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Insulin Resistance Alzheimer's Disease: Pathophysiology and Treatment

Published online by Cambridge University Press:  06 December 2007

G. Stennis Watson  and
Suzanne Craft
G. Stennis Watson
Affiliation:
Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System; Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA; Email: [email protected]
Suzanne Craft
Affiliation:
Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System; Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA; Email: [email protected]
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Extract

ABSTRACT

Insulin and insulin resistance likely play a significant role in the pathophysiology and cognitive decline associated with Alzheimer's disease (AD). Insulin, insulin receptors, and insulin-sensitive glucose transporters are selectively localized the brain, including medial temporal areas that support memory. Raising brain insulin levels can facilitate memory and increase cerebrospinal fluid levels of β-amyloid (Aβ) and inflammatory markers. Insulin's effects on cognition may reflect normal regulation of glucose metabolism, long-term potentiation, and neurotransmitter levels. Consequently, insulin abnormalities may disrupt normal memory functioning and promote pathophysiological processes observed in patients with neurodegenerative disorders. Conversely, restoring normal insulin activity may exert a beneficial effect on pathophysiological processes. For example, peroxisome proliferator-activated receptor (PPAR)-gamma agonists (insulin sensitizing agents used to treat type 2 diabetes mellitus) modulate neuronal cell survival, inflammatory responses, mitochondrial functioning, and possibly Aβ processing and deposition. One PPAR-gamma agonist, rosiglitazone, facilitates memory and modulates plasma Aβ levels in patients with AD. Likewise, a healthy diet and regular exercise may improve insulin sensitivity and decrease the risk for both AD. Furthermore, intranasal insulin administration rapidly delivers insulin to the brain without altering plasma insulin or glucose levels. Studies to date suggest that this procedure can facilitate memory and modulate plasma Aβ levels in memory-impaired adults. Interestingly, the adverse effects of insulin abnormalities and the beneficial effects of improving insulin sensitivity may differ by apolipoprotein E (APOE) genotype, an established risk factor for AD. Patients who do carry lower doses of the APOE e4 allele have an enhanced risk for insulin abnormalities and are also more responsive to the memory enhancing effects of both rosiglitazone and intranasal insulin administration, relative to other patients. Therefore, future therapeutic trials should consider the moderating effects of APOE genotype.

Keywords

apolipoprotein Eβ-amyloiddiabetesexerciseglucose metabolisminflammationinsulinmemorymitochondriaPPAR-gamma agonists.
Type
Research Article
Information
Progress in Neurotherapeutics and Neuropsychopharmacology , Volume 3 , Issue 1 , January 2008 , pp. 85 - 110
Copyright
© 2008 Cambridge University Press

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References

Abbott, M.A., Wells, D.G., & Fallon, J.R. (1999). The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. Journal of Neurosciences, 19, 7300–7308.Google Scholar
Akiyama, H., Barger, S., Barnum, S., et al. (2000). Inflammation and Alzheimer's disease. Neurobiology of Aging, 21, 383–421.Google Scholar
Andreasen, N., & Blennow, K. (2002). Beta-amyloid (Abeta) protein in cerebrospinal fluid as a biomarker for Alzheimer's disease. Peptides, 23, 1205–1214.Google Scholar
Apelt, J., Mehlhorn, G., & Schliebs, R. (1999). Insulin-sensitive GLUT4 glucose transporters are colocalized with GLUT3-expressing cells and demonstrate a chemically distinct neuron-specific localization in rat brain. Journal of Neuroscience Research, 57, 693–705.Google Scholar
