I nsulin Resistance and I nsulin Resistance and Alzheimer s - PowerPoint PPT Presentation

I nsulin Resistance and I nsulin Resistance and Alzheimer’ ’s Disease: s Disease: Alzheimer A Novel Therapeutic Target A Novel Therapeutic Target Suzanne Craft Suzanne Craft Geriatric Research, Education, and Clinical Center Geriatric Research, Education, and Clinical Center VA Puget Sound VA Puget Sound Professor of Psychiatry and Behavioral Sciences Professor of Psychiatry and Behavioral Sciences University of Washington School of Medicine University of Washington School of Medicine

Overview Overview • Insulin plays a role in cognition and normal Insulin plays a role in cognition and normal • brain function brain function • Dysregulation of insulin increases risk for AD Dysregulation of insulin increases risk for AD • and other neurodegenerative diseases and other neurodegenerative diseases • Potential mechanisms of increased risk: Potential mechanisms of increased risk: • Effects on inflammation and β β - -amyloid amyloid Effects on inflammation and • Therapeutic applications: Effects of treating Therapeutic applications: Effects of treating • insulin resistance and normalzing normalzing CNS insulin CNS insulin insulin resistance and

I nsulin and the Brain I nsulin and the Brain • I nsulin crosses BBB via • I nsulin crosses BBB via saturable saturable receptor receptor- - mediated trancytosis trancytosis (Banks et al, 97) mediated (Banks et al, 97) • I nsulin receptors have synaptic localization in • I nsulin receptors have synaptic localization in hippocampus and throughout cortex ( hippocampus and throughout cortex ( Apelt Apelt et al, 2001) et al, 2001) • I ncreases glucose utilization in specific brain • I ncreases glucose utilization in specific brain regions (Bingham et al, 2002) regions (Bingham et al, 2002) • I ncreases levels of dopamine, acetylcholine, • I ncreases levels of dopamine, acetylcholine, norepinephrine ( norepinephrine ( Figlewicz Figlewicz et al, 1993) et al, 1993) • Modulates membrane potentials, membrane • Modulates membrane potentials, membrane expression of NMDA receptors, and neuronal expression of NMDA receptors, and neuronal firing/ LTP in hippocampus and EC ( firing/ LTP in hippocampus and EC ( Skeberdis Skeberdis et al, 2001) et al, 2001) • Enhances memory at • Enhances memory at optimal optimal dose dose

Chronic Effects of I nsulin: Chronic Effects of I nsulin: Too Much of a Good Thing Too Much of a Good Thing • Insulin typically secreted and cleared quickly • Insulin typically secreted and cleared quickly • High, chronic elevations problematic • High, chronic elevations problematic � Reduced brain insulin uptake Reduced brain insulin uptake � (Schwartz et al, 1990; Stein et al, 1987) (Schwartz et al, 1990; Stein et al, 1987) � Reduced neurotransmitter levels Reduced neurotransmitter levels � � Reduced glucose utilization (periphery Reduced glucose utilization (periphery � and CNS?) and CNS?) � Memory impairment Memory impairment �

I nsulin Resistance and I nsulin Resistance and Alzheimer’ ’s Disease s Disease Alzheimer • Insulin resistance/hyperinsulinemia increase risk of AD and memory impairment (Ott et al, 1999; Peila et al, 2002; Luchsinger et al, 2004) • Risk increases with age (Ryan et al, 2001) • Insulin resistance a particular risk factor for AD patients without the APOE-e4 allele (Kuusisto et al, 97; Liotsa et al, 02; Craft et al, 03) • Insulin may modulate risk in part through effects on A β 42 � Modulates A β 42 levels in vitro � Enhances release, regulates degradation by IDE (Gasparini et al, 2001; Qiu et al, 2001; Zhao et al, 2004)

Does I nsulin Affect CNS Does I nsulin Affect CNS β ? Levels of A β ? Levels of A • Will insulin administration raise A Will insulin administration raise A β β 42 levels in 42 levels in • CSF, consistent with in vitro in vitro effects of insulin effects of insulin CSF, consistent with on A β β release & degradation? release & degradation? on A • Will effects differ according to age? Will effects differ according to age? • • Will results be related to changes in Will results be related to changes in • biomarkers associated with inflammation? biomarkers associated with inflammation?

