Abstract
Diabetes mellitus is a metabolic disease where improper glycaemic control may induce severe complications in different organs. In this review, we will discuss alterations occurring in peripheral and central nervous system of patients with type 1 (i.e., insulin dependent diabetes mellitus,) or type 2 diabetes (i.e., non-insulin dependent diabetes mellitus), as well as related experimental models. A particular focus will be on the role exerted by neuroactive steroids (i.e., important regulators of nervous functions) in the nervous damage induced by diabetes. Indeed, the nervous levels of these molecules are affected by the pathology and, in agreement, their neuroprotective effects have been reported. Interestingly, the sex is another important variable. As discussed, nervous diabetic complications show sex dimorphic features in term of incidence, functional outcomes and neuroactive steroid levels. Therefore, these features represent an interesting background for possible sex-oriented therapies with neuroactive steroids aimed to counteract nervous damage observed in diabetic pathology.
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References
Aaberg ML, Burch DM, Hud ZR, Zacharias MP (2008) Gender differences in the onset of diabetic neuropathy. J Diabetes Complicat 22(2):83–87
Abadie JM, Wright B, Correa G, Browne ES, Porter JR, Svec F (1993) Effect of dehydroepiandrosterone on neurotransmitter levels and appetite regulation of the obese Zucker rat. The Obesity Research Program Diabetes 42(5):662–669
Afrazi S, Esmaeili-Mahani S, Sheibani V, Abbasnejad M (2014) Neurosteroid allopregnanolone attenuates high glucose-induced apoptosis and prevents experimental diabetic neuropathic pain: in vitro and in vivo studies. J Steroid Biochem Mol Biol 139:98–103
Albers JW, Brown MB, Sima AA, Greene DA (1996) Nerve conduction measures in mild diabetic neuropathy in the Early Diabetes Intervention Trial: the effects of age, sex, type of diabetes, disease duration, and anthropometric factors. Tolrestat Study Group for the Early Diabetes Intervention Trial. Neurology 46(1):85–91
Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A, Copeland JR, Dartigues JF, Kragh-Sorensen P, Baldereschi M, Brayne C, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A (1999) Gender differences in the incidence of AD and vascular dementia: the EURODEM Studies. EURODEM Incidence Research Group. Neurology 53(9):1992–1997
Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY, Ahima RS, Craft S, Gandy S, Buettner C, Stoeckel LE, Holtzman DM, Nathan DM (2018) Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol 14(3):168–181
Atif F, Prunty MC, Turan N, Stein DG, Yousuf S (2017) Progesterone modulates diabetes/hyperglycemia-induced changes in the central nervous system and sciatic nerve. Neuroscience 350:1–12
Baglietto-Vargas D, Shi J, Yaeger DM, Ager R, LaFerla FM (2016) Diabetes and Alzheimer’s disease crosstalk. Neurosci Biobehav Rev 64:272–287
Baptista FI, Pinto MJ, Elvas F, Almeida RD, Ambrosio AF (2013) Diabetes alters KIF1A and KIF5B motor proteins in the hippocampus. PLoS ONE 8(6):e65515
Basit A, Hydrie MZ, Hakeem R, Ahmedani MY, Masood Q (2004) Frequency of chronic complications of type II diabetes. J Coll Physicians Surg Pak 14(2):79–83
Baulieu EE, Robel P (1990) Neurosteroids: a new brain function? J Steroid Biochem Mol Biol 37(3):395–403
Belelli D, Lambert JJ (2005) Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci 6(7):565–575
Bharadwaj P, Wijesekara N, Liyanapathirana M, Newsholme P, Ittner L, Fraser P, Verdile G (2017) The link between type 2 diabetes and neurodegeneration: roles for amyloid-beta, amylin, and tau proteins. J Alzheimers Dis 59(2):421–432