Balakrishnan, K., Verdile, G., Mehta, P.D., et al. (2005). Plasma Abeta42 correlates positively with increased body fat in healthy individuals. Journal of Alzheimers Disease, 8, 269–282.Google Scholar
Banks, W.A., Jaspan, J.B., Huang, W., & Kastin, A.J. (1997a). Transport of insulin across the blood–brain barrier: saturability at euglycemic doses of insulin. Peptides, 18, 1423–1429.Google Scholar
Banks, W.A., Jaspan, J.B., & Kastin, A.J. (1997b). Selective, physiological transport of insulin across the blood–brain barrier: novel demonstration by species-specific radioimmunoassays. Peptides, 18, 1257–1262.Google Scholar
Baskin, D.G., Figlewicz, D.P., Woods, S.C., Porte Jr, D., & Dorsa, D.M. (1987). Insulin in the brain. Annual Review of Physiology, 49, 335–347.Google Scholar
Baura, G.D., Foster, D.M., Porte Jr, D., et al. (1993). Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. Journal of Clinical Investigation, 92, 1824–1830.Google Scholar
Benedict, C., Hallschmid, M., Hatke, A., et al. (2004). Intranasal insulin improves memory in humans. Psychoneuroendocrinology, 29, 1326–1334.Google Scholar
Bernard, N., Kitabgi, P., & Rovere-Jovene, C. (2003). The Arg617-Arg618 cleavage site in the C-terminal domain of PC1 plays a major role in the processing and targeting of the enzyme within the regulated secretory pathway. Journal of Neurochemistry, 85, 1592–1603.Google Scholar
Bingham, E.M., Hopkins, D., Smith, D., et al. (2002). The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes, 51, 3384–3390.Google Scholar
Blanchard, J.G., & Duncan, P.M. (1997). Effect of combinations of insulin, glucose and scopolamine on radial arm maze performance. Pharmacology, Biochemistry and Behavior, 58, 209–214.Google Scholar
Boden, G., Lebed, B., Schatz, M., Homko, C., & Lemieux, S. (2001). Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes, 50, 1612–1617.Google Scholar
Born, J., Lange, T., Kern, W., McGregor, G.P., Bickel, U., & Fehm, H.L. (2002). Sniffing neuropeptides: a transnasal approach to the human brain. Nature Neuroscience, 5, 514–516.Google Scholar
Boyd Jr, F.T., Clarke, D.W., Muther, T.F., & Raizada, M.K. (1985). Insulin receptors and insulin modulation of norepinephrine uptake in neuronal cultures from rat brain. Journal of Biological Chemistry, 260, 15880–15884.Google Scholar
Brechtel, K., Dahl, D.B., Machann, J., et al. (2001). Fast elevation of the intramyocellular lipid content in the presence of circulating free fatty acids and hyperinsulinemia: a dynamic 1H-MRS study. Magnetic Resonance Medicine, 45, 179–183.Google Scholar
Byrne, J.H. (2003). Learning and memory: basic mechanisms. In: Squire, L.R., Bloom, F.E., McConnell, S.K., Roberts, J.L., Spitzer, N.C., & Zigmond, M.J. (eds.), Fundamental Neuroscience (2nd ed.). San Diego, CA: Academic Press, pp. 1276–1298.
Cacquevel, M., Lebeurrier, N., Cheenne, S., & Vivien, D. (2004). Cytokines in neuroinflammation and Alzheimer's disease. Current Drug Targets, 5, 529–534.Google Scholar
Carro, E., Trejo, J.L., Gomez-Isla, T., LeRoith, D., & Torres-Aleman, I. (2002). Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nature Medicine, 8, 1390–1397.Google Scholar
Combs, C.K., Johnson, D.E., Karlo, J.C., Cannady, S.B., & Landreth, G.E. (2000). Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. Journal of Neuroscience, 20, 558–567.Google Scholar
Craft, S., & Watson, G.S. (2004). Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurology, 3, 169–178.Google Scholar
Craft, S., Newcomer, J., Kanne, S., et al. (1996) Memory improvement following induced hyperinsulinemia in Alzheimer's disease. Neurobiology of Aging, 17, 123–130.Google Scholar
Craft, S., Peskind, E., Schwartz, M.W., Schellenberg, G.D., Raskind, M., & Porte Jr, D. (1998). Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology, 50, 164–168.Google Scholar
