Insulin Impact in Glaucoma Neurodegeneration and Vascular Dysfunction
Main Article Content
Abstract
Neurodegeneration in glaucoma remains a significant challenge, even with efforts to lower intraocular pressure (IOP). Many patients continue to experience visual field loss. This review will highlight the role that insulin signalling plays in neurodegeneration and also in vascular dysfunction.
Neurodegeneration glaucoma and Alzheimer's disease (AD) share many identical characteristics, deposits of beta-amyloid, cell apoptosis, Tau hyperphosphorylation, NFT formation, and mitochondrial dysfunction with elevated OS.
Vascular autoregulation in glaucoma is abnormal with a high level of endothelin-1 (ET-1) and impaired nitric oxide (NO) signaling.
There is insulin resistance by an increase of serine of insulin receptor -1 phosphorylation (p(ser)IRS-1) instead of tyrosine –IRS-1 phosphorylation (p (Tyr) IRS-1) causing alteration in insulin signaling.
C-peptide presence in the brain and insulin detection in neuron culture reinforce the evidence of insulin central secretion.
In this review, we will see the capacity of insulin intravitreal injection to promote visual function, restore the balance between NO/ET-1 secretions, and ameliorate neurite outgrowth and function.
Article Details
How to Cite
BOUDGHENE, Amine Chaoui; DJA BOUABDALLAH, Abderrazak; BELBACHIR, Kaoutar.
Insulin Impact in Glaucoma Neurodegeneration and Vascular Dysfunction.
Medical Research Archives, [S.l.], v. 12, n. 10, oct. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5928>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i10.5928.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2. Blumberg D, Skatt A, Liebmann JM. Chaopter 5 emerging risk factors for glaucoma onset and progression Prong Brain Res. 2015;221:81-101.
3. Noel CY, Chan MBCHB, FRCSED, Jane W, Chan MD. Glaucoma as a neurodegenerative disease: A clinician perspective. Advances in Ophthalmology andOptometry. 2021;263-274.
4. Paolini Paoletti F, Simoni S, Parnetti L, Gaetani L. The contribution of small vessel disease to neurodegeneration: Focus on Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. International Journal of Molecular Sciences. 2021;22(9):4958.
5. Newman, A., Andrew, N., and Casson, R. (2018). Review of the association between retinal microvascular characteristics and eye disease. Clin. Exp. Ophthalmol. 46, 531–552. Doi: 10.1111/ceo.13119
6. Kitsos G. Zikou A. Bagli E. Conventional MRI and magnetisation transfer imaging of the brain and optic pathway in primary open-angle glaucoma. B J Ophthalmol. 2009; 82: 896-900.
7. Stroman G.A. Stewart W.C. Golnik K.C. et al. Magnetic resonance imaging in patients with low-tension glaucoma. Arch Ophthalmol. 1995;113:168-172.
8. arris A, Zarfati D, Zalish M. Reduced cerebrovascular blood flow velocities and vasoreactivity in open-angle glaucoma. Am J Ophthalmol 2003;135:144–7.
9. Buttery, R. G., Hinrichsen, C. F., Weller, W. L., and Haight, J. R. (1991). How thick should a retina be? A comparative study of mammalian species with and without intraretinal vasculature. Vision Res. 31, 169–187. Doi: 10.1016/0042- 6989(91)90110-q.
10. Jonas, J. B., Fernandez, M. C., and Naumann, G. O. (1991). Parapapillary atrophy and retinal vessel diameter in nonglaucomatous optic nerve damage. Invest. Ophthalmol. Vis. Sci. 32, 2942–2947.
11. Quigley, H. A., Hohman, R. M., Addicks, E. M., and Green, W. R. (1984). Blood vessels of the glaucomatous optic disc in experimental primate and human eyes. Invest. Ophthalmol. Vis. Sci. 25, 918–931.
12. Alm, A., and Bill, A. (1973). Ocular and optic nerve blood flow at normal and increased intraocular pressures in monkeys (Macaca irus): a study with radioactively labelled microspheres including flow determinations in brain and some other tissues. Exp. Eye Res. 15, 15–29. Doi: 10.1016/0014-4835(73)90185-1
13. Boltz, A., Schmidl, D., Werkmeister, R. M., Lasta, M., Kaya, S., Palkovits, S., et al. (2013). Regulation of optic nerve head blood flow during combined changes in intraocular pressure and arterial blood pressure. J. Cereb. Blood Flow Metab. 33, 1850–1856. Doi: 10.1038/jcbfm.2013.137.
