The role of insulin receptor signaling in the brain

Plum, Leona; Schubert, Markus; Brüning, Jens C.

doi:10.1016/j.tem.2005.01.008

Cited by 604Regulation of Appetite and ObesityMetabolism, Diabetes, and CancerAdipokines, Inflammation, and Metabolic Diseases

The role of insulin receptor signaling in the brain

Plum, Leona, Schubert, Markus, Brüning, Jens C.·2005·Trends in Endocrinology & Metabolism

DOI 10.1016/j.tem.2005.01.008

Open this paper in CoChat — free account

Abstract

The insulin receptor (IR) is expressed in various regions of the developing and adult brain, and its functions have become the focus of recent research. Insulin enters the central nervous system (CNS) through the blood-brain barrier by receptor-mediated transport to regulate food intake, sympathetic activity and peripheral insulin action through the inhibition of hepatic gluconeogenesis and reproductive endocrinology. On a molecular level, some of the effects of insulin converge with those of the leptin signaling machinery at the point of activation of phosphatidylinositol 3-kinase (PI3K), resulting in the regulation of ATP-dependent potassium channels. Furthermore, insulin inhibits neuronal apoptosis via activation of protein kinase B in vitro, and it regulates phosphorylation of tau, metabolism of the amyloid precursor protein and clearance of beta-amyloid from the brain in vivo. These findings indicate that neuronal IR signaling has a direct role in the link between energy homeostasis, reproduction and the development of neurodegenerative diseases.

Integrity signals

Registry

Crossref · 10.1016/j.tem.2005.01.008

Cites

86 of 86 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

Deficient insulin signaling results in impaired removal of Aβ and Aβ oligomers from the extracellular milieu.
“At the cellular level, deficient insulin signaling results in impaired removal of Aβ (Plum et al., 2005) and Aβ oligomers from the extracellular milieu (Zhao et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Plum et al., 2005
The permeability transition pore acts as a regulator of the apoptotic cascade under stress conditions, triggering release of apoptotic proteins and subsequent cell death.
“In this setting, the permeability transition pore (PTP) acts as a regulator of the apoptotic cascade under stress conditions, triggering the release of apoptotic proteins and subsequent cell death [127].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [127]

