Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Pharmacological treatments presently available can slow down the progression of symptoms but can not cure the disease. Currently there is widening recognition that AD is closely associated with impaired insulin signaling and glucose metabolism in brain, suggesting it to be a brain-specific form of diabetes and so also termed as "type 3 diabetes". Hence investigating the role of pharmacological agents that could ameliorate neuronal insulin resistance merit attention in AD therapeutics, however the therapeutics for pathophysiological condition like neuronal insulin resistance itself is largely unknown. In the present study we have determined the effect of metformin on neuronal insulin resistance and AD-associated characteristics in an in vitro model of "type 3 diabetes" by differentiating neuronal cell line Neuro-2a under prolonged presence of insulin. We observed that prolonged hyperinsulinemic conditions in addition to generating insulin resistance also led to development of hallmark AD-associated neuropathological changes. Treatment with metformin sensitized the impaired insulin actions and also prevented appearance of molecular and pathological characteristics observed in AD. The results thus demonstrate possible therapeutic efficacy of peripheral insulin-sensitizer drug metformin in AD by its ability to sensitize neuronal insulin resistance. These findings also provide direct evidences linking hyperinsulinemia and AD and suggest a unique opportunity for prevention and treatment of "type 3 diabetes".
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Two retrospective studies reported that among persons with T2D, a diagnosis of dementia was associated with metformin use.
“two retrospective studies reported that among persons with T2D, a diagnosis of dementia was associated with metformin use[85, 86].”
From Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial (2016) · cites this paper as [85]
When insulin is added to metformin, it potentiates insulin's effects on amyloid reduction, improves neuronal insulin resistance, and impairs glucose uptake and Alzheimer's disease-associated neuropathological characteristics by activating the insulin signaling pathway.
“However, when insulin is added to metformin, it potentiates insulin’s effects on amyloid reduction, improves neuronal insulin resistance, and impairs glucose uptake and AD-associated neuropathological characteristics by activating the insulin signaling pathway [129].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [129]
Insulin regulates food intake, energy homeostasis, reproduction, sympathetic activity, learning and memory, as well as neuronal proliferation, apoptosis, and synaptic transmission in the central nervous system.
“Insulin has been shown to regulate a wide range of processes in the central nervous system such as food intake, energy homeostasis, reproduction, sympathetic activity, learning and memory [129], as well as neuronal proliferation, apoptosis, and synaptic transmission [130].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [129]
Cites
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652 · see citing works
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744 · see citing works
Alzheimer's Disease: A Disorder of Cortical Cholinergic Innervation
Coyle, J. T., Price, D. L., & DeLong, M. R. (1983) · Science · doi:10.1126/science.6338589 · Cited by 3,050 · see citing works
Steen, E., Terry, B. M., J. Rivera, E., Cannon, J. L., Neely, T. R., Tavares, R., Xu, X. J., Wands, J. R., & de la Monte, S. M. (2005) · Journal of Alzheimer's Disease · doi:10.3233/jad-2005-7107 · Cited by 1,703 · see citing works
The GSK3 hypothesis of Alzheimer’s disease
Hooper, C., Killick, R., & Lovestone, S. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05194.x · Cited by 1,191 · see citing works
Bramblett, G. T., Goedert, M., Jakes, R., Merrick, S. E., Trojanowski, J. Q., & Lee, V. M. Y. (1993) · Neuron · doi:10.1016/0896-6273(93)90057-x · Cited by 903 · see citing works
Allan Butterfield, D. (2002) · Free Radical Research · doi:10.1080/1071576021000049890 · Cited by 786 · see citing works
Resveratrol Promotes Clearance of Alzheimer's Disease Amyloid-β Peptides
Marambaud, P., Zhao, H., & Davies, P. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508246200 · Cited by 750 · see citing works
Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease
Frölich, L., Blum-Degen, D., Bernstein, H.-G., Engelsberger, S., Humrich, J., Laufer, S., Muschner, D., Thalheimer, A., Türk, A., Hoyer, S., et al. (1998) · Journal of Neural Transmission · doi:10.1007/s007020050068 · Cited by 748 · see citing works
Rivera, E. J., Goldin, A., Fulmer, N., Tavares, R., Wands, J. R., & de la Monte, S. M. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2005-8304 · Cited by 723 · see citing works
Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: An update
Soldani, C., & Scovassi, A. I. (2002) · APOPTOSIS · doi:10.1023/a:1016119328968 · Cited by 697 · see citing works
Hyperinsulinemia and risk of Alzheimer disease
Luchsinger, J. A., Tang, M.-X., Shea, S., & Mayeux, R. (2004) · Neurology · doi:10.1212/01.wnl.0000140292.04932.87 · Cited by 683 · see citing works
De Felice, F. G., Vieira, M. N. N., Bomfim, T. R., Decker, H., Velasco, P. T., Lambert, M. P., Viola, K. L., Zhao, W.-Q., Ferreira, S. T., & Klein, W. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809158106 · Cited by 657 · see citing works
Vingtdeux, V., Giliberto, L., Zhao, H., Chandakkar, P., Wu, Q., Simon, J. E., Janle, E. M., Lobo, J., Ferruzzi, M. G., Davies, P. J., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.060061 · Cited by 648 · see citing works