Craft, S., Asthana, S., Newcomer, J.W., et al. (1999a). Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. The Archives of General Psychiatry, 56, 1135–1140.Google Scholar
Craft, S., Asthana, S., Schellenberg, G., et al. (1999b). Insulin metabolism in Alzheimer's disease differs according to apolipoprotein E genotype and gender. Neuroendocrinology, 70, 146–152.Google Scholar
Craft, S., Asthana, S., Cook, D.G., et al. (2003). Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology, 28, 809–822.Google Scholar
Cuzzocrea, S., Pisano, B., Dugo, L., et al. (2004). Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. European Journal of Pharmacology, 483, 79–93.Google Scholar
Dandona, P. (2002). Endothelium, inflammation, and diabetes. Current Diabetes Reports, 2, 311–315.Google Scholar
de la Monte, S.M., & Wands, J.R. (2005). Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease. Journal of Alzheimers Disease, 7, 45–61.Google Scholar
de la Monte, S.M., Tong, M., Lester-Coll, N., Plater Jr, M., & Wands, J.R. (2006). Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer's disease. Journal of Alzheimers Disease, 10, 89–109.Google Scholar
de Rivera, C., Shukitt-Hale, B., Joseph, J.A., & Mendelson, J.R. (2006). The effects of antioxidants in the senescent auditory cortex. Neurobiology of Aging, 27, 1035–1044.Google Scholar
Dello Russo, C., Gavrilyuk, V., Weinberg, G., et al. (2003). Peroxisome proliferator-activated receptor gamma thiazolidinedione agonists increase glucose metabolism in astrocytes. Journal of Biological Chemistry, 278, 5828–5836.Google Scholar
Di Luca, M., Ruts, L., Gardoni, F., Cattabeni, F., Biessels, G.J., & Gispen, W.H. (1999). NMDA receptor subunits are modified transcriptionally and post-translationally in the brain of streptozotocin-diabetic rats. Diabetologia, 42, 693–701.Google Scholar
Diab, A., Deng, C., Smith, J.D., et al. (2002). Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis. Journal of Immunology, 168, 2508–2515.Google Scholar
Doyle, P., Cusin, I., Rohner-Jeanrenaud, F., & Jeanrenaud, B. (1995). Four-day hyperinsulinemia in euglycemic conditions alters local cerebral glucose utilization in specific brain nuclei of freely moving rats. Brain Research, 684, 47–55.Google Scholar
Feinstein, D.L., Galea, E., Gavrilyuk, V., et al. (2002). Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis. Annals of Neurology, 51, 694–702.Google Scholar
Feinstein, D.L., Spagnolo, A., Akar, C., et al. (2005). Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key? Biochemical Pharmacology, 70, 177–188.Google Scholar
Ferre, P. (2004). The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes, 53 (Suppl. 1), S43–S50.Google Scholar
Figlewicz, D.P., Bentson, K., & Ocrant, I. (1993a). The effect of insulin on norepinephrine uptake by PC12 cells. Brain Research Bulletin, 32, 425–431.Google Scholar
Figlewicz, D.P., Szot, P., Israel, P.A., Payne, C., & Dorsa, D.M. (1993b). Insulin reduces norepinephrine transporter mRNA in vivo in rat locus coeruleus. Brain Research, 602, 161–164.Google Scholar
Fishel, M.A., Watson, G.S., Montine, T.J., et al. (2005). Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Archives of Neurology, 62, 1539–1544.Google Scholar
Frolich, L., Blum-Degen, D., Bernstein, H.G., et al. (1998). Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. Journal of Neural Transmission, 105, 423–438.Google Scholar
Frolich, L, Blum-Degen, D., Riederer, P., & Hoyer, S. (1999). A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer's disease. Annals of the New York Academic Sciences, 893, 290–293.Google Scholar
Gasparini, L., Gouras, G.K., Wang, R., et al. (2001). Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. Journal of Neuroscience, 21, 2561–2570.Google Scholar