Bianchi R, Buyukakilli B, Brines M, Savino C, Cavaletti G, Oggioni N, Lauria G, Borgna M, Lombardi R, Cimen B, Comelekoglu U, Kanik A, Tataroglu C, Cerami A, Ghezzi P (2004) Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci USA 101(3):823–828
Biessels GJ, Reijmer YD (2014) Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI? Diabetes 63(7):2244–2252
Biessels GJ, Kamal A, Ramakers GM, Urban IJ, Spruijt BM, Erkelens DW, Gispen WH (1996) Place learning and hippocampal synaptic plasticity in streptozotocin-induced diabetic rats. Diabetes 45(9):1259–1266
Biessels GJ, Kamal A, Urban IJ, Spruijt BM, Erkelens DW, Gispen WH (1998) Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res 800(1):125–135
Biessels GJ, Cristino NA, Rutten GJ, Hamers FP, Erkelens DW, Gispen WH (1999) Neurophysiological changes in the central and peripheral nervous system of streptozotocin-diabetic rats. Course of development and effects of insulin treatment. Brain 122(Pt 4):757–768
Biessels GJ, van der Heide LP, Kamal A, Bleys RL, Gispen WH (2002) Ageing and diabetes: implications for brain function. Eur J Pharmacol 441(1–2):1–14
Biessels GJ, Deary IJ, Ryan CM (2008) Cognition and diabetes: a lifespan perspective. Lancet Neurol 7(2):184–190
Booya F, Bandarian F, Larijani B, Pajouhi M, Nooraei M, Lotfi J (2005) Potential risk factors for diabetic neuropathy: a case control study. BMC Neurol 5:24
Burul-Bozkurt N, Pekiner C, Kelicen P (2010) Diabetes alters aromatase enzyme levels in sciatic nerve and hippocampus tissues of rats. Cell Mol Neurobiol 30(3):445–451
Calabrese D, Giatti S, Romano S, Porretta-Serapiglia C, Bianchi R, Milanese M, Bonanno G, Caruso D, Viviani B, Gardoni F, Garcia-Segura LM, Melcangi RC (2014) Diabetic neuropathic pain: a role for testosterone metabolites. J Endocrinol 221(1):1–13
Calcutt NA, Chaplan SR (1997) Spinal pharmacology of tactile allodynia in diabetic rats. Br J Pharmacol 122(7):1478–1482
Candeias E, Duarte AI, Sebastiao I, Fernandes MA, Placido AI, Carvalho C, Correia S, Santos RX, Seica R, Santos MS, Oliveira CR, Moreira PI (2017) Middle-aged diabetic females and males present distinct susceptibility to Alzheimer disease-like pathology. Mol Neurobiol 54(8):6471–6489
Carcaillon L, Brailly-Tabard S, Ancelin ML, Rouaud O, Dartigues JF, Guiochon-Mantel A, Scarabin PY (2014) High plasma estradiol interacts with diabetes on risk of dementia in older postmenopausal women. Neurology 82(6):504–511
Cardoso SM, Correia SC, Carvalho C, Moreira PI (2017) Mitochondria in Alzheimer’s disease and diabetes-associated neurodegeneration: license to heal! Handb Exp Pharmacol 240:281–308
Caruso D, Barron AM, Brown MA, Abbiati F, Carrero P, Pike CJ, Garcia-Segura LM, Melcangi RC (2013) Age-related changes in neuroactive steroid levels in 3xTg-AD mice. Neurobiol Aging 34:1080–1089
Casanova-Molla J, Morales M, Garrabou G, Sola-Valls N, Soriano A, Calvo M, Grau JM, Valls-Sole J (2012) Mitochondrial loss indicates early axonal damage in small fiber neuropathies. J Peripher Nerv Syst 17(2):147–157
Cashman CR, Hoke A (2015) Mechanisms of distal axonal degeneration in peripheral neuropathies. Neurosci Lett 596:33–50
Cermenati G, Giatti S, Cavaletti G, Bianchi R, Maschi O, Pesaresi M, Abbiati F, Volonterio A, Saez E, Caruso D, Melcangi RC, Mitro N (2010) Activation of the liver X receptor increases neuroactive steroid levels and protects from diabetes-induced peripheral neuropathy. J Neurosci 30(36):11896–11901
Cermenati G, Abbiati F, Cermenati S, Brioschi E, Volonterio A, Cavaletti G, Saez E, De Fabiani E, Crestani M, Garcia-Segura LM, Melcangi RC, Caruso D, Mitro N (2012) Diabetes-induced myelin abnormalities are associated with an altered lipid pattern: protective effects of LXR activation. J Lipid Res 53(2):300–310