The role of insulin receptor signaling in the brain
Plum, L., Schubert, M., & Brüning, J. C. (2005) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2005.01.008 · Cited by 604 · see citing works
Amyloid beta oligomers induce impairment of neuronal insulin receptors
Zhao, W., De Felice, F. G., Fernandez, S., Chen, H., Lambert, M. P., Quon, M. J., Krafft, G. A., & Klein, W. L. (2008) · The FASEB Journal · doi:10.1096/fj.06-7703com · Cited by 587 · see citing works
Proline-directed and non-proline-directed phosphorylation of PHF-tau
Morishima-Kawashima, M., Hasegawa, M., Takio, K., Suzuki, M., Yoshida, H., Titani, K., & Ihara, Y. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.2.823 · Cited by 557 · see citing works
de la Monte, S. M., & Wands, J. R. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2005-7106 · Cited by 552 · see citing works
Role of insulin and insulin receptor in learning and memory
Zhao, W., & Alkon, D. L. (2001) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(01)00455-5 · Cited by 492 · see citing works
Lovestone, S., Reynolds, C. H., Latimer, D. A., Davis, D. R., Anderton, B. H., Gallo, J., Hanger, D. P., Mulot, S., Marquardt, B., Stabel, S., et al. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00246-3 · Cited by 470 · see citing works
Intracerebral streptozotocin model of type 3 diabetes: Relevance to sporadic Alzheimer’s disease
Lester-Coll, N., Rivera, E. J., Soscia, S. J., Doiron, K., Wands, J. R., & de la Monte, S. M. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-9102 · Cited by 467 · see citing works
Insulin signaling in the central nervous system: Learning to survive
van der Heide, L. P., Ramakers, G. M. J., & Smidt, M. P. (2006) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2006.06.003 · Cited by 444 · see citing works
Chen, Y., Zhou, K., Wang, R., Liu, Y., Kwak, Y.-D., Ma, T., Thompson, R. C., Zhao, Y., Smith, L., Gasparini, L., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807991106 · Cited by 390 · see citing works
Perry, G., Roder, H., Nunomura, A., Takeda, A., Friedlich, A., Zhu, X.-W., Raina, A., Holbrook, N., Siedlak, S., Harris, P., et al. (1999) · NeuroReport · doi:10.1097/00001756-199908020-00035 · Cited by 296 · see citing works
Maturation of neuroblastoma cells in the presence of dimethylsulfoxide.
Kimhi, Y., Palfrey, C., Spector, I., Barak, Y., & Littauer, U. Z. (1976) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.73.2.462 · Cited by 291 · see citing works
Stein, T. D., & Johnson, J. A. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-17-07380.2002 · Cited by 288 · see citing works
Insulin increases CSF Aβ42 levels in normal older adults
Watson, G. S., Peskind, E. R., Asthana, S., Purganan, K., Wait, C., Chapman, D., Schwartz, M. W., Plymate, S. R., & Craft, S. (2003) · Neurology · doi:10.1212/01.wnl.0000065916.25128.25 · Cited by 265 · see citing works
El‐Mir, M., Détaille, D., R-Villanueva, G., Delgado‐Esteban, M., Guigas, B., Attia, S., Fontaine, E. M., Almeida, Á., & Leverve, X. M. (2007) · Journal of Molecular Neuroscience · doi:10.1007/s12031-007-9002-1 · Cited by 243 · see citing works
PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease
Alkon, D. L., Sun, M., & Nelson, T. J. (2007) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2006.12.002 · Cited by 243 · see citing works
Structural Principles of Tau and the Paired Helical Filaments of Alzheimer's Disease
Mandelkow, E., Von Bergen, M., Biernat, J., & Mandelkow, E. (2007) · Brain Pathology · doi:10.1111/j.1750-3639.2007.00053.x · Cited by 243 · see citing works
Williamson, R., Scales, T., Clark, B. R., Gibb, G., Reynolds, C. H., Kellie, S., Bird, I. N., Varndell, I. M., Sheppard, P. W., Everall, I., et al. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-01-00010.2002 · Cited by 227 · see citing works
Metformin therapy in a transgenic mouse model of Huntington's disease
Ma, T. C., Buescher, J. L., Oatis, B., Funk, J. A., Nash, A. J., Carrier, R. L., & Hoyt, K. R. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.10.039 · Cited by 220 · see citing works
Chronic activation of ERK and neurodegenerative diseases
Colucci‐D'Amato, L., Perrone‐Capano, C., & di Porzio, U. (2003) · BioEssays · doi:10.1002/bies.10355 · Cited by 195 · see citing works
Liu, Y. M., Liu, F., Grundke, I., Iqbal, K., & Gong, C. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06320.x · Cited by 193 · see citing works
Wei, W., Wang, X., & Kusiak, J. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111704200 · Cited by 190 · see citing works
Hoyer, S. (2004) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-8969-7_8 · Cited by 173 · see citing works
Subramaniam, S., Zirrgiebel, U., Halbach, O. V. B. U., Strelau, J., Laliberté, C. L., Kaplan, D. R., & Unsicker, K. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200403028 · Cited by 150 · see citing works
Sun, A.-Y., Nguyen, X. V., & Bing, G. (2002) · Journal of Histochemistry and Cytochemistry · doi:10.1177/002215540205000403 · Cited by 146 · see citing works
de la Monte, S. M., & Wands, J. R. (2002) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-002-8475-x · Cited by 123 · see citing works
Haddad, J. J. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.10.008 · Cited by 121 · see citing works
Grace, E. A., & Busciglio, J. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-02-00493.2003 · Cited by 113 · see citing works
Altered regulation of the PINK1 locus: a link between type 2 diabetes and neurodegeneration?