Gordon, E.S. (1968). Efficiency of energy metabolism in obesity. American Journal of Clinical Nutrition, 21, 1480–1485.Google Scholar
Gurnell, M. (2003). PPARgamma and metabolism: insights from the study of human genetic variants. Clinical Endocrinology (Oxf), 59, 267–277.Google Scholar
Gustafson, D., Rothenberg, E., Blennow, K., Steen, B., & Skoog, I. (2003). An 18-year follow-up of overweight and risk of Alzheimer disease. Archives of Internal Medicine, 163, 1524–1528.Google Scholar
Hak, A.E., Pols, H.A., Stehouwer, C.D., et al. (2001). Markers of inflammation and cellular adhesion molecules in relation to insulin resistance in nondiabetic elderly: the Rotterdam study. Journal of Clinical Endocrinology and Metabolism, 86, 4398–4405.Google Scholar
Hallschmid, M., Benedict, C., Schultes, B., Fehm, H.L., Born, J., & Kern, W. (2004). Intranasal insulin reduces body fat in men but not in women. Diabetes, 53, 3024–3029.Google Scholar
Harris, M.I., Flegal, K.M., Cowie, C.C., et al. (1998). Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults. The Third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care, 21, 518–524.Google Scholar
Havrankova, J., Roth, J., & Brownstein, M. (1978a). Insulin receptors are widely distributed in the central nervous system of the rat. Nature, 272, 827–829.Google Scholar
Havrankova, J., Schmechel, D., Roth, J., & Brownstein, M. (1978b). Identification of insulin in rat brain. Proceedings of the National Academy of Sciences of the United States of America, 75, 5737–5741.Google Scholar
Heneka, M.T., Klockgether, T., & Feinstein, D.L. (2000). Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. Journal of Neuroscience, 20, 6862–6867.Google Scholar
Heneka, M.T., Galea, E., Gavriluyk, V., et al. (2002). Noradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for Alzheimer's disease. Journal of Neuroscience, 22, 2434–2442.Google Scholar
Ho, L., Qin, W., Pompl, P.N., et al. (2004). Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB Journal, 18, 902–904.Google Scholar
Hoyer, S., & Lannert, H. (1999). Inhibition of the neuronal insulin receptor causes Alzheimer-like disturbances in oxidative/energy brain metabolism and in behavior in adult rats. Annals of the New York Academic Sciences, 893, 301–303.Google Scholar
Hull, M., Strauss, S., Berger, M., Volk, B., & Bauer, J. (1996). The participation of interleukin-6, a stress-inducible cytokine, in the pathogenesis of Alzheimer's disease. Behavioral Brain Research, 78, 37–41.Google Scholar
Kaiyala, K.J., Prigeon, R.L., Kahn, S.E., Woods, S.C., & Schwartz, M.W. (2000). Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes, 49, 1525–1533.Google Scholar
Kern, W., Born, J., Schreiber, H., & Fehm, H.L. (1999). Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes, 48, 557–563.Google Scholar
Kim, Y.P., Kim, H., Shin, M.S., et al. (2004). Age-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats. Neuroscience Letters, 355, 152–154.Google Scholar
Kitamura, Y., Kakimura, J., Matsuoka, Y., Nomura, Y., Gebicke-Haerter, P.J., & Taniguchi, T. (1999a). Activators of peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibit inducible nitric oxide synthase expression but increase heme oxygenase-1 expression in rat glial cells. Neuroscience Letters, 262, 129–132.Google Scholar
Kitamura, Y., Shimohama, S., Koike, H., et al. (1999b). Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer's disease brains. Biochemical and Biophysical Research Communications, 254, 582–586.Google Scholar
Knowler, W.C., Barrett-Connor, E., Fowler, S.E., et al. (2002). Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. TheNew England Journal of Medicine, 346, 393–403.Google Scholar
Kopf, S.R., & Baratti, C.M. (1996). Effects of post-training administration of glucose on retention of a habituation response in mice: participation of a central cholinergic mechanism. Neurobiology of Learning and Memory, 65, 253–260.Google Scholar