14. Prada, D., Harris, A., Guidoboni, G., Siesky, B., Huang, A. M., and Arciero, J. (2016). Autoregulation and neurovascular coupling in the optic nerve head. Surv. Ophthalmol. 61, 164–186. Doi: 10.1016/j.survophthal.2015. 10.004
15. Kur, J., Newman, E. A., and Chan-Ling, T. (2012). Cellular and physiological mechanisms underlying blood flow regulation in the retina and choroid in health and disease. Prog. Retin. Eye Res. 31, 377–406. Doi: 10.1016/j.preteyeres. 2012.04.004.
16. Chauhan, B. C., Levatte, T. L., Jollimore, C. A., Yu, P. K., Reitsamer, H. A., Kelly, M. E., et al. (2004). Model of endothelin-1-induced chronic optic neuropathy in rat. Invest. Ophthalmol. Vis. Sci. 45, 144–152.
17. Howell, G. R., Macalinao, D. G., Sousa, G. L., Walden, M., Soto, I., Kneeland, S. C., et al. (2011). Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J. Clin. Invest. 121, 1429–1444. Doi: 10.1172/JCI44646.
18. Hemma Resch; Katharina Karl; Günther Weigert; Michael Wolzt; Anton Hommer; Leopold Schmetterer; Gerhard Garhöfer 2009. Effect of Dual Endothelin Receptor Blockade on Ocular Blood Flow in Patients with Glaucoma and Healthy Subjects Investigative Ophthalmology & Visual Science, January 2009, Vol. 50, No. 1 Doi:https://doi.org/10.1167/iovs.08-2460
19. Doganay, S., Evereklioglu, C., Turkoz, Y., and Er, H. (2002). Decreased nitric oxide production in primary open-angle glaucoma. Eur. J. Ophthalmol. 12, 44–48. Doi: 10.1177/112067210201200109.
20. Roy, C. S., and Sherrington, C. S. (1890). On the Regulation of the Blood-supply of the Brain. J. Physiol. 11, 85–158.
21. Attwell, D., Buchan, A. M., Charpak, S., Lauritzen, M., Macvicar, B. A., and Newman, E. A. (2010). Glial and neuronal control of brain blood flow. Nature 468, 232–243. Doi: 10.1038/nature09613.
22. Kondo, M., Wang, L., and Bill, A. (1997). The role of nitric oxide in hyperaemic response to flicker in the retina and optic nerve in cats. Acta Ophthalmol. Scand. 75, 232–235. Doi: 10.1111/j.1600-0420.1997.tb00762.x.
23. Herman, I. M., and D’amore, P. A. (1985). Microvascular pericytes contain muscle and nonmuscle actins. J. Cell Biol. 101, 43–52. Doi: 10.1083/jcb.101.1.43.
24. Bolotina, V. M., Najibi, S., Palacino, J. J., Pagano, P. J., and Cohen, R. A. (1994). Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 368, 850–853. Doi: 10.1038/368850a0.
25. Ranganath Muniyappa & James R. Sowers Role of insulin resistance in endothelial dysfunction Rev Endocr Metab Disord (2013) 14:5–12 DOI 10.1007/s11154-012-9229-1
26. Kijin Kim ;Rudy J. Valentine ;Yoonjung Shin,Kyungmin Gong Associations of visceral adiposity and exercise participation with C-reactive protein, insulin resistance, and endothelial dysfunction in Korean healthy adults Doi:https://doi.org/10.1016/j.metabol.2008.04.009
27. Biessels, G. J., and Reagan, L. P. (2015). Hippocampal insulin resistance and cognitive dysfunction. Nat. Rev. Neurosci. 16, 660–671. Doi: 10.1038/nrn4019
28. Steen, E., Terry, B. M., Rivera, E. J., Cannon, J. L., Neely, T. R., Tavares, R., et al. (2005). Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J. Alzheimers Dis. 7, 63–80. Doi: 10.3233/JAD-2005-7107.