Cermenati G, Giatti S, Audano M, Pesaresi M, Spezzano R, Caruso D, Mitro N, Melcangi RC (2017) Diabetes alters myelin lipid profile in rat cerebral cortex: protective effects of dihydroprogesterone. J Steroid Biochem Mol Biol 168:60–70
Chandel A, Dhindsa S, Topiwala S, Chaudhuri A, Dandona P (2008) Testosterone concentration in young patients with diabetes. Diabetes Care 31(10):2013–2017
Chen X, Levine JD (2001) Hyper-responsivity in a subset of C-fiber nociceptors in a model of painful diabetic neuropathy in the rat. Neuroscience 102(1):185–192
Chen X, Levine JD (2003) Altered temporal pattern of mechanically evoked C-fiber activity in a model of diabetic neuropathy in the rat. Neuroscience 121(4):1007–1015
Chen SR, Pan HL (2002) Hypersensitivity of spinothalamic tract neurons associated with diabetic neuropathic pain in rats. J Neurophysiol 87(6):2726–2733
Chowdhury SK, Zherebitskaya E, Smith DR, Akude E, Chattopadhyay S, Jolivalt CG, Calcutt NA, Fernyhough P (2010) Mitochondrial respiratory chain dysfunction in dorsal root ganglia of streptozotocin-induced diabetic rats and its correction by insulin treatment. Diabetes 59(4):1082–1091
Cummins CL, Mangelsdorf DJ (2006) Liver X receptors and cholesterol homoeostasis: spotlight on the adrenal gland. Biochem Soc Trans 34(Pt 6):1110–1113
Edwards JL, Quattrini A, Lentz SI, Figueroa-Romero C, Cerri F, Backus C, Hong Y, Feldman EL (2010) Diabetes regulates mitochondrial biogenesis and fission in mouse neurons. Diabetologia 53(1):160–169
Escames G, Diaz-Casado ME, Doerrier C, Luna-Sanchez M, Lopez LC, Acuna-Castroviejo D (2013) Early gender differences in the redox status of the brain mitochondria with age: effects of melatonin therapy. Horm Mol Biol Clin Investig 16(2):91–100
Espeland MA, Brinton RD, Hugenschmidt C, Manson JE, Craft S, Yaffe K, Weitlauf J, Vaughan L, Johnson KC, Padula CB, Jackson RD, Resnick SM, Group WS (2015a) Impact of type 2 diabetes and postmenopausal hormone therapy on incidence of cognitive impairment in older women. Diabetes Care 38(12):2316–2324
Espeland MA, Brinton RD, Manson JE, Yaffe K, Hugenschmidt C, Vaughan L, Craft S, Edwards BJ, Casanova R, Masaki K, Resnick SM, Group W-MS (2015b) Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes. Neurology 85(13):1131–1138
Farace E, Alves WM (2000) Do women fare worse: a metaanalysis of gender differences in traumatic brain injury outcome. J Neurosurg 93(4):539–545
Fernyhough P (2015) Mitochondrial dysfunction in diabetic neuropathy: a series of unfortunate metabolic events. Curr Diabetes Rep 15(11):89
Fernyhough P, Roy Chowdhury SK, Schmidt RE (2010) Mitochondrial stress and the pathogenesis of diabetic neuropathy. Expert Rev Endocrinol Metab 5(1):39–49
Fratiglioni L, Viitanen M, von Strauss E, Tontodonati V, Herlitz A, Winblad B (1997) Very old women at highest risk of dementia and Alzheimer’s disease: incidence data from the Kungsholmen Project. Stockholm Neurology 48(1):132–138
Gaignard P, Savouroux S, Liere P, Pianos A, Therond P, Schumacher M, Slama A, Guennoun R (2015) Effect of sex differences on brain mitochondrial function and its suppression by ovariectomy and in aged mice. Endocrinology 156(8):2893–2904
Gaspar JM, Baptista FI, Macedo MP, Ambrosio AF (2016) Inside the diabetic brain: role of different players involved in cognitive decline. ACS Chem Neurosci 7(2):131–142
Giatti S, Pesaresi M, Cavaletti G, Bianchi R, Carozzi V, Lombardi R, Maschi O, Lauria G, Garcia-Segura LM, Caruso D, Melcangi RC (2009) Neuroprotective effects of a ligand of translocator protein-18 kDa (Ro5-4864) in experimental diabetic neuropathy. Neuroscience 164:520–529