Neurodegenerative Tauopathies
Lee, V. M.-Y., Goedert, M., & Trojanowski, J. Q. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1121 · Cited by 2,480 · see citing works
Regulation of neuronal survival by the serine-threonine protein kinase Akt
Dudek, H., Datta, S. R., Franke, T. F., Birnbaum, M. J., Yao, R., Cooper, G. M., Segal, R. A., Kaplan, D. R., & Greenberg, M. E. (1997) · Science · doi:10.1126/science.275.5300.661 · Cited by 2,436 · see citing works
Role of Brain Insulin Receptor in Control of Body Weight and Reproduction
Brüning, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., Klein, R., Krone, W., Müller-Wieland, D., & Kahn, C. R. (2000) · Science · doi:10.1126/science.289.5487.2122 · Cited by 2,235 · see citing works
Self-citation
Brain Dopamine and Reward
Wise, R. A., & Rompre, P.-P. (1989) · Annual Review of Psychology · doi:10.1146/annurev.ps.40.020189.001203 · Cited by 1,968 · see citing works
Identification of targets of leptin action in rat hypothalamus.
Schwartz, M. W., Seeley, R. J., Campfield, L. A., Burn, P., & Baskin, D. G. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118891 · Cited by 1,475 · see citing works
Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo
Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E., Frosch, M., Eckman, C., Tanzi, R., Selkoe, D., & Guénette, S. (2003) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0230450100 · Cited by 1,361 · see citing works
Sniffing neuropeptides: A transnasal approach to the human brain
Born, J., Lange, T., Kern, W., McGregor, G. P., Bickel, U., & Fehm, H. L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-849 · Cited by 1,356 · see citing works
Trophic Action of Leptin on Hypothalamic Neurons That Regulate Feeding
Bouret, S. G., Draper, S. J., & Simerly, R. B. (2004) · Science · doi:10.1126/science.1095004 · Cited by 1,219 · see citing works
Insulin receptors are widely distributed in the central nervous system of the rat
Havránková, J., Roth, J., & Brownstein, M. (1978) · Nature · doi:10.1038/272827a0 · Cited by 1,116 · see citing works
Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons
Woods, S. C., Lotter, E. C., McKay, L. D., & Porte, D. (1979) · Nature · doi:10.1038/282503a0 · Cited by 1,114 · see citing works
Rapid Rewiring of Arcuate Nucleus Feeding Circuits by Leptin
Pinto, S., Roseberry, A. G., Liu, H., Diano, S., Shanabrough, M., Cai, X., Friedman, J. M., & Horvath, T. L. (2004) · Science · doi:10.1126/science.1089459 · Cited by 987 · see citing works
Hypothalamic insulin signaling is required for inhibition of glucose production
Obici, S., Zhang, B. B., Karkanias, G., & Rossetti, L. (2002) · Nature Medicine · doi:10.1038/nm1202-798 · Cited by 904 · see citing works
Decreased nuclear β‐catenin, tau hyperphosphorylation and neurodegeneration in GSK‐3β conditional transgenic mice
Lucas, J. J., Hernández, F., Gómez‐Ramos, P., Morán, M. A., Hen, R., & Avila, J. (2001) · The EMBO Journal · doi:10.1093/emboj/20.1.27 · Cited by 903 · see citing works
Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects.
Polonsky, K. S., Given, B. D., & Van Cauter, E. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113339 · Cited by 763 · 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
Insulin signaling in health and disease
White, M. F. (2003) · Science · doi:10.1126/science.1092952 · Cited by 733 · see citing works
Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G., Baskin, D. G., & Rossetti, L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-861 · Cited by 719 · see citing works
The Significance of Basal Insulin Levels in the Evaluation of the Insulin Response to Glucose in Diabetic and Nondiabetic Subjects*
Bagdade, J. D., Bierman, E. L., & Porte, D. (1967) · Journal of Clinical Investigation · doi:10.1172/jci105646 · Cited by 672 · see citing works
Diet‐induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease
Ho, L., Qin, W., Pompl, P., Xiang, Z.-M., Wang, J., Zhao, Z., Peng, Y., Cambareri, G., Rocher, A., Mobbs, C., et al. (2004) · The FASEB Journal · doi:10.1096/fj.03-0978fje · Cited by 646 · see citing works
Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels
Spanswick, D., Smith, M. A., Groppi, V. E., Logan, S. D., & Ashford, M. L. J. (1997) · Nature · doi:10.1038/37379 · Cited by 628 · see citing works
Glucose and Osmosensitive Neurones of the Rat Hypothalamus
Oomura, Y., Ono, T., Ooyama, H., & Wayner, M. J. (1969) · Nature · doi:10.1038/222282a0 · Cited by 597 · see citing works
Key enzyme in leptin-induced anorexia
Niswender, K. D., Morton, G. J., Stearns, W. H., Rhodes, C. J., Myers, M. G., & Schwartz, M. W. (2001) · Nature · doi:10.1038/35101657 · Cited by 585 · see citing works
Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G. B., et al. (2002) · Nature Neuroscience · doi:10.1038/nn861 · Cited by 572 · see citing works
Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: Relationship to severity of dementia and apolipoprotein E genotype
Craft, S., Peskind, E., Schwartz, M. W., Schellenberg, G. D., Raskind, M., & Porte, D. (1998) · Neurology · doi:10.1212/wnl.50.1.164 · Cited by 560 · see citing works
Inhibition of hypothalamic neuropeptide Y gene expression by insulin.
Schwartz, M. W., Sipols, A. J., Marks, J. L., Sanacora, G., White, J. D., Scheurink, A., Kahn, S. E., Baskin, D. G., Woods, S. C., & Figlewicz, D. P. (1992) · Endocrinology · doi:10.1210/endo.130.6.1597158 · Cited by 555 · see citing works
Clearing the brain's amyloid cobwebs
Selkoe, D. J. (2001) · Neuron · doi:10.1016/s0896-6273(01)00475-5 · Cited by 541 · see citing works
Insulin and Insulin-like Growth Factor-1 Regulate Tau Phosphorylation in Cultured Human Neurons*
Hong, M., & Lee, V. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.31.19547 · Cited by 533 · see citing works
Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats
Spanswick, D., Smith, M. A., Mirshamsi, S., Routh, V. H., & Ashford, M. L. J. (2000) · Nature Neuroscience · doi:10.1038/77660 · Cited by 495 · see citing works
The source of cerebral insulin
Banks, W. A. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.02.040 · Cited by 489 · see citing works
Insulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation
Schubert, M., Brazil, D. P., Burks, D. J., Kushner, J. A., Ye, J., Flint, C. L., Farhang-Fallah, J., Dikkes, P., Warot, X. M., Rio, C., et al. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-18-07084.2003 · Cited by 488 · see citing works
Self-citation
Insulin Activation of Phosphatidylinositol 3-Kinase in the Hypothalamic Arcuate Nucleus
Niswender, K. D., Morrison, C. D., Clegg, D. J., Olson, R., Baskin, D. G., Myers, M. G., Seeley, R. J., & Schwartz, M. W. (2003) · Diabetes · doi:10.2337/diabetes.52.2.227 · Cited by 476 · see citing works
Receptor-Mediated Transport of Insulin Across Endothelial Cells
King, G. L., & Johnson, S. M. (1985) · Science · doi:10.1126/science.3883490 · Cited by 474 · see citing works
IRS-2 pathways integrate female reproduction and energy homeostasis
Burks, D. J., de Mora, J. F., Schubert, M., Withers, D. J., Myers, M. G., Towery, H. H., Altamuro, S. L., Flint, C. L., & White, M. F. (2000) · Nature · doi:10.1038/35030105 · Cited by 455 · see citing works
Self-citation
Serum insulin-like growth factor I regulates brain amyloid-β levels
Carro, E., Trejo, J. L., Gómez‐Isla, T., LeRoith, D., & Torres‐Alemán, I. (2002) · Nature Medicine · doi:10.1038/nm793 · Cited by 448 · see citing works
Quantitative study of insulin secretion and clearance in normal and obese subjects
Polonsky, K. S., Given, B. D., Hirsch, L., Shapiro, E. T., Tillil, H., Beebe, C., Galloway, J. A., Frank, B. H., Karrison, T., & Van Cauter, E. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113338 · Cited by 444 · see citing works
Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities
Niswender, K. D., & Schwartz, M. W. (2003) · Frontiers in Neuroendocrinology · doi:10.1016/s0091-3022(02)00105-x · Cited by 421 · see citing works
The Catabolic Action of Insulin in the Brain Is Mediated by Melanocortins
Benoit, S. C., Air, E. L., Coolen, L. M., Strauss, R., Jackman, A., Clegg, D. J., Seeley, R. J., & Woods, S. C. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-20-09048.2002 · Cited by 417 · see citing works
Effect of Intracerebroventricular Insulin Infusion on Diabetic Hyperphagia and Hypothalamic Neuropeptide Gene Expression
Sipols, A. J., Baskin, D. G., & Schwartz, M. W. (1995) · Diabetes · doi:10.2337/diab.44.2.147 · Cited by 389 · see citing works
Central melanocortin receptors regulate insulin action
Obici, S., Feng, Z., Tan, J., Liu, L., Karkanias, G. B., & Rossetti, L. (2001) · Journal of Clinical Investigation · doi:10.1172/jci12954 · Cited by 370 · see citing works
Central melanocortin receptors regulate insulin action
Obici, S., Feng, Z., Tan, J., Liu, L., Karkanias, G., & Rossetti, L. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200112954 · Cited by 370 · see citing works
NIDDM and Blood Pressure as Risk Factors for Poor Cognitive Performance: The Framingham Study
Elias, P. K., Elias, M. F., D'Agostino, R. B., Cupples, L. A., Wilson, P. W., Silbershatz, H., & Wolf, P. A. (1997) · Diabetes Care · doi:10.2337/diacare.20.9.1388 · Cited by 368 · see citing works
Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats.
Borg, M. A., Sherwin, R. S., Borg, W. P., Tamborlane, W. V., & Shulman, G. I. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119165 · Cited by 359 · see citing works
Role for neuronal insulin resistance in neurodegenerative diseases
Schubert, M., Gautam, D., Surjo, D., Ueki, K., Baudler, S., Schubert, D., Kondo, T., Alber, J., Galldiks, N., Kustermann, E., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308724101 · Cited by 339 · see citing works
Self-citation
Relationship Between Hyperglycemia and Cognitive Function in Older NIDDM Patients
Reaven, G. M., Thompson, L. W., Nahum, D., & Haskins, E. (1990) · Diabetes Care · doi:10.2337/diacare.13.1.16 · Cited by 334 · see citing works
Insulin-Binding Sites in the Rat Brain: In Vivo Localization to the Circumventricular Organs by Quantitative Radioautography*
van Houten, M., Posner, B. I., Kopriwa, B. M., & Brawer, J. R. (1979) · Endocrinology · doi:10.1210/endo-105-3-666 · Cited by 321 · see citing works
Insulin and the Blood-Brain Barrier
Woods, S. C., Seeley, R. J., Baskin, D. G., & Schwartz, M. W. (2003) · Current Pharmaceutical Design · doi:10.2174/1381612033455323 · Cited by 321 · see citing works
Enhancement of Memory in Alzheimer Disease With Insulin and Somatostatin, but Not Glucose
Craft, S., Asthana, S., Newcomer, J. W., Wilkinson, C. W., Matos, I. T., Baker, L. D., Cherrier, M., Lofgreen, C., Latendresse, S., Petrova, A., et al. (1999) · Archives of General Psychiatry · doi:10.1001/archpsyc.56.12.1135 · Cited by 312 · see citing works
Improving influence of insulin on cognitive functions in humans
Kern, W., Peters, A., Fruehwald-Schultes, B., Deininger, E., Born, J., & Fehm, H. L. (2001) · Neuroendocrinology · doi:10.1159/000054694 · Cited by 308 · see citing works
Modulation of memory by insulin and glucose: Neuropsychological observations in Alzheimer’s disease
Watson, G. S., & Craft, S. (2004) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.02.048 · Cited by 307 · see citing works
Short Term Effects of Leptin on Hepatic Gluconeogenesis and in Vivo Insulin Action
Rossetti, L., Massillon, D., Barzilai, N., Vuguin, P., Chen, W., Hawkins, M., Wu, J., & Wang, J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.44.27758 · Cited by 304 · see citing works
Lack of Neurodegeneration in Transgenic Mice Overexpressing Mutant Amyloid Precursor Protein Is Associated with Increased Levels of Transthyretin and the Activation of Cell Survival Pathways
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 in the Cerebrospinal Fluid