Krogh-Madsen, R., Plomgaard, P., Keller, P., Keller, C., & Pedersen, B.K. (2004). Insulin stimulates interleukin-6 and tumor necrosis factor-alpha gene expression in human subcutaneous adipose tissue. American Journal of Physiology, Endocrinology and Metabolism, 286, E234–E238.Google Scholar
Kulstad, J.J., Green, P.S., Cook, D.G., et al. (2006). Differential modulation of plasma beta-amyloid by insulin in patients with Alzheimer disease. Neurology, 66, 1506–1510.Google Scholar
Kuusisto, J., Koivisto, K., Mykkanen, L., et al. (1997). Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study. British Medical Journal, 315, 1045–1049.Google Scholar
Landreth, G.E., & Heneka, M.T. (2001). Anti-inflammatory actions of peroxisome proliferator-activated receptor gamma agonists in Alzheimer's disease. Neurobiology of Aging, 22, 937–944.Google Scholar
Larson, E.B., Wang, L., Bowen, J.D., et al. (2006). Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Annals of Internal Medicine, 144, 73–81.Google Scholar
Leibson, C.L., Rocca, W.A., & Hanson, V.A., et al. (1997). The risk of dementia among persons with diabetes mellitus: a population-based cohort study. Annals of the New York Academy of Sciences, 826, 422–427.Google Scholar
Lester-Coll, N., Rivera, E.J., Soscia, S.J., Doiron, K., Wands, J.R., & de la Monte, S.M. (2006). Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. Journal of Alzheimers Disesae, 9, 13–33.Google Scholar
Luchsinger, J.A., Tang, M.X., Shea, S., & Mayeux, R. (2004). Hyperinsulinemia and risk of Alzheimer disease. Neurology, 63, 1187–1192.Google Scholar
Malinowski, J.M., & Bolesta, S. (2000). Rosiglitazone in the treatment of type 2 diabetes mellitus: a critical review. Clinical Therapeutics, 22, 1151–1168; discussion 1149–1150.Google Scholar
Marfaing, P., Penicaud, L., Broer, Y., Mraovitch, S., Calando, Y., & Picon, L. (1990). Effects of hyperinsulinemia on local cerebral insulin binding and glucose utilization in normoglycemic awake rats. Neuroscience Letters, 115, 279–285.Google Scholar
Marfella, R., D'Amico, M., Esposito, K., et al. (2006). The ubiquitin-proteasome system and inflammatory activity in diabetic atherosclerotic plaques: effects of rosiglitazone treatment. Diabetes, 55, 622–632.Google Scholar
Matsuoka, Y., Saito, M., LaFrancois, J., et al. (2003). Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to beta-amyloid. Journal of Neuroscience, 23, 29–33.Google Scholar
Mayeux, R., Honig, L.S., Tang, M.X., et al. (2003). Plasma A[beta]40 and A[beta]42 and Alzheimer's disease: relation to age, mortality, and risk. Neurology, 61, 1185–1190.Google Scholar
Meneilly, G.S., Cheung, E., Tessier, D., Yakura, C., & Tuokko, H. (1993). The effect of improved glycemic control on cognitive functions in the elderly patient with diabetes. Journal of Gerontology, 48, M117–M121.Google Scholar
Messier, C. (2003). Diabetes, Alzheimer's disease and apolipoprotein genotype. Experimental Gerontology, 38, 941–946.Google Scholar
MMWR Report (2003). Prevalence of diabetes and impaired fasting glucose in adults – United States, 1999–2000. Morbidity Mortality Weekly Report, 52, 833–837.Google Scholar
Molteni, R., Wu, A., Vaynman, S., Ying, Z., Barnard, R.J., & Gomez-Pinilla, F. (2004). Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor. Neuroscience, 123, 429–440.Google Scholar
Montine, T.J., Kaye, J.A., Montine, K.S., McFarland, L., Morrow, J.D., & Quinn, J.F. (2001). Cerebrospinal fluid abeta42, tau, and F2-isoprostane concentrations in patients with Alzheimer disease, other dementias, and in age-matched controls. Archives of Pathology and Laboratory Medicine, 125, 510–512.Google Scholar
Moreno, S., Farioli-Vecchioli, S., & Ceru, M.P. (2004). Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience, 123, 131–145.Google Scholar
