aß42 levels (R 2 =0.44, P=.007); subjects with higher

TNF-á levels during insulin infusion had greater in-creases

in plasma Aß42 levels (r=0.64, P=.01). Higher

plasma Aß42 levels were also associated with increased

CSF transthyretin levels (Figure 2C; r=0.63, P=.02),

which binds Aß and facilitates its transport from the brain

to the periphery. Interestingly, insulin infusion did not

affect plasma Aß40 levels (mean [sEM] plasma Aß40 level

was 224.7 [26.2] pg/mL for saline conditions and 221.6

[26.4] pg/mL for insulin conditions). Insulin-induced

changes in plasma Aß40 or Aß42 levels were unrelated

to changes in plasma inflammatory markers.

We previously reported that insulin provoked an age-dependent

increase in CSF Aß42 levels for this group of

normal adults.18 We have now determined that transthy-retin

and inflammatory marker levels strongly predict in-sulin-

induced changes in CSF Aß42 levels (omnibus

F4,9=11.14, P=.002). The best predictors were age

(P=.003) and difference scores for IL-6 (P=.003), F2-isoprostane

(P=.002), and transthyretin (P=.01). Older

age and greater increases in IL-6 and F2-isoprostane lev-els

were associated with greater increases in CSF Aß42

levels following insulin infusion. In contrast, increased

transthyretin levels predicted lowering of CSF Aß42 lev-els,

which is consistent with enhanced transport from the

CNS to the periphery (Figure 2D; r= & #8722;0.59, P=.03).

CSF NOREPINEPHRINE, IL-1ß, AND Aß42

Since norepinephrine attenuates Aß42-provoked in-creases

in IL-1ß levels in rodents,15 we examined whether

insulin-induced increases in CSF norepinephrine levels

attenuate increases in CSF Aß42 and IL-1ß levels. Sub-jects

with higher CSF norepinephrine levels during in-sulin

infusion had lower levels of Aß42 (Figure 3A;

r= & #8722;0.51, P=.04) and IL-1ß (Figure 3B; r= & #8722;0.60, P=.02).

CSF APOE AND CYTOKINES

Insulin regulates apoE levels,16 and apoE moderates the

inflammatory cascade.17 Hyperinsulinemia provoked age-related

changes in CSF apoE levels (P=.04). Insulin raised

apoE levels for most subjects, which was an effect that

increased with age (Figure 4B; r=0.46, P=.08). Higher

CSF apoE levels with insulin infusion were associated with

smaller increases in CSF IL-6 (r= & #8722;0.54, P=.04) and

TNF-á (r= & #8722;0.42, P=.12) levels, and they were associ-ated

with greater CSF IL-1á levels (r=0.60, P=.02).

Plasma and CSF apoE levels were uncorrelated.

COMMENT

Moderate peripheral hyperinsulinemia provoked strik-ing

increases in CNS inflammatory markers. Our find-ings

suggest that insulin-resistant conditions such as dia-betes

mellitus and hypertension may increase the risk for

AD, in part through insulin-induced inflammation. Al-though

our study cannot determine the precise mecha-nisms

through which insulin increases CSF inflamma-tory

marker levels, the results suggest several possibilities.

We observed neither insulin-induced changes in plasma

cytokines nor correlations between CSF and plasma cy-tokines.

Thus, elevated CSF cytokine levels are likely not

due to peripheral cytokine transport into the CNS, but

may instead reflect insulin’s effects on blood-brain bar-rier

endothelial cells, brain glia, or neurons, all of which

express insulin receptors.23

Insulin may also have indirectly affected CSF cyto-kine

levels through modulation of CSF and plasma Aß42

levels. Our data provide, to our knowledge, the first dem-onstration

of acute manipulation of peripheral Aß42 in

vivo in humans. The role of plasma Aß42 in AD patho-genesis

is uncertain; however, elevations have been docu-

mented in patients with AD and in adults who later de-velop

AD.24 Notably, insulin’s effect on plasma Aß42 levels

was enhanced in subjects with greater BMIs, a charac-teristic

associated with both insulin resistance and AD

risk.25 Thus, the interactive effects of hyperinsulinemia

and BMI on plasma Aß42 levels may contribute to this

increased risk. It has been hypothesized that prolonged

elevations of plasma Aß levels obstruct a peripheral sink

through which CNS Aß is cleared, leading to increased

accumulation in the brain.26 High insulin levels may in-hibit

peripheral clearance of Aß42 by insulin-degrading

enzyme in the liver or other tissues. The selective effects

of insulin on Aß42 levels but not on Aß40 levels are puz-zling.

Such effects may reflect the increased tendency of

Aß42 to oligomerize, rendering it impervious to degra-dation

by insulin-degrading enzyme, or insulin-induced

changes in lipids that differentially bind and en-hance

clearance of Aß species.

Alternatively, insulin may have increased Aß42 ef-flux

from the brain to the plasma. Levels of transthyre-tin,

a protein that can bind Aß and facilitate transport

from the CNS to the periphery, are reduced in patients

with AD.13 We found that insulin-induced elevations of

CSF transthyretin levels were associated with increased

plasma Aß42 levels and decreased CSF Aß42 levels. This

inverse relationship suggests that insulin-induced trans-thyretin

changes facilitated Aß clearance from the CNS

to the periphery for some participants. Transthyretin is

synthesized in the liver and the choroid plexus, sites rich

with insulin receptors, and its synthesis is increased by

insulin-like growth factor I, a peptide closely related to

insulin. An insulin-responsive element has recently been

identified in the promoter region of the transthyretin gene

(D.G., unpublished data, 2004). Transthyretin is also regu-lated

by IL-6 and TNF-á.27,28 Thus, insulin-induced in-creases

of cytokine levels may have reduced transthyre-tin

levels for some participants.