MARGOLIS, R. U., & ALTSZULER, N. (1967) · Nature · doi:10.1038/2151375a0 · Cited by 278 · see citing works
Brain glucose sensing and body energy homeostasis: role in obesity and diabetes
Levin, B. E., Dunn-Meynell, A. A., & Routh, V. H. (1999) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1999.276.5.r1223 · Cited by 270 · see citing works
Insulin and Leptin as Adiposity Signals
Benoit, S. C. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.267 · Cited by 266 · see citing works
Ventromedial hypothalamic lesions in rats suppress counterregulatory responses to hypoglycemia.
Borg, W. P., During, M. J., Sherwin, R. S., Borg, M. A., Brines, M. L., & Shulman, G. I. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117150 · Cited by 265 · see citing works
INSULIN ACTION IN THE NORMAL AND POLYCYSTIC OVARY
Franks, S., Gilling‐Smith, C., Watson, H., & Willis, D. (1999) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70074-8 · Cited by 262 · see citing works
Brain Insulin: Regulation, Mechanisms of Action and Functions
Gerozissis, K. (2003) · Cellular and Molecular Neurobiology · doi:10.1023/a:1022598900246 · Cited by 235 · see citing works
Hypothalamic control of energy balance: different peptides, different functions
LEIBOWITZ, S. F., & Wortley, K. E. (2004) · Peptides · doi:10.1016/j.peptides.2004.02.006 · Cited by 235 · see citing works
Adiposity signals and food reward: expanding the CNS roles of insulin and leptin
Figlewicz, D. P. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00602.2002 · Cited by 221 · see citing works
Minireview: Nutrient Sensing and the Regulation of Insulin Action and Energy Balance
Obici, S., & Rossetti, L. (2003) · Endocrinology · doi:10.1210/en.2003-0999 · Cited by 218 · see citing works
Relationship between plasma and cerebrospinal fluid insulin levels of dogs.
Woods, S. C., & Porte, D. (1977) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1977.233.4.e331 · Cited by 218 · see citing works
Central nervous system effects of intranasally administered insulin during euglycemia in men.
Kern, W., Jan Born, A., Schreiber, H., & Fehm, H. (1999) · Diabetes · doi:10.2337/diabetes.48.3.557 · Cited by 192 · see citing works
Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats
Carvalheira, J. B. C., Ribeiro, E. B., Ara�jo, E. P., Guimar�es, R. B., Telles, M. M., Torsoni, M., Gontijo, J. A. R., Velloso, L. A., & Saad, M. J. A. (2003) · Diabetologia · doi:10.1007/s00125-003-1246-x · Cited by 176 · see citing works
Gonadotropin-Releasing Hormone Secretion from Hypothalamic Neurons: Stimulation by Insulin and Potentiation by Leptin
Burcelin, R., Thorens, B., Glauser, M., Gaillard, R. C., & Pralong, F. P. (2003) · Endocrinology · doi:10.1210/en.2003-0457 · Cited by 173 · see citing works
Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity
Air, E. L., Strowski, M. Z., Benoit, S. C., Conarello, S., Salituro, G., Guan, X.-M., Liu, K., Woods, S. C., & Zhang, B. B. (2002) · Nature Medicine · doi:10.1038/nm0202-179 · Cited by 169 · see citing works
Increased feeding in response to bilateral injection of insulin antibodies in the VMH
STRUBBE, J. H., & Mein, C. G. (1977) · Physiology & Behavior · doi:10.1016/0031-9384(77)90343-2 · Cited by 161 · see citing works
A Disturbance in the Neuronal Insulin Receptor Signal Transduction in Sporadic Alzheimer's Disease
Frölich, L., Blum-Degen, D., Riederer, P. F., & Hoyer, S. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb07839.x · Cited by 160 · see citing works
Insulin Activates ATP-Sensitive K+ Channels in Pancreatic β-Cells Through a Phosphatidylinositol 3-Kinase–Dependent Pathway
Khan, F. A., Goforth, P. B., Zhang, M., & Satin, L. S. (2001) · Diabetes · doi:10.2337/diabetes.50.10.2192 · Cited by 148 · see citing works
Phenotype and genotype in polycystic ovary syndrome
Legro, R. S. (2001) · Cambridge University Press eBooks · doi:10.1017/cbo9780511545191.003 · Cited by 147 · see citing works
