Аннотация
Регуляция метаболизма глюкозы инсулином осуществляется как за счет прямого взаимодействия гормона с его сигнальной системой и транспортерами глюкозы в клетках периферических тканей, так и опосредованно через центральную нервную систему (ЦНС). При сахарном диабете 2-го типа (СД2) наблюдается недостаток инсулина в мозге вследствие нарушенного рецептор-опосредуемого транспорта гормона через гематоэнцефалический барьер, что приводит к дисфункциям пищевого поведения, термогенеза, метаболизма углеводов и жиров. Использование интраназально вводимого инсулина (ИВИ) позволяет увеличить его содержание в мозге. ИВИ в комплексе с различными сенситизаторами обеспечивает восстановление толерантности к глюкозе за более короткий срок при меньших дозах инсулина. Комбинированная терапия в виде ИВИ (0.5 МЕ/крысу/сутки) крысам с СД2 и суммарных ганглиозидов мозга теленка (6 мг/кг/сутки) использовалась впервые. Через 4 недели у животных с СД2 после совместного интраназального введения инсулина и ганглиозидов восстанавливалась толерантность к глюкозе, в то время как по отдельности препараты были менее эффективны. С помощью Вестерн-блоттинга было показано, что увеличение чувствительности к инсулину в печени может быть обусловлено значительным снижением экспрессии негативного регулятора инсулинового сигналинга протеинфосфотирозинфосфатазы РТР1В и увеличением степени фосфорилирования ключевых эффекторных протеинкиназ Akt по Ser473, GSK3β по Ser9 и р38-МАРК по Thr180/Tyr182. При этом ингибирующее фосфорилирование GSK3β по Ser9 может осуществляться как вследствие активации Akt-киназы, так и р38-МАРК, и вклад последней, как мы полагаем, более значимый. Поскольку инсулин и ганглиозиды при интраназальном введении непосредственно воздействовали на структуры мозга, компетентные в отношении регуляции периферической инсулиновой чувствительности и углеводного обмена в печени, сделан вывод о превалировании в этом случае центрального механизма их действия.
Литература
Brøns C, Jensen CB, Storgaard H, Hiscock NJ, White A, Appel JS, Jacobsen S, Nilsson E, Larsen CM, Astrup A, Quistorff B, Vaag A (2009) Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men. J Physiol 587: 2387-2397. https://doi.org/10.1113/jphysiol.2009.169078
Small L, Brandon AE, Turner N, Cooney GJ (2018) Modeling insulin resistance in rodents by alterations in diet: what have high-fat and high-calorie diets revealed? Am J Physiol Endocrinol Metab 314: E251-E265. https://doi.org/10.1152/ajpendo.00337.2017
Duarte AI, Moreira PI, Oliveira CR (2012) Insulin in central nervous system: more than just a peripheral hormone. J Aging Res 2012:384017. https://doi.org/10.1155/2012/384017
Heni M, Kullmann S, Preissl H, Fritsche A, Häring HU (2015) Impaired insulin action in the human brain: causes and metabolic consequences. Nat Rev Endocrinol 11:701-711. https://doi.org/10.1038/nrendo.2015.173
Scherer T, Sakamoto K, Buettner C (2021) Brain insulin signalling in metabolic homeostasis and disease. Nat Rev Endocrinol 17:468-483. https://doi.org/10.1038/s41574-021-00498-x
Adam CL, Findlay PA, Aitken RP, Milne JS, Wallace JM (2012) In vivo changes in central and peripheral insulin sensitivity in a large animal model of obesity. Endocrinology 153:3147-3157. https://doi.org/10.1210/en.2012-1134
Chua LM, Lim ML, Chong PR, Hu ZP, Cheung NS, Wong BS (2012) Impaired neuronal insulin signaling precedes Aβ42 accumulation in female AβPPsw/PS1ΔE9 mice. J. Alzheimers Dis 29:783-791. https://doi.org/10.3233/JAD-2012-111880
Ruegsegger GN, Manjunatha S, Summer P, Gopala S, Zabeilski P, Dasari S, Vanderboom PM, Lanza IR, Klaus KA, Nair KS (2019) Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes. FASEB J 33:4458-4472. https://doi.org/10.1096/fj.201802043R
Shpakov AO, Derkach KV, Berstein LM (2015) Brain signaling systems in the Type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases. Future Sci OA 1:FSO25. https://doi.org/10.4155/fso.15.23
Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL (2002) Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 5:514-516. https://doi.org/10.1038/nn849