Scheele, C., Nielsen, A. R., Walden, T. B., Sewell, D. A., Fischer, C. P., Brogan, R. J., Petrovic, N., Larsson, O., Tesch, P. A., Wennmalm, K., et al. (2007) · The FASEB Journal · doi:10.1096/fj.07-8520com · Cited by 110 · see citing works
Metformin Protects the Brain Against the Oxidative Imbalance Promoted by Type 2 Diabetes
Correia, S. C., Carvalho, C., Santos, M. S., Proenca, T., Nunes, E., Duarte, A. I., Monteiro, P. F., Seiça, R. M. F., Oliveira, C. R., & Moreira, P. I. (2008) · Medicinal Chemistry · doi:10.2174/157340608784872299 · Cited by 110 · see citing works
Focal adhesions regulate Aβ signaling and cell death in Alzheimer's disease
Caltagarone, J., Jing, Z., & Bowser, R. (2007) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2006.11.007 · Cited by 102 · see citing works
Brain Insulin Impairs Amyloid-β(1-40) Clearance from the Brain
Shiiki, T., Ohtsuki, S., Kurihara, A., Naganuma, H., Nishimura, K., Tachikawa, M., Hosoya, K., & Terasaki, T. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2236-04.2004 · Cited by 101 · see citing works
Zhang, C., Lambert, M. P., Bunch, C., Barber, K., Wade, W. S., Krafft, G. A., & Klein, W. L. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47238-9 · Cited by 97 · see citing works
Mayer, C., & Belsham, D. D. (2009) · Endocrinology · doi:10.1210/en.2009-0838 · Cited by 85 · see citing works
Mielke, J. G., Taghibiglou, C., & Wang, Y. T. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.07.055 · Cited by 81 · see citing works
Development of insulin resistance and reversal by thiazolidinediones in C2C12 skeletal muscle cells
Kumar, N., & Dey, C. S. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01509-5 · Cited by 75 · see citing works
Self-citationFocal adhesion kinase regulates insulin resistance in skeletal muscle
Bisht, B., Goel, H. L., & Dey, C. S. (2007) · Diabetologia · doi:10.1007/s00125-007-0591-6 · Cited by 63 · see citing works
Self-citationHoyer, S., & Lannert, H. (2007) · Springer eBooks · doi:10.1007/978-3-211-73574-9_25 · Cited by 59 · see citing works
Receptor and postreceptor insulin resistance induced by in vivo hyperinsuiinemia
Martin, C., DESAI, K. S., & Steiner, G. A. (1983) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y83-123 · Cited by 47 · see citing works
Ayasolla, K., Giri, S., Singh, A. K., & Singh, I. (2005) · Journal of Neuroinflammation · doi:10.1186/1742-2094-2-21 · Cited by 45 · see citing works
Models of Alzheimer’s disease: cellular and molecular aspects
Hoyer, S. (1997) · Springer eBooks · doi:10.1007/978-3-7091-6844-8_2 · Cited by 43 · see citing works
Hwang, I. K., Kim, I. Y., Joo, E. J., Shin, J. H., Choi, J. W., Won, M., Yoon, Y. S., & Seong, J. K. (2010) · Neurochemical Research · doi:10.1007/s11064-009-0115-5 · Cited by 43 · see citing works
Chauhan, N. B., & Siegel, G. J. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.01.008 · Cited by 40 · see citing works
van der Heide, L. P., Hoekman, M. F. M., Biessels, G. J., & Gispen, W. H. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01828.x · Cited by 36 · see citing works
Roberts, J. S., & Tersegno, S. M. (2010) · Future Neurology · doi:10.2217/fnl.10.31 · Cited by 31 · see citing works
Sinha, M. K., Taylor, L. G., Pories, W. J., Flickinger, E. G., Meelheim, D., Atkinson, S. A., Sehgal, N. S., & Caro, J. F. (1987) · Journal of Clinical Investigation · doi:10.1172/jci113163 · Cited by 26 · see citing works
Involvement of Elk‐1 in L6E9 skeletal muscle differentiation
Khurana, A., & Dey, C. S. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03192-7 · Cited by 19 · see citing works
Self-citationNilsson (1999) · doi:10.1002/(sici)1097-4695(19990615)39:4
Flagged first, then by citations
Cited by
Sorted by citations
Talbot, K., Wang, H.-Y., Kazi, H., Han, L.-Y., Bakshi, K. P., Stucky, A., Fuino, R. L., Kawaguchi, K. R., Samoyedny, A. J., Wilson, R. S., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59903 · Cited by 1,871 · see citing works
Metformin: An Old But Still the Best Treatment for Type 2 Diabetes
Rojas, L. B. A., & Gomes, M. B. (2013) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-5-6 · Cited by 567 · see citing works
Butterfield, D. A., Di Domenico, F., & Barone, E. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.06.010 · Cited by 402 · see citing works