Giatti S, Garcia-Segura LM, Melcangi RC (2015) New steps forward in the neuroactive steroid field. J Steroid Biochem Mol Biol 153:127–134
Giatti S, Mastrangelo R, D’Antonio M, Pesaresi M, Romano S, Diviccaro S, Caruso D, Mitro N, Melcangi RC (2018) Neuroactive steroids and diabetic complications in the nervous system. Front Neuroendocrinol 48:58–69
Gispen WH, Biessels GJ (2000) Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 23(11):542–549
Guevara R, Gianotti M, Roca P, Oliver J (2011) Age and sex-related changes in rat brain mitochondrial function. Cell Physiol Biochem 27(3–4):201–206
Handa RJ, Pak TR, Kudwa AE, Lund TD, Hinds L (2008) An alternate pathway for androgen regulation of brain function: activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5alpha-androstane-3beta,17beta-diol. Horm Behav 53(5):741–752
Hempel R, Onopa R, Convit A (2012) Type 2 diabetes affects hippocampus volume differentially in men and women. Diabetes Metab Res Rev 28(1):76–83
Hernandez-Fonseca JP, Rincon J, Pedreanez A, Viera N, Arcaya JL, Carrizo E, Mosquera J (2009) Structural and ultrastructural analysis of cerebral cortex, cerebellum, and hypothalamus from diabetic rats. Exp Diabetes Res 2009:329632
Hudkins KL, Pichaiwong W, Wietecha T, Kowalewska J, Banas MC, Spencer MW, Muhlfeld A, Koelling M, Pippin JW, Shankland SJ, Askari B, Rabaglia ME, Keller MP, Attie AD, Alpers CE (2010) BTBR Ob/Ob mutant mice model progressive diabetic nephropathy. J Am Soc Nephrol 21(9):1533–1542
Jacobson AM, Samson JA, Weinger K, Ryan CM (2002) Diabetes, the brain, and behavior: is there a biological mechanism underlying the association between diabetes and depression? Int Rev Neurobiol 51:455–479
Joseph EK, Levine JD (2003) Sexual dimorphism in the contribution of protein kinase C isoforms to nociception in the streptozotocin diabetic rat. Neuroscience 120(4):907–913
Kalocayova B, Mezesova L, Bartekova M, Vlkovicova J, Jendruchova V, Vrbjar N (2017) Properties of Na,K-ATPase in cerebellum of male and female rats: effects of acute and prolonged diabetes. Mol Cell Biochem 425(1–2):25–36
Kamal A, Biessels GJ, Gispen WH, Ramakers GM (2006) Synaptic transmission changes in the pyramidal cells of the hippocampus in streptozotocin-induced diabetes mellitus in rats. Brain Res 1073–1074:276–280
Kawashima R, Kojima H, Nakamura K, Arahata A, Fujita Y, Tokuyama Y, Saito T, Furudate S, Kurihara T, Yagishita S, Kitamura K, Tamai Y (2007) Alterations in mRNA expression of myelin proteins in the sciatic nerves and brains of streptozotocin-induced diabetic rats. Neurochem Res 32(6):1002–1010
Kaye W (2008) Neurobiology of anorexia and bulimia nervosa. Physiol Behav 94(1):121–135
Kiziltan ME, Benbir G (2008) Clinical and electrophysiological differences in male and female patients with diabetic foot. Diabetes Res Clin Pract 79(1):e17–e18
Kiziltan ME, Gunduz A, Kiziltan G, Akalin MA, Uzun N (2007) Peripheral neuropathy in patients with diabetic foot ulcers: clinical and nerve conduction study. J Neurol Sci 258(1–2):75–79
Kodl CT, Seaquist ER (2008) Cognitive dysfunction and diabetes mellitus. Endocr Rev 29(4):494–511
Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA (2003) Neurosteroid modulation of GABAA receptors. Prog Neurobiol 71(1):67–80
Lambert JJ, Cooper MA, Simmons RD, Weir CJ, Belelli D (2009) Neurosteroids: endogenous allosteric modulators of GABA(A) receptors. Psychoneuroendocrinology 34(Suppl 1):S48–S58
Lauria G, Lombardi R, Borgna M, Penza P, Bianchi R, Savino C, Canta A, Nicolini G, Marmiroli P, Cavaletti G (2005) Intraepidermal nerve fiber density in rat foot pad: neuropathologic-neurophysiologic correlation. J Peripher Nerv Syst 10(2):202–208