29. Moloney, A. M., Griffin, R. J., Timmons, S., O’Connor, R., Ravid, R., and O’Neill, C. (2010). Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol. Aging 31, 224–243. Doi: 10.1016/j.neurobiolaging.2008.04.002.
30. Bomfim, T. R., Forny-Germano, L., Sathler, L. B., Brito-Moreira, J., Houzel, J.- C., Decker, H., et al. (2012). An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers. J. Clin. Invest. 122, 1339–1353. Doi: 10.1172/JCI57256.
31. Talbot, K., Wang, H.-Y., Kazi, H., Han, L.-Y., Bakshi, K. P., Stucky, A., et al. (2012). Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Invest. 122, 1316–1338. Doi: 10.1172/JCI59903.
32. Kourembanas S, McQuillan LP, Leung GK, Faller DV. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 92: 99 –104, 1993.
33. Demuro G, Obici S. Central nervous system and control of endogenous glucose production. Curr Diab Rep (2006) 6(3):188–93. Doi:10.1007/s11892-006- 0033-8.
34. Boulanger C, Luscher TF. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 85: 587– 590, 1990.
35. Luscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation 102: 2434 –2440, 2000.
36. Weissberg PL, Witchell C, Davenport AP, Hesketh TR, Metcalfe JC. The endothelin peptides ET-1, ET-2, ET-3 and sarafotoxin S6b are co-mitogenic with platelet-derived growth factor for vascular smooth muscle cells. Atherosclerosis 85: 257–262, 1990.
37. Amine Chaoui Boudghene Clinical Study of Neurodegenerative Treatment on Glaucoma by Insulin Intravitreal Injection 2022 ; Ophthalmology Research: An International Journal 17(4): 1-14, 2022; Article no.OR.91862 ISSN: 2321-7227 Doi: 10.9734/OR/2022/v17i4368.
38. Muneeb A. Faiq, Rima Dada, Daman Saluja, Tanuj Dada. Glaucoma – diabetes of the brain: A radical hypothesis about its nature and pathogenesis. Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi 110029, India c Medical Biotechnology Laboratory, Dr. B.R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India; 2014. Available: http://dx.doi.org/10.1016/j.mehy. 2014.02.005
39. Devaskar SU, Giddings SJ, Rajakumar PA, Carnaghi LR, Menon RK, Zahm DS. Insulin gene expression and insulin synthesis in mammalian neuronal cells. J. Biol. Chem. 1994;269:8445–8454.
40. Schechter R, Beju D, Gaffney T, Schaefer F, Whetsell L. Preproinsulin I and II mRNAs and insulin electron microscopic immunoreaction are present within the rat fetal nervous system. Brain Res. 1996;736:16–27
41. Wei LT, Matsumoto H, Rhoads DE. Release of immunoreactive insulin from rat brain synaptosomes under depolarizing conditions. J Neurochem. 1990;54(5): 1661–5.
42. Weiss M, Steiner DF, Philipson LH. Insulin biosynthesis, secretion, structure, and structure-activity relationships. Endotext, K.R., Ed.; MDText.com, Inc.: South Dartmouth, MA, USA; 2000
43. Plum L, Schubert M, Brüning JC. The role of insulin receptor signaling in the brain. Trends Endocrinol. Metab. 2005;16:59– 65.
44. Bateman JM, McNeill AH. Visions & reflections insulin/IGF signalling inneurogenesis. The wolfson centre for age- related disease, Hodgkin Building, King’s College London, Guy’s Campus, London, SE1 1UL (United Kingdom), Samuel Lunenfeld Research Institute, 600 University Avenue, Room 884, Toronto, Ontario M5G 1X5 (Canada). Doi: 10.1007/s00018-006-6036-4
45. Santos MS, Pereira EM, Carvaho AP. Stimulation of immunoreactive insulin release by glucose in rat brain synaptosomes. Neurochem Res. 1999;24(1):33–6. Doi:10.1023/A:1020971812098.