Imfeld, P., Bodmer, M., Jick, S. S., & Meier, C. R. (2012) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2012.03916.x · Cited by 389 · see citing works
Effects of the Insulin Sensitizer Metformin in Alzheimer Disease
Koenig, A. M., Mechanic-Hamilton, D. J., Xie, S. X., Combs, M., Cappola, A. R., Xie, L., Detre, J. A., Wolk, D. A., & Arnold, S. E. (2017) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0000000000000202 · Cited by 352 · see citing works
Insulin resistance and Parkinson’s disease: A new target for disease modification?
Athauda, D. S., & Foltynie, T. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.10.001 · Cited by 333 · see citing works
Arnold, S. E., Lucki, I., Brookshire, B. R., Carlson, G. C., Browne, C. A., Kazi, H., Bang, S., Choi, B., Chen, Y., McMullen, M. F., et al. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.03.011 · Cited by 315 · see citing works
The Therapeutic Potential of Metformin in Neurodegenerative Diseases
Rotermund, C., Machetanz, G., & Fitzgerald, J. C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00400 · Cited by 310 · see citing works
Drug repositioning for Alzheimer's disease
Corbett, A., Pickett, J., Burns, A. S., Corcoran, J. P. T., Dunnett, S. B., Edison, P., Hagan, J. J., Holmes, C., Jones, E., Katona, C., et al. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3869 · Cited by 302 · see citing works
Luchsinger, J. A., Perez, T., Chang, H., Mehta, P., Steffener, J., Pradabhan, G., Ichise, M., Manly, J., Devanand, D. P., & Bagiella, E. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-150493 · Cited by 285 · see citing works
“These reports conflict with animal studies showing that metformin decreases AD neuropathology [87, 88] and an epidemiologic study that showed that metformin is related to lower AD risk among persons with T2D [89].”
Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer's disease
Akhtar, A., & Sah, S. P. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104707 · Cited by 286 · see citing works
The role of type 2 diabetes in neurodegeneration
Verdile, G., Fuller, S. J., & Martins, R. N. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.04.008 · Cited by 276 · see citing works
Metformin: Is it a drug for all reasons and diseases?
Triggle, C. R., Mohammed, I., Bshesh, K., Marei, I., Ye, K., Ding, H., MacDonald, R. S., Hollenberg, M. D., & Hill, M. A. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155223 · Cited by 282 · see citing works
Gomes, M. B., & Negrato, C. A. (2014) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-6-80 · Cited by 273 · see citing works
Diabetes Mellitus and the Risk of Alzheimer’s Disease: A Nationwide Population-Based Study
Huang, C., Chung, C., Leu, H., Lin, L., Chiu, C.-C., Hsu, C., Chiang, C.-H., Huang, P., Chen, T., Lin, S., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087095 · Cited by 266 · see citing works
Metformin attenuates Alzheimer’s disease-like neuropathology in obese, leptin-resistant mice
Li, J., Deng, J., Sheng, W., & Zuo, Z. (2012) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2012.03.002 · Cited by 260 · see citing works
Metformin – a Future Therapy for Neurodegenerative Diseases
Markowicz-Piasecka, M., Sikora, J., Szydłowska, A., Skupień, A., Mikiciuk-Olasik, E., & Huttunen, K. (2017) · Pharmaceutical Research · doi:10.1007/s11095-017-2199-y · Cited by 248 · see citing works
Tumminia, A., Vinciguerra, F., Parisi, M., & Frittitta, L. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113306 · Cited by 252 · see citing works
Reich, N., & Hölscher, C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.970925 · Cited by 248 · see citing works
A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies
Orr, M. E., Sullivan, A. C., & Frost, B. E. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.03.011 · Cited by 232 · see citing works
Repurposing Diabetes Drugs for Brain Insulin Resistance in Alzheimer Disease
Yarchoan, M. M., & Arnold, S. E. (2014) · Diabetes · doi:10.2337/db14-0287 · Cited by 228 · see citing works
Samaras, K., Makkar, S. R., Crawford, J. D., Kochan, N. A., Wen, W. X., Draper, B., Trollor, J. N., Brodaty, H., & Sachdev, P. S. (2020) · Diabetes Care · doi:10.2337/dc20-0892 · Cited by 228 · see citing works
Copper signalling: causes and consequences