Morgan, D. (2005). Mechanisms of A beta plaque clearance following passive A beta immunization. Neurodegenerative Diseases, 2, 261–266.Google Scholar
Ott, A., Stolk, R.P., van Harskamp, F., Pols, H.A., Hofman, A., & Breteler, M.M. (1999). Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology, 53, 1937–1942.Google Scholar
Park, C.R., Seeley, R.J., Craft, S., & Woods, S.C. (2000). Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiology & Behavior, 68, 509–514.Google Scholar
Peila, R., Rodriguez, B.L., & Launer, L.J. (2002). Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes, 51, 1256–1262.Google Scholar
Pershadsingh, H.A., Heneka, M.T., Saini, R., Amin, N.M., Broeske, D.J., & Feinstein, D.L. (2004). Effect of pioglitazone treatment in a patient with secondary multiple sclerosis. Journal of Neuroinflammation, 1, 3.Google Scholar
Pickup, J.C., Mattock, M.B., Chusney, G.D., & Burt, D. (1997). NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia, 40, 1286–1292.Google Scholar
Qiu, W.Q., Walsh, D.M., Ye, Z., et al. (1998). Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. Journal of Biological Chemistry, 273, 32730–32738.Google Scholar
Ragozzino, M.E., Arankowsky-Sandoval, G., & Gold, P.E. (1994). Glucose attenuates the effect of combined muscarinic-nicotinic receptor blockade on spontaneous alternation. European Journal of Pharmacology, 256, 31–36.Google Scholar
Ramlo-Halsted, B.A., & Edelman, S.V. (1999). The natural history of type 2 diabetes. Implications for clinical practice. Primary Care, 26, 771–789.Google Scholar
Razay, G., & Wilcock, G.K. (1994). Hyperinsulinaemia and Alzheimer's disease. Age and Ageing, 23, 396–399.Google Scholar
Reagan, L.P., Gorovits, N., Hoskin, E.K., et al. (2001). Localization and regulation of GLUTx1 glucose transporter in the hippocampus of streptozotocin diabetic rats. Proceedings of the National Academy of Sciences of United States America, 98, 2820–2825.Google Scholar
Reaven, G.M., Chang, H., & Hoffman, B.B. (1988). Additive hypoglycemic effects of drugs that modify free-fatty acid metabolism by different mechanisms in rats with streptozocin-induced diabetes. Diabetes, 37, 28–32.Google Scholar
Reger, M.A., Watson, G.S., Frey 2nd, W.H., et al. (2006). Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiology of Aging, 27, 451–458.Google Scholar
Risner, M.E., Saunders, A.M., Altman, J.F., et al. (2006). Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics Journal, 6, 246–254.Google Scholar
Rivera, E.J., Goldin, A., Fulmer, N., Tavares, R., Wands, J.R., & de la Monte, S.M. (2005). Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. Journal of Alzheimers Disease, 8, 247–268.Google Scholar
Rosler, N., Wichart, I., & Jellinger, K.A. (2001). Intra vitam lumbar and post mortem ventricular cerebrospinal fluid immunoreactive interleukin-6 in Alzheimer's disease patients. Acta Neurologica Scandinavica, 103, 126–130.Google Scholar
Ruan, H., & Lodish, H.F. (2003). Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine & Growth Factor Reviews, 14, 447–455.Google Scholar
Santomauro, A.T., Boden, G., Silva, M.E., et al. (1999). Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes, 48, 1836–1841.Google Scholar
Sastre, M., Dewachter, I., Landreth, G.E., et al. (2003). Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. Journal of Neuroscience, 23, 9796–9804.Google Scholar
Schubert, M., Gautam, D., Surjo, D., et al. (2004). Role for neuronal insulin resistance in neurodegenerative diseases. Proceedings of the National Academy of Sciences of the United States of America, 101, 3100–3105.Google Scholar
Schulingkamp, R.J., Pagano, T.C., Hung, D., & Raffa, R.B. (2000). Insulin receptors and insulin action in the brain: review and clinical implications. Neuroscience and Biobehavioral Reviews, 24, 855–872.Google Scholar