Methods Methods Fasted Subjects (n=16, mean age = 68.7) Fasted Subjects (n=16, mean age = 68.7) Separate days, counterbalanced order I nsulin ( 85 µ U/ml ) Saline I nsulin Saline ) Dextrose ( 95 mg/dl ) Dextrose Insulin/dextrose or saline infusion Insulin/dextrose or saline infusion 90 105 90 105 min min min min Plasma glucose Plasma glucose measured every LP for CSF measured every LP for CSF IV IV Cognitive Cognitive 5- -10 min 10 min collection 5 collection testing testing

Effects of I nsulin on CSF Aß ß42 Levels in 42 Levels in Effects of I nsulin on CSF A Normal Older Adults: Results Normal Older Adults: Results Insulin- -induced change in A induced change in A β β 42 42 Insulin is correlated with age is correlated with age 70 < 70 yrs r = .64, p < .008 r = .64, p < .008 ≥ 70 yrs 50 % Change in r = .85 r = .85 30 30 CSF A β 42 Levels p < .008 p < .008 ( pg / ml ) 10 -10 -30 50 60 70 80 90 Age Watson GS, et al. Neurology 2003;60(12):1899-903 Watson GS, et al.

Results Cytokines Results Cytokines 5 3.5 CSF IL-1 α CSF IL-1 β 3 4 (pg / ml) (pg / ml) 2.5 3 2 2 1.5 1 1 0.5 0 0 Insulin Insulin Saline Saline 3 1.8 CSF CSF IL-6 TNF α (pg / ml) 2 1.2 (pg / ml) 1 0.6 0 0 Saline Insulin Saline Insulin *p-values < .0001-.002 Fishel et al. Neurology , 2005

CSF F2- -I soP I soP Results CSF F2 Results CSF F2-Isoprostane levels increase in response to insulin 50 50 40 40 30 30 F2-IsoP (pg / ml) 20 20 10 10 0 0 * p < .01 Insulin Saline

Results Results Insulin-induced change in CSF A β 42 is correlated with F2-Isoprostane levels for the OLDER normal adults OLDER normal adults 800 ALL : r = .15, p = ns 600 OLD : r = .87, p = .005 400 200 Insulin - Saline CSF A β 42 Levels 0 ( pg / ml ) -200 -400 -20 0 20 40 60 Insulin - Saline CSF F2-IsoP Levels ( pg / ml )

Does insulin have similar role Does insulin have similar role β regulation in periphery? A β in A regulation in periphery? in • A A β β cleared in liver and other peripheral sites cleared in liver and other peripheral sites • (Ghiso ( Ghiso et al 04) et al 04) • Plasma A Plasma A β β elevated for some AD patients, declines elevated for some AD patients, declines • with progression ( with progression (Mayeux Mayeux et al. 03; et al. 03; Ertekin Ertekin- -Taner Taner et al. 04) et al. 04) • A A β β transported between periphery and brain transported between periphery and brain • (Mackic Mackic et al. 02; et al. 02; DeMattos DeMattos et al. 02) et al. 02) ( • IGF IGF- -1 and insulin increase levels of carrier proteins 1 and insulin increase levels of carrier proteins • that bind A β β and regulate its transport and regulate its transport that bind A (Carro ( Carro et al. 02) et al. 02) • High plasma A High plasma A β β may obstruct clearance from or may obstruct clearance from or • increase transport into brain increase transport into brain

Dose- -response effects of response effects of Dose β 42 intravenous insulin on plasma A β 42 intravenous insulin on plasma A 200 200 150 150 % change AD AD in plasma 100 100 Normal Normal A β 42 50 50 0 0 -50 50 - -100 100 - -0.33 0.33 1 1.67 - 1 1.67 *p=0.009 *p=0.009 Infusion Rate Infusion Rate (µ µU/kg/min) U/kg/min) ( Reger et al. et al. in press in press Reger

Model of Peripheral I nsulin Resistance & Model of Peripheral I nsulin Resistance & β Regulation Effects on A β Hyperinsulinemia Effects on A Regulation Hyperinsulinemia

Therapeutic I mplications Therapeutic I mplications • Raising plasma insulin invoked age • Raising plasma insulin invoked age- -related related increases in CSF A β β 42 & inflammatory markers for 42 & inflammatory markers for increases in CSF A normal adults, raised plasma A β β for AD patients for AD patients normal adults, raised plasma A • Mechanisms through which insulin resistance • Mechanisms through which insulin resistance increases risk of AD with age? increases risk of AD with age? • Treatment of insulin resistance that lowers insulin • Treatment of insulin resistance that lowers insulin and improves its effectiveness may be of and improves its effectiveness may be of therapeutic benefit therapeutic benefit • PPAR • PPAR γ γ agonists ( agonists (TZDs TZDs) promising because they ) promising because they increase peripheral insulin sensitivity, reduce increase peripheral insulin sensitivity, reduce peripheral insulin and inflammation peripheral insulin and inflammation