Kardos, J., Héja, L., Simon, Á., Jablonkai, I., Kovács, R., & Jemnitz, K. (2018) · Cell Communication and Signaling · doi:10.1186/s12964-018-0277-3 · Cited by 214 · see citing works
Type 2 diabetes as a redox disease
Watson, J. D. (2014) · The Lancet · doi:10.1016/s0140-6736(13)62365-x · Cited by 203 · see citing works
Roles of AMP-activated Protein Kinase in Alzheimer’s Disease
Cai, Z., Yan, L., Li, K., Quazi, S. H., & Zhao, B. (2012) · NeuroMolecular Medicine · doi:10.1007/s12017-012-8173-2 · Cited by 191 · see citing works
Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease
Nowell, J., Blunt, E., Gupta, D., & Edison, P. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101979 · Cited by 179 · see citing works
Rad, S. K., Arya, A., Karimian, H., Madhavan, P., Rizwan, F., Koshy, S., & Prabhu, G. (2018) · Drug Design Development and Therapy · doi:10.2147/dddt.s173970 · Cited by 155 · see citing works
Diabetes drugs and neurological disorders: new views and therapeutic possibilities
Patrone, C., Eriksson, O., & Lindholm, D. (2013) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(13)70125-6 · Cited by 154 · see citing works
Shi, Q., Liu, S., Fonseca, V. A., Thethi, T. K., & Shi, L. (2019) · BMJ Open · doi:10.1136/bmjopen-2018-024954 · Cited by 144 · see citing works
Metformin and ageing: improving ageing outcomes beyond glycaemic control
Valencia, W. M., Palacio, A., Tamariz, L., & Florez, H. (2017) · Diabetologia · doi:10.1007/s00125-017-4349-5 · Cited by 142 · see citing works
Diabetes drugs in the fight against Alzheimer's disease
Boccardi, V., Murasecco, I., & Mecocci, P. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100936 · Cited by 142 · see citing works
G lycation in P arkinson's disease and Alzheimer's disease
Miranda, H. V., El‐Agnaf, O. M. A., & Outeiro, T. F. (2016) · Movement Disorders · doi:10.1002/mds.26566 · Cited by 142 · see citing works
Ott, V., Benedict, C., Schultes, B., Born, J., & Hallschmid, M. (2012) · Diabetes, Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01490.x · Cited by 139 · see citing works
Metformin: A Novel Weapon Against Inflammation
Bai, B., & Chen, H. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.622262 · Cited by 139 · see citing works
Differential effects of metformin on age related comorbidities in older men with type 2 diabetes
Wang, C.-P., Lorenzo, C., Habib, S. L., Jo, B., & Espinoza, S. E. (2017) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2017.01.013 · Cited by 134 · see citing works
Chen, F., Dong, R. R., Zhong, K. L., Ghosh, A., Tang, S. S., Long, Y., Hu, M. Y., Miao, M. X., Liao, J. M., Sun, H. B., et al. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.07.023 · Cited by 137 · see citing works
Association of metformin administration with gut microbiome dysbiosis in healthy volunteers
Elbere, I., Kalniņa, I., Silamiķelis, I., Konrāde, I., Zaharenko, L., Sekace, K., Radoviča-Spalviņa, I., Frīdmanis, D., Gudrā, D., Pīrāgs, V., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0204317 · Cited by 134 · see citing works
Stanciu, G. D., Bild, V., Ababei, D. C., Rusu, R.-N., Cobzaru, A., Păduraru, L., & Bulea, D. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9061713 · Cited by 126 · see citing works
Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy
Barini, E., Antico, O., Zhao, Y., Asta, F., Tucci, V., Catelani, T., Marotta, R., Xu, H., & Gasparini, L. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0082-7 · Cited by 126 · see citing works
Chiang, M., Cheng, Y., Chen, S., Yen, C., & Huang, R. (2016) · Experimental Cell Research · doi:10.1016/j.yexcr.2016.08.013 · Cited by 123 · see citing works
Insulin resistance in Alzheimer's disease
Dineley, K. T., Jahrling, J. B., & Denner, L. A. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.09.001 · Cited by 124 · see citing works
Gupta, A. K., & Dey, C. S. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-05-0337 · Cited by 119 · see citing works
Self-citationAMPK: A bridge between diabetes mellitus and Alzheimer's disease
Chen, M., Huang, N., Liu, J., Huang, J., Shi, J., & Jin, F. J. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.113043 · Cited by 118 · see citing works
Inverse cancer comorbidity: a serendipitous opportunity to gain insight into CNS disorders
Tabarés‐Seisdedos, R., & Rubenstein, J. L. R. (2013) · Nature reviews. Neuroscience · doi:10.1038/nrn3464 · Cited by 114 · see citing works