Hypothalamic insulin signaling is required for inhibition of glucose production
Obici, S., Zhang, B. B., Karkanias, G. B., et al. (2002) · Nature Medicine · doi:10.1038/nm798 · Cited by 138 · see citing works
Essential Role of Phosphoinositide 3-Kinase in Leptin-inducedK ATP Channel Activation in the Rat CRI-G1 Insulinoma Cell Line
Harvey, J., McKay, N. G., Walker, K. S., KAAY, J. V. D., Downes, C. P., & Ashford, M. L. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.7.4660 · Cited by 136 · see citing works
Differential effects of melanocortin peptides on neural melanocortin receptors.
Adan, R. A. H., Cone, R. D., Burbach, J. P. H., & Gispen, W. H. (1994) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)09867-0 · Cited by 130 · see citing works
Immunocytochemical localization of cannabinoid CB1 receptor and fatty acid amide hydrolase in rat retina
Yazulla, S., Studholme, K. M., McIntosh, H. H., & Deutsch, D. G. (1999) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19991206)415:1 · Cited by 128 · see citing works
Immunocytochemical Detection of Insulin in Rat Hypothalamus and Its Possible Uptake from Cerebrospinal Fluid*
Baskin, D. G., Woods, S. C., West, D. B., van Houten, M., Posner, B. I., Dorsa, D. M., & Porte, D. (1983) · Endocrinology · doi:10.1210/endo-113-5-1818 · Cited by 122 · see citing works
Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression
Sipols, A. J., Baskin, D. G., & Schwartz, M. W. (1995) · Diabetes · doi:10.2337/diabetes.44.2.147 · Cited by 117 · see citing works
Effects of chronic intrahypothalamic infusion of insulin on food intake and diurnal meal patterning in the rat.
McGowan, M. K., Andrews, K. M., Kelly, J., & Grossman, S. P. (1990) · Behavioral Neuroscience · doi:10.1037/0735-7044.104.2.373 · Cited by 109 · see citing works
PHYSIOLOGY OF GLUCOSE COUNTERREGULATION TO HYPOGLYCEMIA
Bolli, G. B., & Fanelli, C. G. (1999) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70083-9 · Cited by 99 · see citing works
Mechanism of neurofibrillary degeneration in Alzheimer's disease
Iqbal, K., Alonso, A. D. C., Gong, C., Khatoon, S., Singh, T. J., & Grundke, I. (1994) · Molecular Neurobiology · doi:10.1007/bf02816111 · Cited by 72 · see citing works
Anabolic neuropeptides
Williams, G. H., Cai, X., Elliott, J. C., & Harrold, J. A. (2004) · Physiology & Behavior · doi:10.1016/j.physbeh.2004.02.005 · Cited by 69 · see citing works
Effects of age on working memory: an event-related potential study
Pelosi, L., & Blumhardt, L. D. (1999) · Cognitive Brain Research · doi:10.1016/s0926-6410(98)00035-4 · Cited by 49 · see citing works
Effect of Centrally Administered Insulin on Gonadotropin-Releasing Hormone Neuron Activity and Luteinizing Hormone Surge in the Diabetic Female Rat
Kovacs, P. L., Parlow, A. F., & Karkanias, G. B. (2002) · Neuroendocrinology · doi:10.1159/000067585 · Cited by 48 · see citing works
Chronic intrahypothalamic insulin infusion in the rat: Behavioral specificity
McGowan, M. K., Andrews, K. M., Fenner, D., & Grossman, S. P. (1993) · Physiology & Behavior · doi:10.1016/0031-9384(93)90320-f · Cited by 43 · see citing works
Insulin and raclopride combine to decrease short-term intake of sucrose solutions
Sipols, A. J., Stuber, G. D., Klein, S. N., Higgins, M. S., & Figlewicz, D. P. (2000) · Peptides · doi:10.1016/s0196-9781(00)00279-5 · Cited by 38 · see citing works
Neurotransmitter Transporters: Target for Endocrine Regulation
Figlewicz, D. P., Patterson, T. A., Zavosh, A., Brot, M. D., Roitman, M. F., & Szot, P. (1999) · Hormone and Metabolic Research · doi:10.1055/s-2007-978749 · Cited by 30 · see citing works
Single-trial latency variability of auditory evoked potentials may indicate immediate memory in the albino rat
Shucard, D. W. (2003) · International Journal of Psychophysiology · doi:10.1016/s0167-8760(02)00155-1 · Cited by 5 · see citing works
Untitled work
(2000) · doi:10.1002/1520-7560(2000)9999:9999