Schwartz, M.W., Figlewicz, D.F., Kahn, S.E., Baskin, D.G., Greenwood, M.R., & Porte Jr, D. (1990). Insulin binding to brain capillaries is reduced in genetically obese, hyperinsulinemic Zucker rats. Peptides, 11, 467–472.Google Scholar
Sidhu, J.S., Cowan, D., & Kaski, J.C. (2003). The effects of rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients. Journal of the American College of Cardiology, 42, 1757–1763.Google Scholar
Skeberdis, V.A., Lan, J., Zheng, X., Zukin, R.S., & Bennett, M.V. (2001). Insulin promotes rapid delivery of N-methyl-d-aspartate receptors to the cell surface by exocytosis. Proceedings of the National Academy of Sciences of United States of America, 98, 3561–3566.Google Scholar
Soop, M., Duxbury, H., Agwunobi, A.O., et al. (2002). Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin in humans. American Journal of Physiology, Endocrinology and Metabolism, 282, E1276–E1285.Google Scholar
Steen, E., Terry, B.M., Rivera, E.J., et al. (2005). Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease – is this type 3 diabetes? Journal of Alzheimers Disease, 7, 63–80.Google Scholar
Strachan, M.W., Deary, I.J., Ewing, F.M., & Frier, B.M. (1997). Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies. Diabetes Care, 20, 438–445.Google Scholar
Thorne, R.G., Pronk, G.J., Padmanabhan, V., & Frey 2nd, W.H. (2004). Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience, 127, 481–496.Google Scholar
Trejo, J.L., Carro, E., & Torres-Aleman, I. (2001). Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. Journal of Neuroscience, 21, 1628–1634.Google Scholar
Tuomilehto, J., Lindstrom, J., Eriksson, J.G., et al. (2001). Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. The New England Journal of Medicine, 344, 1343–1350.Google Scholar
Unger, J.W., Livingston, J.N., & Moss, A.M. (1991). Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Progress in Neurobiology, 36, 343–362.Google Scholar
Uryu, S., Harada, J., Hisamoto, M., & Oda, T. (2002). Troglitazone inhibits both post-glutamate neurotoxicity and low-potassium-induced apoptosis in cerebellar granule neurons. Brain Research, 924, 229–236.Google Scholar
van der Heide, L.P., Kamal, A., Artola, A., Gispen, W.H., & Ramakers, G.M. (2005). Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner. Journal of Neurochemistry, 94, 1158–1166.Google Scholar
Vanhanen, M., Koivisto, K., Kuusisto, J., et al. (1998). Cognitive function in an elderly population with persistent impaired glucose tolerance. Diabetes Care, 21, 398–402.Google Scholar
Wang, J., Ho, L., Qin, W., et al. (2005). Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer's disease. FASEB Journal, 19, 659–661.Google Scholar
Watson, G.S., & Craft, S. (2003). The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs, 17, 27–45.Google Scholar
Watson, G.S., & Craft, S. (2004). Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease. European Journal of Pharmacology, 490, 97–113.Google Scholar
Watson, G.S., Peskind, E.R., Asthana, S., et al. (2003). Insulin increases CSF Abeta42 levels in normal older adults. Neurology, 60, 1899–1903.Google Scholar
Watson, G.S., Cholerton, B.A., Reger, M.A., et al. (2005). Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. American Journal of Geriatric Psychiatry, 13, 950–958.Google Scholar
Watson, G.S., Bernhardt, T., Reger, M.A., et al. (2006a). Insulin effects on CSF norepinephrine and cognition in Alzheimer's disease. Neurobiology of Aging, 27, 38–41.Google Scholar
Watson, G.S., Reger, M.A., Baker, L.D., et al. (2006b). Effects of exercise and nutrition on memory in Japanese-Americans with impaired glucose tolerance. Diabetes Care, 29, 135–136.Google Scholar
Zhao, W., Chen, H., Xu, H., et al. (1999). Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. Journal of Biological Chemistry, 274, 34893–34902.Google Scholar