Kashani, L., Omidvar, T., Farazmand, B., Modabbernia, A., Ramzanzadeh, F., Tehraninejad, E. S., Ashrafi, M., Tabrizi, M., & Akhondzadeh, S. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.08.010 · Cited by 116 · see citing works
Weinstein, G., Davis‐Plourde, K. L., Conner, S. C., Himali, J. J., Beiser, A., Lee, A., Rawlings, A. M., Sedaghat, S., Ding, J., Moshier, E. L., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0212293 · Cited by 115 · see citing works
Zhang, L., Zhang, S., Maezawa, I., Trushin, S., Minhas, P. S., Pinto, M., Jin, L., Prasain, K., Nguyen, T. D. T., Yamazaki, Y., et al. (2015) · EBioMedicine · doi:10.1016/j.ebiom.2015.03.009 · Cited by 110 · see citing works
Metformin Treatment Alters Memory Function in a Mouse Model of Alzheimer's Disease
DiTacchio, K. A., Heinemann, S. F., & Dziewczapolski, G. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-141332 · Cited by 110 · see citing works
Saffari, P. M., Alijanpour, S., Takzaree, N., Sahebgharani, M., Etemad‐Moghadam, S., Noorbakhsh, F., & Partoazar, A. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117861 · Cited by 104 · see citing works
Differential metformin dose-dependent effects on cognition in rats: role of Akt
Mostafa, D. K., Ismail, C. A., & Ghareeb, D. A. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4301-2 · Cited by 101 · see citing works
BACE1: More than just a β‐secretase
Taylor, H. A., Przemyłska, L., Clavane, E. M., & Meakin, P. J. (2022) · Obesity Reviews · doi:10.1111/obr.13430 · Cited by 102 · see citing works
Metformin role in Parkinson’s disease: a double-sword effect
Alrouji, M., Al-Kuraishy, H. M., Al-Gareeb, A. I., Ashour, N. A., Jabir, M. S., Negm, W. A., & Batiha, G. E. (2023) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-023-04771-7 · Cited by 104 · see citing works
Asadbegi, M., Yaghmaei, P., Salehi, I., Komaki, A., & Ebrahim‐Habibi, A. (2017) · Metabolic Brain Disease · doi:10.1007/s11011-017-9960-0 · Cited by 100 · see citing works
Lipid metabolism and neuroinflammation in Alzheimer’s disease: a role for liver X receptors
Kang, J., & Rivest, S. (2012) · Endocrine Reviews · doi:10.1210/er.2011-1049 · Cited by 94 · see citing works
Zheng, M., & Wang, P. (2021) · 3 Biotech · doi:10.1007/s13205-021-02738-3 · Cited by 98 · see citing works
Sebastião, I., Candeias, E., Santos, M. S., Oliveira, C. R., Moreira, P. I., & Duarte, A. I. (2014) · Frontiers in Endocrinology · doi:10.3389/fendo.2014.00110 · Cited by 92 · see citing works
Chen, Q., Mo, R., Wu, N., Zou, X., Shi, C., Gong, J., Li, J., Fang, K., Wang, D., De-shen, Y., et al. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00334 · Cited by 91 · see citing works
A Review: Treatment of Alzheimer’s Disease Discovered in Repurposed Agents
Appleby, B. S., Nacopoulos, D. A., Milano, N. J., Zhong, K., & Cummings, J. L. (2013) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000345791 · Cited by 90 · see citing works
Yin, Q., Ma, Y., Yan, H., Hou, X., Chen, J., Shen, C., Sun, M., Shang, Y., Dong, S., Zeng, Z., et al. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.07.020 · Cited by 90 · see citing works
The Anti-Diabetic Drug Metformin Reduces BACE1 Protein Level by Interfering with the MID1 Complex
Hettich, M. M., Matthes, F., Ryan, D. P., Griesche, N., Schröder, S., Dorn, S., Krauß, S., & Ehninger, D. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102420 · Cited by 90 · see citing works
Kang, S., Kim, C. H., Jung, H., Kim, E., Song, H., & Lee, J. E. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.10.029 · Cited by 89 · see citing works
Adak, T., Samadi, A., Ünal, A. Z., & Sabuncuoğlu, S. (2017) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2017.12.023 · Cited by 88 · see citing works
Asadbegi, M., Yaghmaei, P., Salehi, I., Ebrahim‐Habibi, A., & Komaki, A. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.02.005 · Cited by 87 · see citing works
Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice
Zimmermann, H. R., Yang, W., Kasica, N. P., Zhou, X., Wang, X., Beckelman, B. C., Lee, J., Furdui, C. M., Keene, C. D., & Ma, T. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133982 · Cited by 86 · see citing works
Deciphering the Roles of Metformin in Alzheimer’s Disease: A Snapshot