Leibowitz SF (1987) Hypothalamic neurotransmitters in relation to normal and disturbed eating patterns. Ann NY Acad Sci 499:137–143
Leonelli E, Bianchi R, Cavaletti G, Caruso D, Crippa D, Garcia-Segura LM, Lauria G, Magnaghi V, Roglio I, Melcangi RC (2007) Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis. Neuroscience 144(4):1293–1304
Liu RT, Chung MS, Wang PW, Chen CD, Lee JJ, Lee WC, Chancellor MB, Yang KD, Chuang YC (2013) The prevalence and predictors of androgen deficiency in Taiwanese men with type 2 diabetes. Urology 82(1):124–129
Liu Y, Li M, Zhang Z, Ye Y, Zhou J (2018) Role of microglia-neuron interactions in diabetic encephalopathy. Ageing Res Rev 42:28–39
Malcangio M, Tomlinson DR (1998) A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain 76(1–2):151–157
Marcus SM, Kerber KB, Rush AJ, Wisniewski SR, Nierenberg A, Balasubramani GK, Ritz L, Kornstein S, Young EA, Trivedi MH (2008) Sex differences in depression symptoms in treatment-seeking adults: confirmatory analyses from the Sequenced Treatment Alternatives to Relieve Depression study. Compr Psychiatry 49(3):238–246
Marx CE, Trost WT, Shampine LJ, Stevens RD, Hulette CM, Steffens DC, Ervin JF, Butterfield MI, Blazer DG, Massing MW, Lieberman JA (2006) The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer’s disease. Biol Psychiatry 60(12):1287–1294
Mehlig K, Skoog I, Waern M, Miao Jonasson J, Lapidus L, Bjorkelund C, Ostling S, Lissner L (2014) Physical activity, weight status, diabetes and dementia: a 34-year follow-up of the population study of women in Gothenburg. Neuroepidemiology 42(4):252–259
Melcangi RC, Garcia-Segura LM, Mensah-Nyagan AG (2008) Neuroactive steroids: state of the art and new perspectives. Cell Mol Life Sci 65(5):777–797
Melcangi RC, Giatti S, Calabrese D, Pesaresi M, Cermenati G, Mitro N, Viviani B, Garcia-Segura LM, Caruso D (2014) Levels and actions of progesterone and its metabolites in the nervous system during physiological and pathological conditions. Prog Neurobiol 113:56–69
Melcangi RC, Giatti S, Garcia-Segura LM (2016) Levels and actions of neuroactive steroids in the nervous system under physiological and pathological conditions: Sex-specific features. Neurosci Biobehav Rev 67:25–40
Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10(1):23–36
Mitro N, Cermenati G, Giatti S, Abbiati F, Pesaresi M, Calabrese D, Garcia-Segura LM, Caruso D, Melcangi RC (2012) LXR and TSPO as new therapeutic targets to increase the levels of neuroactive steroids in the central nervous system of diabetic animals. Neurochem Int 60(6):616–621
Mitro N, Cermenati G, Brioschi E, Abbiati F, Audano M, Giatti S, Crestani M, De Fabiani E, Azcoitia I, Garcia-Segura LM, Caruso D, Melcangi RC (2014) Neuroactive steroid treatment modulates myelin lipid profile in diabetic peripheral neuropathy. J Steroid Biochem Mol Biol 143:115–121
Moran C, Phan TG, Chen J, Blizzard L, Beare R, Venn A, Munch G, Wood AG, Forbes J, Greenaway TM, Pearson S, Srikanth V (2013) Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care 36(12):4036–4042
Niemeier JP, Marwitz JH, Lesher K, Walker WC, Bushnik T (2007) Gender differences in executive functions following traumatic brain injury. Neuropsychol Rehabil 17(3):293–313
O’Brien PD, Hur J, Robell NJ, Hayes JM, Sakowski SA, Feldman EL (2016) Gender-specific differences in diabetic neuropathy in BTBR ob/ob mice. J Diabetes Complicat 30(1):30–37
Pesaresi M, Giatti S, Calabrese D, Maschi O, Caruso D, Melcangi RC (2010a) Dihydroprogesterone increases the gene expression of myelin basic protein in spinal cord of diabetic rats. J Mol Neurosci 42(2):135–139
