The brain represents an important site for the action of insulin. Besides the traditionally known importance in glucoregulation, insulin has significant neurotrophic properties and influences the brain activity: insulin influences eating behavior, regulates the storage of energy and several aspects concerning memory and knowledge. Insulin resistance and hyperinsulinism could be associated with brain aging, vascular and metabolic pathologies. Elucidating the pathways and metabolism of brain insulin could have a major impact on future targeted therapies.
1. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol 47: 145-171, 2013.
2. Kleinridders A, Ferris HA, Cai W, Kahn CR. Insulin action in the brain regulates systemic metabolism and brain function. Diabetes 63: 2232-2243, 2014.
3. Yin F, Boveris A, Cadenas E. Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration. Antioxid, Redox Signal 20: 353-371, 2014.
4. Camandola S, Mattson MP. Brain metabolism in health, aging, and neurodegeneration. EMBO J 36: 1474–1492, 2017.
5. Wang Y, Brinton RD. Triad of risk for late onset, Alzheimer’s: mitochondrial haplotype, APOE genotype and chromosomal sex. Front Aging Neurosci 8: 232, 2016.
6. Yin F, Cadenas E. Mitochondria: the cellular hub of the dynamic coordinated network. Antioxid Redox Signal 22: 961-964, 2015.
7. Lourenço CF, Ledo A, Dias C, Barbosa RM, Laranjinha J. Neurovascular and neurometabolic derailment in aging and Alzheimer’s disease. Front Aging Neurosci 7: 103, 2015.
8. Brüning JC, Gautam D, Burks DJ et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289: 2122-2125, 2000.
9. Heidenreich KA, Zahniser NR, Berhanu P, Brandenburg D, Olefsky JM. Structural differences between insulin receptors in the brain and peripheral target tissues. J Biol Chem 258: 8527-8530, 1983.
10. Schulingkamp RJ, Pagano TC, Hung D, Raffa RB. Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev 24: 855-872, 2000.
11. McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat induced insulin resistance. Neurobiol Learn Mem 93: 546-553, 2010.
12. Laron Z. Insulin and the brain. Arch Physiol Biochem 115: 112-116, 2009.
13. Pagotto U. Where does insulin resistance start? The brain. Diabetes Care 32[Suppl 2]: S174-S177, 2009.
14. McEwen BS, Reagan LP. Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur J Pharmacol 490: 13-24, 2004.
15. McNay EC, Recknagel AK. Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes. Neurobiol Learn Mem 96: 432-442, 2011.
16. Woods SC, Lotter EC, McKay LD, Porte D Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282: 503-505, 1979.
17. Haj-ali V, Mohaddes G, Babri SH. Intracerebroventricular insulin improves spatial learning and memory in male Wistar rats. Behav Neurosci 123: 1309-1314, 2009.
18. Chapman IM, Goble EA, Wittert GA, Morley JE, Horowitz M. Effect of intravenous glucose and euglycemic insulin infusions on short-term appetite and food intake. Am J Physiol 274: R596-R603, 1998.
19. Scherer T, O’Hare J, Diggs-Andrews K et al. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab 13: 183-194, 2011.
20. Benedict C, Kern W, Schultes B, Born J, Hallschmid M. Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J Clin Endocrinol Metab 93: 1339-1344, 2008.
21. Hallschmid M, Higgs S, Thienel M, Ott V, Lehnert H. Postprandial administration of intranasal insulin intensifies satiety and reduces intake of palatable snacks in women. Diabetes 61: 782-789, 2012.
22. Reger MA, Watson GS, Green PS et al. Intranasal insulin administration dose-dependent modulates vertebral memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 13: 323-331, 2008.
23. Strubbe JH, Porte D, Jr, Woods SC. Insulin responses and glucose levels in plasma and cerebrospinal fluid during fasting and refeeding in the rat. Physiol Behav 44: 205-208, 1988.
24. Wallum BJ, Taborsky GJ Jr, Porte D Jr et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab 64: 190–194, 1987.
25. Kern W, Benedict C, Schultes B et al. Low cerebrospinal fluid insulin levels in obese humans. Diabetologia 49: 2790-2792, 2006.
26. Banks WA. The source of cerebral insulin. Eur J Pharmacol 490: 5-12, 2004.
27. Bouchard P, Ghitescu LD, Bendayan M. Morpho-functional studies of the blood-brain barrier in streptozotocin-induced diabetic rats. Diabetologia 45: 1017-1025, 2002.
28. Banks WA. The blood-brain barrier as a regulatory interface in the gut-brain axes. Physiol Behav 89: 472-476, 2006.
29. Banks WA, Gray AM, Erickson MA et al. Lipopolysaccharide - induced blood-brain barrier disruption: role of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. J Neuroinflammation 12: 223, 2015.
30. Xaio H, Banks WA, Niehoff ML, Morley JE. Effect of LPS on the permeability of the blood-brain barrier to insulin. Brain Res 896: 36-42, 2001.
31. Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther 136: 82-93, 2012.
32. Jazvinšćak Jembrek M, Hof PR, Simic G. Ceramides in Alzheimer’s disease: key mediators of neuronal apoptosis induced by oxidative stress and Aβ accumulation. Oxid Med Cell Longev 2015: 346783, 2015.
33. Zhu X, Lee HG, Raina AK, Perry G, Smith MA. The role of mitogen-activated protein kinase pathways in Alzheimer’s disease. Neurosignals 11: 270-281, 2002.
34. Edland SD. Insulin-degrading enzymes, apolipoprotein E, and Alzheimer’s disease. J Mol Neurosci 23: 213-217, 2004.
35. Li L, Holscher C. Common pathological processes in Alzheimer’s disease and type 2 diabetes: a review. Brain Res Rev 56: 384-402, 2007.
36. Gray SM, Meijer RI, Barrett EJ. Insulin regulates brain function, but how does it get there? Diabetes 63: 3992-3997, 2014.
37. Duarte AI, Proença T, Oliveira CR, Santos MS, Rego AC. Insulin restores metabolic function in cultured cortical neurons subjected to oxidative stress. Diabetes 55: 2863-2870, 2006.
38. Mittal K, Katare DP. Shared links between type 2 diabetes mellitus and Alzheimer’s disease: a review. Diabetes Metab Synd 10[2 Suppl 1]: S144-S149, 2016.
39. Zhong Y, Miao Y, Jia WP, Yan H, Wang BY, Jin J. Hyperinsulinemia, insulin resistance and cognitive decline in the older cohort. Biomed Environ Sci 25: 8-14, 2012.
40. Bala C, Niță C, Hâncu N. Severe mental illnesses and metabolic syndrome: the need for more awarness and better care. Rom J Diabetes Nutr Metab Dis 23: 7-12, 2016.
41. Popescu CD, Graur M, Grosu C, Ignat BE, Alexa D. Insulin, the brain and diabetes complications. In: Diabetes complications. New explanations and solutions Cheta D (ed). Agir Publishing House, pp 180-206, 2016.
42. Yin F, Sancheti H, Patil I, Cadenas M. Energy metabolism and inflammation in brain aging and Alzheimer’s disease. Free Radic Biol Med 100: 108-122, 2016.
43. Patel PS, Buras ED, Balasubramanyam A. The role of the immune system in obesity and insulin resistance. J Obes 2013: 616193, 2013.
44. Sun Q, Li J, Gao F. New insights into insulin: The anti-inflammatory effect and its clinical relevance. World J Diabetes 5: 89-96, 2014.