46. Ryu BR, Ko HW, Jou I, Noh JS, Gwag BJ. Phosphatidylinositol 3-kinasemediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I. J Neurobiol. 1999;39(4):536–46. Doi:10.1002/(SICI)1097-4695(19990615)39
47. Cheng Z, Tseng Y, White MF. Insulin signaling meets mitochondria in metabolism. Trends Endocrinol. Metab. 2010;21:589–598.
48. Yamaguchi A, Tamatani M, Matsuzaki H, Namikawa K, Kiyama H, Vitek MP, Mitsuda N, Tohyama M. Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53. J. Biol. Chem. 2001;276:5256–5264.
49. Rensink AA, Otte-Holler I, de Boer R, Bosch RR, ten Donkelaar HJ, de Waal RM et al. Insulin inhibits amyloid beta-induced cell death in cultured human brain pericytes. Neurobiol Aging 2004;25(1):93–103. Doi:10.1016/S0197-4580(03) 00039-3
2. Blumberg D, Skatt A, Liebmann JM. Chaopter 5 emerging risk factors for glaucoma onset and progression Prong Brain Res. 2015;221:81-101.
3. Noel CY, Chan MBCHB, FRCSED, Jane W, Chan MD. Glaucoma as a neurodegenerative disease: A clinician perspective. Advances in Ophthalmology andOptometry. 2021;263-274.
4. Paolini Paoletti F, Simoni S, Parnetti L, Gaetani L. The contribution of small vessel disease to neurodegeneration: Focus on Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. International Journal of Molecular Sciences. 2021;22(9):4958.
5. Newman, A., Andrew, N., and Casson, R. (2018). Review of the association between retinal microvascular characteristics and eye disease. Clin. Exp. Ophthalmol. 46, 531–552. Doi: 10.1111/ceo.13119
6. Kitsos G. Zikou A. Bagli E. Conventional MRI and magnetisation transfer imaging of the brain and optic pathway in primary open-angle glaucoma. B J Ophthalmol. 2009; 82: 896-900.
7. Stroman G.A. Stewart W.C. Golnik K.C. et al. Magnetic resonance imaging in patients with low-tension glaucoma. Arch Ophthalmol. 1995;113:168-172.
8. arris A, Zarfati D, Zalish M. Reduced cerebrovascular blood flow velocities and vasoreactivity in open-angle glaucoma. Am J Ophthalmol 2003;135:144–7.
9. Buttery, R. G., Hinrichsen, C. F., Weller, W. L., and Haight, J. R. (1991). How thick should a retina be? A comparative study of mammalian species with and without intraretinal vasculature. Vision Res. 31, 169–187. Doi: 10.1016/0042- 6989(91)90110-q.
10. Jonas, J. B., Fernandez, M. C., and Naumann, G. O. (1991). Parapapillary atrophy and retinal vessel diameter in nonglaucomatous optic nerve damage. Invest. Ophthalmol. Vis. Sci. 32, 2942–2947.
11. Quigley, H. A., Hohman, R. M., Addicks, E. M., and Green, W. R. (1984). Blood vessels of the glaucomatous optic disc in experimental primate and human eyes. Invest. Ophthalmol. Vis. Sci. 25, 918–931.
12. Alm, A., and Bill, A. (1973). Ocular and optic nerve blood flow at normal and increased intraocular pressures in monkeys (Macaca irus): a study with radioactively labelled microspheres including flow determinations in brain and some other tissues. Exp. Eye Res. 15, 15–29. Doi: 10.1016/0014-4835(73)90185-1
13. Boltz, A., Schmidl, D., Werkmeister, R. M., Lasta, M., Kaya, S., Palkovits, S., et al. (2013). Regulation of optic nerve head blood flow during combined changes in intraocular pressure and arterial blood pressure. J. Cereb. Blood Flow Metab. 33, 1850–1856. Doi: 10.1038/jcbfm.2013.137.
14. Prada, D., Harris, A., Guidoboni, G., Siesky, B., Huang, A. M., and Arciero, J. (2016). Autoregulation and neurovascular coupling in the optic nerve head. Surv. Ophthalmol. 61, 164–186. Doi: 10.1016/j.survophthal.2015. 10.004
15. Kur, J., Newman, E. A., and Chan-Ling, T. (2012). Cellular and physiological mechanisms underlying blood flow regulation in the retina and choroid in health and disease. Prog. Retin. Eye Res. 31, 377–406. Doi: 10.1016/j.preteyeres. 2012.04.004.