Flagged first, then by citations

Sorted by citations

Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028 · see citing works
Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling
Moloney, A. M., Griffin, R. J., Timmons, S., O’Connor, R., Ravid, R., & O’Neill, C. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.04.002 · Cited by 764 · 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
MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity
Kleinridders, A., Schenten, D., Könner, A. C., Belgardt, B. F., Mauer, J., Okamura, T., Wunderlich, F. T., Medzhitov, R., & Brüning, J. C. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.08.013 · Cited by 483 · see citing works
Self-citation
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
The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease
Ferreira, S. T., & Klein, W. L. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.08.003 · Cited by 442 · see citing works
Elevated risk of type 2 diabetes for development of Alzheimer disease: A key role for oxidative stress in brain
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
Insulin resistance in the nervous system
Kim, B., & Feldman, E. L. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2011.12.004 · Cited by 321 · see citing works
Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes
Gupta, A., Bisht, B., & Dey, C. S. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.01.033 · Cited by 302 · see citing works
Alzheimer's disease and type 2 diabetes: a critical assessment of the shared pathological traits
Chatterjee, S., & Mudher, A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00383 · Cited by 270 · see citing works
Awake Intranasal Insulin Delivery Modifies Protein Complexes and Alters Memory, Anxiety, and Olfactory Behaviors
Marks, D. R., Tucker, K., Cavallin, M. A., Mast, T. G., & Fadool, D. A. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.1350-09.2009 · Cited by 242 · see citing works
PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice
Banno, R., Zimmer, D., De Jonghe, B. C., Atienza, M., Rak, K., Yang, W., & Bence, K. K. (2010) · Journal of Clinical Investigation · doi:10.1172/jci39620 · Cited by 214 · see citing works
Insulin in the nervous system and the mind: Functions in metabolism, memory, and mood
Lee, S.-H., Zabolotny, J. M., Huang, H., Lee, H., & Kim, Y.-B. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.06.011 · Cited by 176 · see citing works
Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes
Zhang, H., Hao, Y., Manor, B., Novak, P., Milberg, W., Zhang, J., Fang, J., & Novak, V. (2015) · Diabetes · doi:10.2337/db14-1000 · Cited by 176 · see citing works
Effect of Intranasal Insulin on Cognitive Function: A Systematic Review
Shemesh, E., Rudich, A., Harman-Boehm, I., & Cukierman-Yaffe, T. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1802 · Cited by 162 · see citing works
Distribution of insulin in trigeminal nerve and brain after intranasal administration
Lochhead, J. J., Kellohen, K. L., Ronaldson, P. T., & Davis, T. P. (2019) · Scientific Reports · doi:10.1038/s41598-019-39191-5 · Cited by 146 · see citing works
The Triangle of Death in Alzheimer's Disease Brain: The Aberrant Cross-Talk Among Energy Metabolism, Mammalian Target of Rapamycin Signaling, and Protein Homeostasis Revealed by Redox Proteomics
Di Domenico, F., Barone, E., Perluigi, M., & Butterfield, D. A. (2017) · Antioxidants & Redox Signaling · doi:10.1089/ars.2016.6759 · Cited by 114 · see citing works
Differential activation of insulin receptor substrates 1 and 2 by insulin-like growth factor-activated insulin receptors
Denley, A., Carroll, J. M., Brierley, G. V., Cosgrove, L., Wallace, J., Forbes, B., & Roberts, C. T. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01447-06 · Cited by 103 · see citing works
GLP-1 mimetics and cognition.
Yaribeygi, H., Rashidy-Pour, A., Atkin, S. L., Jamialahmadi, T., & Sahebkar, A. (2021) · Life Sciences · doi:10.1016/j.lfs.2020.118645 · Cited by 96 · see citing works
Intranasal insulin attenuates the hypothalamic–pituitary–adrenal axis response to psychosocial stress
Bohringer, A., Schwabe, L., Richter, S., & Schachinger, H. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.08.002 · Cited by 89 · see citing works
Insulin rescues amyloid β-induced impairment of hippocampal long-term potentiation
Lee, C.-C., Kuo, Y.-M., Huang, C.-C., & Hsu, K.-S. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.06.014 · Cited by 81 · see citing works
SHIP2 and its involvement in various diseases
Suwa, A., Kurama, T., & Shimokawa, T. (2010) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2010.492780 · Cited by 74 · see citing works
Modulation of midbrain neurocircuitry by intranasal insulin
Edwin Thanarajah, S., Iglesias, S., Kuzmanovic, B., Rigoux, L., Stephan, K. E., Brüning, J. C., & Tittgemeyer, M. (2019) · NeuroImage · doi:10.1016/j.neuroimage.2019.03.050 · Cited by 55 · see citing works
Self-citation
Insulin, Synaptic Function, and Opportunities for Neuroprotection
Mielke, J. G., & Wang, Y.-T. (2011) · Progress in Molecular Biology and Translational Science · doi:10.1016/b978-0-12-385506-0.00004-1 · Cited by 55 · see citing works
Haloperidol Disrupts Lipid Rafts and Impairs Insulin Signaling in SH-SY5Y Cells
Sánchez-Wandelmer, J., Dávalos, A., de la Peña, G., Cano, S., Giera, M., Canfrán-Duque, A., Bracher, F., Martín-Hidalgo, A., Fernández-Hernando, C., Lasunción, M. A., et al. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.01.051 · Cited by 49 · see citing works
Microbiota signatures relating to reduced memory and exploratory behaviour in the offspring of overweight mothers in a murine model
Sanguinetti, E., Guzzardi, M. A., Tripodi, M., Panetta, D., Selma-Royo, M., Zega, A., Telleschi, M., Collado, M. C., & Iozzo, P. (2019) · Scientific Reports · doi:10.1038/s41598-019-48090-8 · Cited by 45 · see citing works
Total ghrelin levels during acute insulin infusion in patients with polycystic ovary syndrome
Micic, D., Sumarac-Dumanovic, M., Kendereski, A., Cvijovic, G., Zoric, S., Pejkovic, D., Micic, J., Milic, N., Dieguez, C., & Casanueva, F. F. (2007) · Journal of Endocrinological Investigation · doi:10.1007/bf03349222 · Cited by 28 · see citing works
Deletion of Specific Sphingolipids in Distinct Neurons Improves Spatial Memory in a Mouse Model of Alzheimer’s Disease
Herzer, S., Hagan, C., von Gerichten, J., Dieterle, V., Munteanu, B., Sandhoff, R., Hopf, C., & Nordström, V. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00206 · Cited by 27 · see citing works
Intranasal insulin decreases circulating cortisol concentrations during early sleep in elderly humans
Thienel, M., Wilhelm, I., Benedict, C., Born, J., & Hallschmid, M. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.03.006 · Cited by 20 · see citing works
Nasal insulin administration does not affect hepatic glucose production at systemic fasting insulin levels
Plomgaard, P., Hansen, J. S., Ingerslev, B., Clemmesen, J. O., Secher, N. H., van Hall, G., Fritsche, A., Weigert, C., Lehmann, R., Häring, H., et al. (2019) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13615 · Cited by 16 · see citing works