The Aß42 peptide interacts with inflammatory agents

in a cyclically reinforcing manner, such that elevations

in Aß levels increase proinflammatory cytokine levels.29

In vitro, soluble Aß oligomers rapidly increase IL-1ß and

TNF-á levels.30 Conversely, several cytokines affect Aß

production or clearance. Both IL-6 and IL-1ß can regu-late

processing of the amyloid precursor protein from

which Aß is derived and can increase production of

Aß42. 31,32 The mutually reinforcing effects of Aß, TNF-á,

IL-1ß, and IL-6 may, therefore, create a “cytokine cycle.”29

Aspects of our results support this model. Changes in CSF

Aß42 levels were predicted by increases in the levels of

these 3 cytokines, but these changes were unrelated to

changes in the levels of IL-1á. Also, levels of CSF F2-isoprostane,

a lipid peroxidation marker produced by neu-rons

and glia, increased with insulin infusion, and the

magnitude of this effect was directly related to eleva-tions

of CSF Aß42 levels. In contrast, elevations of plasma

Aß42 levels following insulin infusion were associated

solely with increased CSF TNF-á levels. This pattern con-tradicts

a rodent study 13 showing that TNF-á inhibits

Aß42 clearance from the brain, although effects of TNF-á

only on CSF Aß and not on plasma Aß were reported. It

is possible that in humans, the insulin-induced rise in

plasma Aß42 levels is multifactorial, reflecting Aß trans-port

from the CNS, effects on peripheral clearance, or Aß

release from peripheral sources such as platelets.

Norepinephrine may also mediate insulin’s effects on

Aß and inflammatory reactants. Insulin can regulate CNS

norepinephrine,14 an endogenous, anti-inflammatory neu-romodulator

that blocks IL-1ß expression.15 Increased

Aß plaque load in AD has been linked to neuronal loss

in the locus coeruleus, the primary source of brain nor-epinephrine.

33 Thus, decreased norepinephrine activity

in AD may potentiate the deleterious inflammatory ef-fects

of Aß. Consistent with this notion, higher CSF nor-

epinephrine levels with insulin infusion were associ-ated

with selective attenuation in elevated IL-1ß levels

and reduced CSF Aß42 levels.

Insulin produced age-dependent effects on CSF lev-els

of apoE, a lipoprotein that plays a critical role in cho-lesterol

metabolism and injury repair and that down-regulates

TNF-á and IL-6 production in animal models.17

In the periphery, insulin reduces hepatic production of

apoE and regulates its uptake by low-density lipopro-tein

receptor–related protein.16 We found that insulin re-duced

plasma apoE levels, an effect that increased with

age. In contrast, insulin increased CSF apoE concentra-tions

for older subjects. Increased brain apoE levels have

been reported in AD in association with polymorphisms

in the promoter region of the APOE gene that influence

protein expression.34 Insulin may influence CNS apoE

expression through interactions with these polymor-phisms

or through other factors, such as low-density li-poprotein

receptor–related protein. We observed that in-sulin-

induced elevations of CSF apoE levels were

associated with attenuated increases in levels of proin-flammatory

cytokines IL-6 and TNF-á and with higher

levels of IL-1á, an anti-inflammatory cytokine. This se-lective

pattern suggests multiple insulin effects that modu-late

the role of apoE in response to inflammation.

Our results can be integrated into a model describing

the role of peripheral insulin resistance and hyperinsu-linemia

in AD pathogenesis. During early pathogenesis,

high plasma insulin levels raise plasma Aß42 levels by

promoting Aß release and inhibiting its clearance by in-sulin-

degrading enzyme. As a result, more Aß42 may be

transported from the periphery into the brain, or the trans-port

of Aß42 from the brain to the periphery may be ob-structed.

Failure of insulin to appropriately regulate trans-thyretin

may also interfere with clearance of Aß42 from

the brain. Concomitantly, peripheral hyperinsulinemia

increases CNS levels of IL-1ß, IL-6, TNF-á, and F2-isoprostane,

agents that interact synergistically to pro-mote

Aß synthesis (IL-6 and IL-1ß) and reduce its clear-ance

(TNF-á). The resulting elevations of Aß levels

provoke a correspondingly greater inflammatory re-sponse.

Prolonged inflammation also likely exerts del-eterious

effects independent of Aß that contribute to AD

pathogenesis. For example, noradrenergic dysfunction

that characterizes patients with insulin resistance may

reduce norepinephrine’s anti-inflammatory influence. Re-duced

availability or efficacy of apoE may affect its abil-ity

to inhibit IL-1ß expression and thereby to modulate

the inflammatory response.

Although this model has obvious relevance for dia-betes

mellitus, hyperinsulinemia and insulin resistance

are widespread conditions that affect many nondiabetic

adults with obesity, impaired glucose tolerance, cardio-vascular

disease, and hypertension. Our results provide

a cautionary note for the current epidemic of such con-ditions,

which, in the context of an aging population, may

provoke a dramatic increase in the prevalence of AD. More

encouragingly, greater understanding of insulin’s role in

AD pathogenesis may lead to novel and more effective

strategies for treating, delaying, or even preventing this

challenging disease.

Al Pater, PhD; email: old542000@...

__________________________________

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