16. Chauhan, B. C., Levatte, T. L., Jollimore, C. A., Yu, P. K., Reitsamer, H. A., Kelly, M. E., et al. (2004). Model of endothelin-1-induced chronic optic neuropathy in rat. Invest. Ophthalmol. Vis. Sci. 45, 144–152.
17. Howell, G. R., Macalinao, D. G., Sousa, G. L., Walden, M., Soto, I., Kneeland, S. C., et al. (2011). Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J. Clin. Invest. 121, 1429–1444. Doi: 10.1172/JCI44646.
18. Hemma Resch; Katharina Karl; Günther Weigert; Michael Wolzt; Anton Hommer; Leopold Schmetterer; Gerhard Garhöfer 2009. Effect of Dual Endothelin Receptor Blockade on Ocular Blood Flow in Patients with Glaucoma and Healthy Subjects Investigative Ophthalmology & Visual Science, January 2009, Vol. 50, No. 1 Doi:https://doi.org/10.1167/iovs.08-2460
19. Doganay, S., Evereklioglu, C., Turkoz, Y., and Er, H. (2002). Decreased nitric oxide production in primary open-angle glaucoma. Eur. J. Ophthalmol. 12, 44–48. Doi: 10.1177/112067210201200109.
20. Roy, C. S., and Sherrington, C. S. (1890). On the Regulation of the Blood-supply of the Brain. J. Physiol. 11, 85–158.
21. Attwell, D., Buchan, A. M., Charpak, S., Lauritzen, M., Macvicar, B. A., and Newman, E. A. (2010). Glial and neuronal control of brain blood flow. Nature 468, 232–243. Doi: 10.1038/nature09613.
22. Kondo, M., Wang, L., and Bill, A. (1997). The role of nitric oxide in hyperaemic response to flicker in the retina and optic nerve in cats. Acta Ophthalmol. Scand. 75, 232–235. Doi: 10.1111/j.1600-0420.1997.tb00762.x.
23. Herman, I. M., and D’amore, P. A. (1985). Microvascular pericytes contain muscle and nonmuscle actins. J. Cell Biol. 101, 43–52. Doi: 10.1083/jcb.101.1.43.
24. Bolotina, V. M., Najibi, S., Palacino, J. J., Pagano, P. J., and Cohen, R. A. (1994). Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 368, 850–853. Doi: 10.1038/368850a0.
25. Ranganath Muniyappa & James R. Sowers Role of insulin resistance in endothelial dysfunction Rev Endocr Metab Disord (2013) 14:5–12 DOI 10.1007/s11154-012-9229-1
26. Kijin Kim ;Rudy J. Valentine ;Yoonjung Shin,Kyungmin Gong Associations of visceral adiposity and exercise participation with C-reactive protein, insulin resistance, and endothelial dysfunction in Korean healthy adults Doi:https://doi.org/10.1016/j.metabol.2008.04.009
27. Biessels, G. J., and Reagan, L. P. (2015). Hippocampal insulin resistance and cognitive dysfunction. Nat. Rev. Neurosci. 16, 660–671. Doi: 10.1038/nrn4019
28. Steen, E., Terry, B. M., Rivera, E. J., Cannon, J. L., Neely, T. R., Tavares, R., et al. (2005). Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J. Alzheimers Dis. 7, 63–80. Doi: 10.3233/JAD-2005-7107.
29. Moloney, A. M., Griffin, R. J., Timmons, S., O’Connor, R., Ravid, R., and O’Neill, C. (2010). Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol. Aging 31, 224–243. Doi: 10.1016/j.neurobiolaging.2008.04.002.
30. Bomfim, T. R., Forny-Germano, L., Sathler, L. B., Brito-Moreira, J., Houzel, J.- C., Decker, H., et al. (2012). An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers. J. Clin. Invest. 122, 1339–1353. Doi: 10.1172/JCI57256.
31. Talbot, K., Wang, H.-Y., Kazi, H., Han, L.-Y., Bakshi, K. P., Stucky, A., et al. (2012). Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Invest. 122, 1316–1338. Doi: 10.1172/JCI59903.