Hypothalamic Proopiomelanocortin Is Necessary for Normal Glucose Homeostasis in Female Mice
Alsina, R., Trotta, M., & Bumaschny, V. F. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00554 · Cited by 9 · see citing works
Central Nervous System Nutrient-sensing and the Regulation of Energy and Glucose Homeostasis
Lam, K. L. C. (2010) · TSpace (University of Toronto)
Role of probiotics in modulating glucose homeostasis: evidence from animal and human studies
Firouzi, S., Yusof, B. N. M., Ismail, A., Majid, H. A., & Azmi, K. N. (2013) · International Journal of Food Sciences and Nutrition · doi:10.3109/09637486.2013.775227 · Cited by 26 · see citing works
Wired on sugar: the role of the CNS in the regulation of glucose homeostasis
Grayson, B. E., Seeley, R. J., & Sandoval, D. A. (2012) · Nature reviews. Neuroscience · doi:10.1038/nrn3409 · Cited by 124 · see citing works
Interaction of glucose sensing and leptin action in the brain
Li, R. J. W., Zhang, S., & Lam, T. K. T. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101011 · Cited by 34 · see citing works

Authors: Plum, L., Schubert, M., & Brüning, J. C.
Affiliations: University of Cologne (DE)
Corresponding author: Brüning, Jens C.
ORCID: Schubert, Markus
Brüning, Jens C.
Venue: Trends in Endocrinology & Metabolism
Publisher: Elsevier BV
Published: 2005-03
Volume: 16
Issue: 2
Pages: 59-65
ISSN: 1043-2760 (ISSN-L)
DOI: 10.1016/j.tem.2005.01.008
OpenAlex: W2011430246
Cited by: 604
References: 86
Citations by year: 2026: 13 · 2025: 19 · 2024: 16 · 2023: 23 · 2022: 33 · 2021: 28 · 2020: 42 · 2019: 40 · 2018: 33 · 2017: 32 · 2016: 46 · 2015: 27 · 2014: 35 · 2013: 23 · 2012: 33
FWCI: 2.44
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Trends in Endocrinology and Metabolism (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords: insulin receptor signaling, brain, food intake regulation, sympathetic activity, hepatic gluconeogenesis, reproductive endocrinology, leptin signaling, phosphatidylinositol 3-kinase, ATP-sensitive potassium channels, neuronal apoptosis, Akt, tau phosphorylation, APP processing, amyloid-beta clearance, energy homeostasis, neurodegenerative diseases
MeSH terms: Animals, Brain, Energy Metabolism, Glucose, Homeostasis, Humans, Insulin, Learning, Memory, Receptor, Insulin, Reproduction, Signal Transduction, Neurodegenerative Diseases

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

The role of insulin receptor signaling in the brain

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks