A review on insulin presence and function in brain

Katayoun Sedaghat


Hormones have major role in maintaining the homeostasis of the body and mental functions. One of the crucial hormones that act to regulate the metabolism and growth is insulin. Insulin activity in the periphery has been the subject of study since long time ago, though, beginning to understand the central activity of insulin is rather recent and because of complexity of actions and interference with neurodegenerative diseases such as Alzheimer’s and Parkinson’s and mood disorders, like anxiety and depression, it is considered very crucial hormone in the maintenance of the mental health. This mini-review will discuss briefly the recent main aspects of insulin transfer to the brain, receptor and mediators, signaling pathways with particular attention to neural system and its role in cognitive and emotional processing in brain. Insulin is an endocrine hormone with receptor distribution in different parts of brain and has role in various neural functions such as; growth factor, modulating learning or memory, mood, neural growth and survival, also controlling neurotransmitters functions in different brain regions. Insulin regulates metabolic homeostasis in brain through complex routes, which inevitably makes it involved with some neurodegenerative or affective disorders, that raises its importance for more serious studies.


Insulin, Brain, Metabolism, Cognition, Neurodegenerative, Depression

Full Text:



Gray SM, Barrett EJ. Insulin transport into the brain. Am J Physiol Cell Physiol. 2018;315:C125-C36.

Sousa RAL. Consequences of gestational diabetes to the brain and behavior of the offspring. An Acad Bras Cienc. 2018;90:2279-91.

van der Heide LP, Ramakers GM, Smidt MP. Insulin signaling in the central nervous system: learning to survive. Progress Neurobiol. 2006;79:205-21.

Vandal M, White PJ, Tremblay C, St-Amour I, Chevrier G, Emond V, et al. Insulin reverses the high-fat diet-induced increase in brain Abeta and improves memory in an animal model of Alzheimer disease. Diabetes. 2014;63:4291-301.

Sedaghat K, Zahediasl S, Ghasemi A. Intrauterine programming. Iran J Basic Med Sci. 2015;18:212-20.

Meijer RI, Gray SM, Aylor KW, Barrett EJ. Pathways for insulin access to the brain: the role of the microvascular endothelial cell. Am J Physiol Heart Circ Physiol. 2016;311:H1132-H8.

Nishijima T, Piriz J, Duflot S, Fernandez AM, Gaitan G, Gomez-Pinedo U, et al. Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS. Neuron. 2010;67:834-46.

Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58:708-19.

Gundlach AL, Ma S, Sang Q, Shen PJ, Piccenna L, Sedaghat K, et al. Relaxin family peptides and receptors in mammalian brain. Ann N Y Acad Sci. 2009;1160:226-35.

Kleinridders A, Ferris HA, Cai W, Kahn CR. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 2014;63:2232-43.

De Meyts P. The Insulin Receptor and Its Signal Transduction Network. Endotext, free online endocrinology books:; 2016.

Cholerton B, Baker LD, Craft S. Insulin, cognition, and dementia. Eur J Pharmacol. 2013;719:170-9.

Mosthaf L, Grako K, Dull TJ, Coussens L, Ullrich A, McClain DA. Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO J 1990;9:2409-13.

Porte D, Baskin DG, Schwartz MW. Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes. 2005;54:1264-76.

Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL, et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci. 2003;23:7084-92.

Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122:1316-38.

Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann RS, Egan JM, et al. Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus. 2008;18:1085-8.

Arnold SE, Lucki I, Brookshire BR, Carlson GC, Browne CA, Kazi H, et al. High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice. Neurobiol Dis. 2014;67:79-87.

Figlewicz DP, Szot P, Israel PA, Payne C, Dorsa DM. Insulin reduces norepinephrine transporter mRNA in vivo in rat locus coeruleus. Brain Res. 1993;602:161-4.

Kopf SR, Baratti CM. Effects of posttraining administration of insulin on retention of a habituation response in mice: participation of a central cholinergic mechanism. Neurobiol Learn Mem. 1999;71:50-61.

van der Heide LP, Kamal A, Artola A, Gispen WH, Ramakers GM. Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner. J Neurochem. 2005;94:1158-66.

Bobsin K, Kreienkamp HJ. Severe learning deficits of IRSp53 mutant mice are caused by altered NMDA receptor-dependent signal transduction. J Neurochem. 2016;136:752-63.

Sedaghat K, Yousefian Z, Vafaei AA, Rashidy-Pour A, Parsaei H, Khaleghian A, Choobdar S. Mesolimbic dopamine system and its modulation by vitamin D in a chronic mild stress model of depression in the rat. Behav Brain Res. 2019;356:156-69.

Finsterwald C, Alberini CM. Stress and glucocorticoid receptor-dependent mechanisms in long-term memory: from adaptive responses to psychopathologies. Neurobiol Learn Mem. 2014;112:17-29.

Kuo T, McQueen A, Chen TC, Wang JC. Regulation of Glucose Homeostasis by Glucocorticoids. Adv Exp Med Biol. 2015;872:99-126.

Kumamaru E, Numakawa T, Adachi N, Yagasaki Y, Izumi A, Niyaz M, et al. Glucocorticoid prevents brain-derived neurotrophic factor-mediated maturation of synaptic function in developing hippocampal neurons through reduction in the activity of mitogen-activated protein kinase. Mol Endocrinol. 2008;22:546-58.

Tiedemann LJ, Schmid SM, Hettel J, Giesen K, Francke P, Buchel C, et al. Central insulin modulates food valuation via mesolimbic pathways. Nat Commun. 2017;8:16052.

Mebel DM, Wong JC, Dong YJ, Borgland SL. Insulin in the ventral tegmental area reduces hedonic feeding and suppresses dopamine concentration via increased reuptake. Eur J Neurosci. 2012;36:2336-46.

Figlewicz DP, Szot P, Chavez M, Woods SC, Veith RC. Intraventricular insulin increases dopamine transporter mRNA in rat VTA/substantia nigra. Brain Res. 1994;644:331-4.

Labouebe G, Liu S, Dias C, Zou H, Wong JC, Karunakaran S, et al. Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids. Nat Neurosci. 2013;16:300-8.

Gardner A, Boles RG. Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:730-43.

Kleinridders A, Lauritzen HP, Ussar S, Christensen JH, Mori MA, Bross P, et al. Leptin regulation of Hsp60 impacts hypothalamic insulin signaling. J Clin Invest. 2013;123:4667-80.

Kleinridders A, Cai W, Cappellucci L, Ghazarian A, Collins WR, Vienberg SG, et al. Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proc Natl Acad Sci U S A. 2015;112:3463-8.

Shih CH, Chen CJ, Chen L. New function of the adaptor protein SH2B1 in brain-derived neurotrophic factor-induced neurite outgrowth. PLoS One. 2013;8:e79619.

Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biological psychiatry. 2006;59:1116-27.

Stepanichev M, Dygalo NN, Grigoryan G, Shishkina GT, Gulyaeva N. Rodent models of depression: neurotrophic and neuroinflammatory biomarkers. Biomed Res Int. 2014;2014:932757.

Nowacka M, Obuchowicz E. BDNF and VEGF in the pathogenesis of stress-induced affective diseases: an insight from experimental studies. Pharmacological reports: PR. 2013;65:535-46.