Liao, W., Xu, J., Li, B., Ruan, Y., Li, T., & Liu, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.728315 · Cited by 84 · see citing works
Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease
Kim, T. (2014) · Neurotherapeutics · doi:10.1007/s13311-014-0325-7 · Cited by 82 · see citing works
Sweet but Bitter: Focus on Fructose Impact on Brain Function in Rodent Models
Spagnuolo, M. S., Iossa, S., & Cigliano, L. (2020) · Nutrients · doi:10.3390/nu13010001 · Cited by 83 · see citing works
Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide
Candeias, E. (2015) · World Journal of Diabetes · doi:10.4239/wjd.v6.i6.807 · Cited by 83 · see citing works
Overlapped Metabolic and Therapeutic Links between Alzheimer and Diabetes
Ahmad, W. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8352-z · Cited by 80 · see citing works
Discovering New Treatments for Alzheimer's Disease by Repurposing Approved Medications
Appleby, B. S., & Cummings, J. L. (2013) · Current Topics in Medicinal Chemistry · doi:10.2174/15680266113136660162 · Cited by 78 · see citing works
Śmieszek, A., Stręk, Z., Kornicka, K., Grzesiak, J., Weiss, C., & Marycz, K. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040872 · Cited by 77 · see citing works
Long-term use of metformin and Alzheimer’s disease: beneficial or detrimental effects
Al-Kuraishy, H. M., Al-Gareeb, A. I., Saad, . M., & Batiha, G. E. (2023) · Inflammopharmacology · doi:10.1007/s10787-023-01163-7 · Cited by 78 · see citing works
Alterations in Glucose Metabolism on Cognition: A Possible Link Between Diabetes and Dementia
González-Reyes, R. E., Aliev, G. M., Ávila-Rodriguez, M., & Barreto, G. E. (2016) · Current Pharmaceutical Design · doi:10.2174/1381612822666151209152013 · Cited by 77 · see citing works
True or false? Alzheimer’s disease is type 3 diabetes: Evidences from bench to bedside
Peng, Y., Yao, S.-Y., Chen, Q., Jin, H., Du, M., Xue, Y.-H., & Liu, S. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102383 · Cited by 76 · see citing works
Tanokashira, D., Kurata, E., Fukuokaya, W., Kawabe, K., Mana, K., Takeuchi, H., Nakazato, M., & Taguchi, A. (2018) · FEBS Open Bio · doi:10.1002/2211-5463.12436 · Cited by 76 · see citing works
The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence
Assefa, B. T., Tafere, G. G., Wondafrash, D. Z., & Gidey, M. T. (2020) · BioMed Research International · doi:10.1155/2020/9895121 · Cited by 75 · see citing works
Metformin, lifestyle intervention, and cognition in the Diabetes Prevention Program Outcomes Study
Luchsinger, J. A., Ma, Y., Christophi, C. A., Florez, H., Golden, S. H., Hazuda, H., Crandall, J., Venditti, E., Watson, K., Jeffries, S., et al. (2017) · Diabetes Care · doi:10.2337/dc16-2376 · Cited by 75 · see citing works
Maniar, K., Moideen, A., Mittal, A., Patil, A., Chakrabarti, A., & Banerjee, D. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.12.003 · Cited by 75 · see citing works
Son, S., Song, H., Byun, J., Park, K., Jang, H., Park, Y., & Mook-Jung, I. (2012) · Diabetes · doi:10.2337/db11-1735 · Cited by 74 · see citing works
Lourenco, M. V., Ferreira, S. T., & Felice, F. G. D. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.03.003 · Cited by 71 · see citing works
Anderson, R. A., Qin, B., Canini, F., Poulet, L., & Roussel, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083243 · Cited by 71 · see citing works
Therapeutic Potential of AMP-Activated Protein Kinase in Alzheimer’s Disease
Wang, X., Zimmermann, H. R., & Ma, T. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-181043 · Cited by 69 · see citing works
Ha, J.-H., Choi, D., Kim, K. J., Cho, S. Y., Kim, H., Kim, K. Y., Koh, Y., Nam, C. M., & Kim, E. (2021) · Scientific Reports · doi:10.1038/s41598-021-03406-5 · Cited by 64 · see citing works
Metformin raises hydrogen sulfide tissue concentrations in various mouse organs
Wiliński, B., Wiliński, J., Somogyi, E., Piotrowska, J., & Opoka, W. (2013) · Pharmacological Reports · doi:10.1016/s1734-1140(13)71053-3 · Cited by 67 · see citing works
Metformin, Cognitive Function, and Changes in the Gut Microbiome
Rosell-Díaz, M., & Fernández‐Real, J. M. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad029 · Cited by 68 · see citing works
Jantrapirom, S., Nimlamool, W., Chattipakorn, N., Chattipakorn, S. C., Temviriyanukul, P., Inthachat, W., Govitrapong, P., & Potikanond, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051725 · Cited by 63 · see citing works
AKT ISOFORMS-AS160-GLUT4: The defining axis of insulin resistance
Sharma, M., & Dey, C. S. (2021) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-021-09652-2 · Cited by 66 · see citing works
Self-citationEvidence for altered insulin receptor signaling in Alzheimer's disease
Griffith, C. M., Eid, T., Rose, G. M., & Patrylo, P. R. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.01.008 · Cited by 61 · see citing works
Li, J., Cesari, M., Liu, F., Dong, B., & Vellas, B. J. (2016) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2016.07.003 · Cited by 60 · see citing works
Potential effects of current drug therapies on cognitive impairment in patients with type 2 diabetes
Palleria, C., Leporini, C., Maida, F., Succurro, E., Sarro, G. D., Arturi, F., & Russo, E. (2016) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2016.07.002 · Cited by 60 · see citing works
Repurposing metformin to treat age-related neurodegenerative disorders and ischemic stroke
Sharma, S., Nozohouri, S., Vaidya, B., & Abbruscato, T. J. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119343 · Cited by 60 · see citing works
(2020) · International Review of Neurobiology · doi:10.1016/bs.irn.2020.02.010 · Cited by 58 · see citing works
Alzheimer's Disease and Diabetes: New Insights and Unifying Therapies
Vignini, A., Giulietti, A., Nanetti, L., Raffaelli, F., Giusti, L., Mazzanti, L., & Provinciali, L. (2013) · Current Diabetes Reviews · doi:10.2174/1573399811309030003 · Cited by 57 · see citing works
Ahmad, W., & Ebert, P. R. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0085-y · Cited by 57 · see citing works
Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer’s Disease
Kim, J. Y., Barua, S., Jeong, Y. J., & Lee, J. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176419 · Cited by 58 · see citing works
Domínguez, R. O., Marschoff, E. R., González, S., Repetto, M. G., & Serra, J. A. (2012) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2012.05.013 · Cited by 57 · see citing works
Effect of metformin on nonalcoholic fatty liver based on meta-analysis and network pharmacology
Huang, Y., Wang, X., Chen, Y., Li, C., Zhang, L., Zhang, L., Liang, E., Liu, T., & Mao, J. (2022) · Medicine · doi:10.1097/md.0000000000031437 · Cited by 56 · see citing works
Antidiabetic Drugs in Alzheimer’s Disease: Mechanisms of Action and Future Perspectives
Femminella, G. D., Bencivenga, L., Petraglia, L., Visaggi, L., Gioia, L., Grieco, F. V., de Lucia, C., Komici, K., Corbi, G., Edison, P., et al. (2017) · Journal of Diabetes Research · doi:10.1155/2017/7420796 · Cited by 56 · see citing works
Mamo, J. C. L., Lam, V., Brook, E., Mooranian, A., Al‐Salami, H., Fimognari, N., Nesbit, M., & Takechi, R. (2018) · Diabetes and Vascular Disease Research · doi:10.1177/1479164118795274 · Cited by 56 · see citing works
Liu, P., Zou, L., Jiao, Q., Chi, T., Ji, X., Qi, Y. A., Xu, Q., & Wang, L. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.02.065 · Cited by 55 · see citing works
- Authors
- Gupta, A., Bisht, B., & Dey, C. S.
- Affiliations
- National Institute of Pharmaceutical Education and Research (IN)
- Corresponding author
- Dey, Chinmoy Sankar
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 60
- Issue
- 6
- Pages
- 910-920
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2001599368
- Cited by
- 302
- References
- 61
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 29 · 2023: 15 · 2022: 26 · 2021: 25 · 2020: 25 · 2019: 19 · 2018: 27 · 2017: 20 · 2016: 22 · 2015: 16 · 2014: 23 · 2013: 16 · 2012: 15
- FWCI
- 12.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Science and Technology, Ministry of Science and Technology, India
- Council of Scientific and Industrial Research, India
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- metformin, Alzheimer's disease, type 3 diabetes, hyperinsulinemia, insulin signaling, N2a cells, insulin-sensitizing drugs, brain glucose metabolism
- MeSH terms
- Alzheimer Disease, Animals, Cell Line, Cholinesterases, Diabetes Mellitus, Experimental, Glucose, Hyperinsulinism, Hypoglycemic Agents, Insulin Resistance, Metformin, Neurons, Peptide Fragments, Amyloid beta-Peptides, Phosphatidylinositol 3-Kinases, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review