32. Kourembanas S, McQuillan LP, Leung GK, Faller DV. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 92: 99 –104, 1993.
33. Demuro G, Obici S. Central nervous system and control of endogenous glucose production. Curr Diab Rep (2006) 6(3):188–93. Doi:10.1007/s11892-006- 0033-8.
34. Boulanger C, Luscher TF. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 85: 587– 590, 1990.
35. Luscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation 102: 2434 –2440, 2000.
36. Weissberg PL, Witchell C, Davenport AP, Hesketh TR, Metcalfe JC. The endothelin peptides ET-1, ET-2, ET-3 and sarafotoxin S6b are co-mitogenic with platelet-derived growth factor for vascular smooth muscle cells. Atherosclerosis 85: 257–262, 1990.
37. Amine Chaoui Boudghene Clinical Study of Neurodegenerative Treatment on Glaucoma by Insulin Intravitreal Injection 2022 ; Ophthalmology Research: An International Journal 17(4): 1-14, 2022; Article no.OR.91862 ISSN: 2321-7227 Doi: 10.9734/OR/2022/v17i4368.
38. Muneeb A. Faiq, Rima Dada, Daman Saluja, Tanuj Dada. Glaucoma – diabetes of the brain: A radical hypothesis about its nature and pathogenesis. Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi 110029, India c Medical Biotechnology Laboratory, Dr. B.R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi 110007, India; 2014. Available: http://dx.doi.org/10.1016/j.mehy. 2014.02.005
39. Devaskar SU, Giddings SJ, Rajakumar PA, Carnaghi LR, Menon RK, Zahm DS. Insulin gene expression and insulin synthesis in mammalian neuronal cells. J. Biol. Chem. 1994;269:8445–8454.
40. Schechter R, Beju D, Gaffney T, Schaefer F, Whetsell L. Preproinsulin I and II mRNAs and insulin electron microscopic immunoreaction are present within the rat fetal nervous system. Brain Res. 1996;736:16–27
41. Wei LT, Matsumoto H, Rhoads DE. Release of immunoreactive insulin from rat brain synaptosomes under depolarizing conditions. J Neurochem. 1990;54(5): 1661–5.
42. Weiss M, Steiner DF, Philipson LH. Insulin biosynthesis, secretion, structure, and structure-activity relationships. Endotext, K.R., Ed.; MDText.com, Inc.: South Dartmouth, MA, USA; 2000
43. Plum L, Schubert M, Brüning JC. The role of insulin receptor signaling in the brain. Trends Endocrinol. Metab. 2005;16:59– 65.
44. Bateman JM, McNeill AH. Visions & reflections insulin/IGF signalling inneurogenesis. The wolfson centre for age- related disease, Hodgkin Building, King’s College London, Guy’s Campus, London, SE1 1UL (United Kingdom), Samuel Lunenfeld Research Institute, 600 University Avenue, Room 884, Toronto, Ontario M5G 1X5 (Canada). Doi: 10.1007/s00018-006-6036-4
45. Santos MS, Pereira EM, Carvaho AP. Stimulation of immunoreactive insulin release by glucose in rat brain synaptosomes. Neurochem Res. 1999;24(1):33–6. Doi:10.1023/A:1020971812098.
46. Ryu BR, Ko HW, Jou I, Noh JS, Gwag BJ. Phosphatidylinositol 3-kinasemediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I. J Neurobiol. 1999;39(4):536–46. Doi:10.1002/(SICI)1097-4695(19990615)39
47. Cheng Z, Tseng Y, White MF. Insulin signaling meets mitochondria in metabolism. Trends Endocrinol. Metab. 2010;21:589–598.
48. Yamaguchi A, Tamatani M, Matsuzaki H, Namikawa K, Kiyama H, Vitek MP, Mitsuda N, Tohyama M. Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53. J. Biol. Chem. 2001;276:5256–5264.
49. Rensink AA, Otte-Holler I, de Boer R, Bosch RR, ten Donkelaar HJ, de Waal RM et al. Insulin inhibits amyloid beta-induced cell death in cultured human brain pericytes. Neurobiol Aging 2004;25(1):93–103. Doi:10.1016/S0197-4580(03) 00039-3