Pesaresi M, Maschi O, Giatti S, Garcia-Segura LM, Caruso D, Melcangi RC (2010b) Sex differences in neuroactive steroid levels in the nervous system of diabetic and non-diabetic rats. Horm Behav 57(1):46–55
Pesaresi M, Giatti S, Cavaletti G, Abbiati F, Calabrese D, Bianchi R, Caruso D, Garcia-Segura LM, Melcangi RC (2011a) Sex differences in the manifestation of peripheral diabetic neuropathy in gonadectomized rats: a correlation with the levels of neuroactive steroids in the sciatic nerve. Exp Neurol 228(2):215–221
Pesaresi M, Giatti S, Cavaletti G, Abbiati F, Calabrese D, Lombardi R, Bianchi R, Lauria G, Caruso D, Garcia-Segura LM, Melcangi RC (2011b) Sex-dimorphic effects of dehydroepiandrosterone in diabetic neuropathy. Neuroscience 199:401–409
Pesaresi M, Giatti S, Spezzano R, Romano S, Diviccaro S, Borsello T, Mitro N, Caruso D, Garcia-Segura LM, Melcangi RC (2018) Axonal transport in a peripheral diabetic neuropathy model: sex-dimorphic features. Biol Sex Differ 9(1):6
Policardo L, Seghieri G, Francesconi P, Anichini R, Franconi F, Seghieri C, Del Prato S (2015) Gender difference in diabetes-associated risk of first-ever and recurrent ischemic stroke. J Diabetes Complicat 29(5):713–717
Rani V, Deshmukh R, Jaswal P, Kumar P, Bariwal J (2016) Alzheimer’s disease: is this a brain specific diabetic condition? Physiol Behav 164(Pt A):259–267
Riederer P, Korczyn AD, Ali SS, Bajenaru O, Choi MS, Chopp M, Dermanovic-Dobrota V, Grunblatt E, Jellinger KA, Kamal MA, Kamal W, Leszek J, Sheldrick-Michel TM, Mushtaq G, Meglic B, Natovich R, Pirtosek Z, Rakusa M, Salkovic-Petrisic M, Schmidt R, Schmitt A, Sridhar GR, Vecsei L, Wojszel ZB, Yaman H, Zhang ZG, Cukierman-Yaffe T (2017) The diabetic brain and cognition. J Neural Transm (Vienna) 124(11):1431–1454
Roglio I, Bianchi R, Giatti S, Cavaletti G, Caruso D, Scurati S, Crippa D, Garcia-Segura LM, Camozzi F, Lauria G, Melcangi RC (2007) Testosterone derivatives are neuroprotective agents in experimental diabetic neuropathy. Cell Mol Life Sci 64(9):1158–1168
Romano S, Mitro N, Diviccaro S, Spezzano R, Audano M, Garcia-Segura LM, Caruso D, Melcangi RC (2017) Short-term effects of diabetes on neurosteroidogenesis in the rat hippocampus. J Steroid Biochem Mol Biol 167:135–143
Romano S, Mitro N, Giatti S, Diviccaro S, Pesaresi M, Spezzano R, Audano M, Garcia-Segura LM, Caruso D, Melcangi RC (2018) Diabetes induces mitochondrial dysfunction and alters cholesterol homeostasis and neurosteroidogenesis in the rat cerebral cortex. J Steroid Biochem Mol Biol 178:108–116
Roy Chowdhury SK, Smith DR, Saleh A, Schapansky J, Marquez A, Gomes S, Akude E, Morrow D, Calcutt NA, Fernyhough P (2012) Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes. Brain 135(Pt 6):1751–1766
Sadeghi A, Hami J, Razavi S, Esfandiary E, Hejazi Z (2016) The effect of diabetes mellitus on apoptosis in hippocampus: cellular and molecular aspects. Int J Prev Med 7:57
Sakata A, Mogi M, Iwanami J, Tsukuda K, Min LJ, Jing F, Iwai M, Ito M, Horiuchi M (2010) Female exhibited severe cognitive impairment in type 2 diabetes mellitus mice. Life Sci 86(17–18):638–645
Sakata A, Mogi M, Iwanami J, Tsukuda K, Min LJ, Jing F, Ohshima K, Ito M, Horiuchi M (2011) Female type 2 diabetes mellitus mice exhibit severe ischemic brain damage. J Am Soc Hypertens 5(1):7–11
Schoenle EJ, Schoenle D, Molinari L, Largo RH (2002) Impaired intellectual development in children with type I diabetes: association with HbA(1c), age at diagnosis and sex. Diabetologia 45(1):108–114
Simonds VM, Whiffen VE (2003) Are gender differences in depression explained by gender differences in co-morbid anxiety? J Affect Disord 77(3):197–202
Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (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(1):63–80
Sugimoto K, Murakawa Y, Sima AA (2000) Diabetic neuropathy–a continuing enigma. Diabetes Metab Res Rev 16(6):408–433
Takeda S, Sato N, Rakugi H, Morishita R (2011) Molecular mechanisms linking diabetes mellitus and Alzheimer disease: beta-amyloid peptide, insulin signaling, and neuronal function. Mol Biosyst 7(6):1822–1827
Tanaka Y, Niwa S, Dong M, Farkhondeh A, Wang L, Zhou R, Hirokawa N (2016) The molecular motor KIF1A transports the trka neurotrophin receptor and is essential for sensory neuron survival and function. Neuron 90(6):1215–1229
Tomiyama M, Furusawa K, Kamijo M, Kimura T, Matsunaga M, Baba M (2005) Upregulation of mRNAs coding for AMPA and NMDA receptor subunits and metabotropic glutamate receptors in the dorsal horn of the spinal cord in a rat model of diabetes mellitus. Brain Res Mol Brain Res 136(1–2):275–281
Toth C, Schmidt AM, Tuor UI, Francis G, Foniok T, Brussee V, Kaur J, Yan SF, Martinez JA, Barber PA, Buchan A, Zochodne DW (2006) Diabetes, leukoencephalopathy and rage. Neurobiol Dis 23(2):445–461
Tsutsui K (2012) Neurosteroid biosynthesis and action during cerebellar development. Cerebellum 11(2):414–415
van Dam EW, Dekker JM, Lentjes EG, Romijn FP, Smulders YM, Post WJ, Romijn JA, Krans HM (2003) Steroids in adult men with type 1 diabetes: a tendency to hypogonadism. Diabetes Care 26(6):1812–1818
Vannucci SJ, Willing LB, Goto S, Alkayed NJ, Brucklacher RM, Wood TL, Towfighi J, Hurn PD, Simpson IA (2001) Experimental stroke in the female diabetic, db/db, mouse. J Cereb Blood Flow Metab 21(1):52–60
Veiga S, Leonelli E, Beelke M, Garcia-Segura LM, Melcangi RC (2006) Neuroactive steroids prevent peripheral myelin alterations induced by diabetes. Neurosci Lett 402(1–2):150–153
Vincent AM, Edwards JL, McLean LL, Hong Y, Cerri F, Lopez I, Quattrini A, Feldman EL (2010) Mitochondrial biogenesis and fission in axons in cell culture and animal models of diabetic neuropathy. Acta Neuropathol 120(4):477–489
Vinik AI, Park TS, Stansberry KB, Pittenger GL (2000) Diabetic neuropathies. Diabetologia 43(8):957–973
Watkins LR, Maier SF (2003) Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2(12):973–985
Yagihashi S (1997) Pathogenetic mechanisms of diabetic neuropathy: lessons from animal models. J Peripher Nerv Syst 2(2):113–132
Yorek MA, Coppey LJ, Gellett JS, Davidson EP, Bing X, Lund DD, Dillon JS (2002) Effect of treatment of diabetic rats with dehydroepiandrosterone on vascular and neural function. Am J Physiol Endocrinol Metab 283(5):E1067–E1075
Zhou Y, Luo Y, Dai J (2013) Axonal and dendritic changes are associated with diabetic encephalopathy in rats: an important risk factor for Alzheimer’s disease. J Alzheimers Dis 34(4):937–947
Zochodne DW (2007) Diabetes mellitus and the peripheral nervous system: manifestations and mechanisms. Muscle Nerve 36(2):144–166
Zychowska M, Rojewska E, Przewlocka B, Mika J (2013) Mechanisms and pharmacology of diabetic neuropathy—Experimental and clinical studies. Pharmacol Rep 65(6):1601–1610
Acknowledgements
We acknowledge support from MIUR-Progetto Eccellenza, Fondazione Cariplo to R.C.M. (Grant Number 2012-0547) and from Università degli Studi di Milano to S.G. (intramural Grant line-B).
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Giatti, S., Diviccaro, S. & Melcangi, R.C. Neuroactive Steroids and Sex-Dimorphic Nervous Damage Induced by Diabetes Mellitus. Cell Mol Neurobiol 39, 493–502 (2019). https://doi.org/10.1007/s10571-018-0613-6
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DOI: https://doi.org/10.1007/s10571-018-0613-6