Derkach KV, Bogush IV, Berstein LM, Shpakov AO (2015) The influence of intranasal insulin on hypothalamic-pituitary axis in normal and diabetic rats. Horm Metab Res 47: 916-924. https://doi.org/10.1055/s-0035-1547236
Derkach KV, Bondareva VM, Perminova AA, Shpakov AO (2019) C-peptide and insulin during combined intranasal administration improve the metabolic parameters and activity of the adenylate cyclase system in the hypothalamus, myocardium, and epididymal fat of rats with type 2 diabetes. Cell and Tissue Biol 13:228-236. https://doi.org/10.1134/S1990519X1903003
Landreh M, Johansson J, Jörnvall H (2013) C-peptide: a molecule balancing insulin states in secretion and diabetes-associated depository conditions. Horm Metab Res 45:769-773. https://doi.org/10.1055/s-0033-1347208
Galic S, Hauser C, Kahn BB, Haj FG, Neel BG, Tonks NK, Tiganis T (200) Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP. Mol Cell Biol 25:819-829. https://doi.org/10.1128/MCB.25.2.819-829.2005
Zhang ZY, Dodd GT, Tiganis T (2015) Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling. Trends Pharmacol Sci 36:661-674. https://doi.org/10.1016/j.tips.2015.07.003
Xu W, Caracciolo B, Wang HX, Winblad B, Backman L, Qiu, C, Fratiglioni L (2010) Accelerated progression from mild cognitive impairment to dementia in people with diabetes. Diabetes 59:2928–2935. https://doi.org/10.2337/db10-0539
Asslih S, Damri O, Agam G (2021) Neuroinflammation as a Common Denominator of Complex Diseases (Cancer, Diabetes Type 2, and Neuropsychiatric Disorders). Int J Mol Sci 22:6138. https://doi.org/10.3390/ijms22116138
André C, Guzman-Quevedo O, Rey C, Rémus-Borel J, Clark S, Castellanos-Jankiewicz A, Ladeveze E, Leste-Lasserre T, Nadjar A, Abrous DN, Laye S, Cota D (2017) Inhibiting Microglia Expansion Prevents Diet-Induced Hypothalamic and Peripheral Inflammation. Diabetes 66:908-919. https://doi.org/10.2337/db16-0586
Avrova NF, Victorov IV, Tyurin VA, Zakharova IO, Sokolova TV, Andreeva NA, Stelmaschuk EV, Tyurina YY, Gonchar VS (1998) Inhibition of glutamate-induced intensification of free radical reactions by gangliosides: possible role in their protective effect in rat cerebellar granule cells and brain synaptosomes. Neurochem Res 23:945-952. https://doi.org/10.1023/a:1021076220411
Gorria M, Huc L, Sergent O, Rebillard A, Gaboriau F, Dimanche-Boitrel MT, Lagadic-Gossmann D (2006) Protective effect of monosialoganglioside GM1 against chemically induced apoptosis through targeting of mitochondrial function and iron transport. Biochem Pharmacol 72:1343-1353. https://doi.org/10.1016/j.bcp.2006.07.014
Zakharova IO, Sokolova TV, Vlasova YA, Furaev VV, Rychkova MP, Avrova NF (2014) GM1 ganglioside activates ERK1/2 and Akt downstream of Trk tyrosine kinase and protects PC12 cells against hydrogen peroxide toxicity. Neurochem Res 39:2262-2275. https://doi.org/10.1007/s11064-014-1428-6
Nikolaeva S, Bayunova L, Sokolova T, Vlasova Y, Bachteeva V, Avrova N, Parnova R (2015) GM1 and GD1a gangliosides modulate toxic and inflammatory effects of E. coli lipopolysaccharide by preventing TLR4 translocation into lipid rafts. Biochim Biophys Acta 1851:239-247. https://doi.org/10.1016/j.bbalip.2014.12.004
Sipione S, Monyror J, Galleguillos D, Steinberg N, Kadam V (2020) Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications. Front Neurosci 14:572965. https://doi.org/10.3389/fnins.2020.572965
Galleguillos D, Wang Q, Steinberg N, Shrivastava G, Dhami K, Rubinstein K, Giuliani F, Churchward M, Power C, Todd K, Sipione S (2020) Anti-inflammatory role of GM1 and modulatory effects of gangliosides on microglia functions. bioRxiv. https://doi.org/10.1101/2020.03.04.975862
Dholakia J, Prabhakar B, Shende P (2021) Strategies for the delivery of antidiabetic drugs via intranasal route. Int J Pharm 608:121068. https://doi.org/10.1016/j.ijpharm.2021.121068
Zakharova IO, Avrova NF (2001) The effect of cold stress on ganglioside fatty acid composition and ganglioside-bound sialic acid content of rat brain subcellular fractions. J Therm Biol 26:215-222. https://doi.org/10.1016/s0306-4565(00)00045-0
Vanier MT, Holm M, Ohman R, Svennerholm L (1971) Developmental profiles of gangliosides in human and rat brain. J Neurochem 18:581-592. https://doi.org/10.1111/j.1471-4159.1971.tb11988.x
Derkach KV, Bondareva VM, Chistyakova OV, Berstein LM, Shpakov AO (2015) The Effect of Long-Term Intranasal Serotonin Treatment on Metabolic Parameters and Hormonal Signaling in Rats with High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes. Int J Endocrinol 2015:245459. https://doi.org/10.1155/2015/245459
Ruud J, Steculorum S M, Brüning J (2017) Neuronal control of peripheral insulin sensitivity and glucose metabolism. Nat Commun 8:15259. https://doi.org/10.1038/ncomms15259
Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376-1382. https://doi.org/10.1038/nm1202-798
Scherer T, O'Hare J, Diggs-Andrews K, Schweiger M, Cheng B, Lindtner C, Zielinski E, Vempati P, Su K, Dighe S, Milsom T, Puchowicz M, Scheja L, Zechner R, Fisher SJ, Previs SF, Buettner C (2011) Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab 13:183-194. https://doi.org/10.1016/j.cmet.2011.01.008
Romanova IV, Derkach KV, Mikhrina AL, Sukhov IB, Mikhailova EV, Shpakov AO (2018) The Leptin, Dopamine and Serotonin Receptors in Hypothalamic POMC-Neurons of Normal and Obese Rodents. Neurochem Res 43:821-837. https://doi.org/10.1007/s11064-018-2485-z
Derkach K, Zakharova I, Zorina I, Bakhtyukov A, Romanova I, Bayunova L, Shpakov A (2019) The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect. PLoS One 14:e0213779. https://doi.org/10.1371/journal.pone.0213779
Zakharova IO, Bayunova LV, Zorina II, Sokolova TV, Shpakov AO, Avrova NF (2021) Insulin and α-Tocopherol Enhance the Protective Effect of Each Other on Brain Cortical Neurons under Oxidative Stress Conditions and in Rat Two-Vessel Forebrain Ischemia/Reperfusion Injury. Int J Mol Sci 220:11768. https://doi.org/10.3390/ijms222111768
Sukhov IB, Lebedeva MF, Zakharova IO, Derkach KV, Bayunova LV, Zorina II, Avrova NF, Shpakov AO (2019) Intranasal administration of insulin and gangliosides improves spatial memory in rats with neonatal type 2 Diabetes Mellitus. Bull Exp Biol Medicine 168:317-320. https://doi.org/10.1007/s10517-020-04699-8
Tettamanti G, Bonali F, Marchesini S, Zambotti V (1973) A new procedure for the extraction, purification and fractionation of brain gangliosides. Biochim Biophys Acta 296:160-170. https://doi.org/10.1016/0005-2760(73)90055-6
Yamamoto HA, Mohanan PV (2003) Ganglioside GT1b and melatonin inhibit brain mitochondrial DNA damage and seizures induced by kainic acid in mice. Brain Res 964: 100-106. https://doi.org/10.1016/s0006-8993(02)04083-0
Nishio M, Fukumoto S, Furukawa K, Ichimura A, Miyazaki H, Kusunoki S, Urano T, Furukawa K (2004) Overexpressed GM1 suppresses nerve growth factor (NGF) signals by modulating the intracellular localization of NGF receptors and membrane fluidity in PC12 cells. J Biol Chem 279:33368-33378. https://doi.org/10.1074/jbc.M403816200
Farooqui T, Franklin T, Pearl DK, Yates AJ (1997) Ganglioside GM1 enhances induction by nerve growth factor of a putative dimer of TrkA. J Neurochem 68:2348-2355. https://doi.org/10.1046/j.1471-4159.1997.68062348.x
Prasanna X, Jafurulla M, Sengupta D, Chattopadhyay A (2016) The ganglioside GM1 interacts with the serotonin 1A receptor via the sphingolipid binding domain. Biochim Biophys Acta 1858:2818-2826. https://doi.org/10.1016/j.bbamem.2016.08.009
Ji S, Tokizane K, Ohkawa Y, Ohmi Y, Banno R, Okajima T, Kiyama H, Furukawa K, Furukawa K (2016) Increased a-series gangliosides positively regulate leptin/Ob receptor-mediated signals in hypothalamus of GD3 synthase-deficient mice. Biochem Biophys Res Commun 479:453-460. https://doi.org/10.1016/j.bbrc.2016.09.077
Inamori KI, Inokuchi JI (2020) Roles of Gangliosides in Hypothalamic Control of Energy Balance: New Insights. Int J Mol Sci 21:5349. https://doi.org/10.3390/ijms21155349
Furian AF, Rattmann YD, Oliveira MS, Royes, LF, Marques MC, Santos AR, Mello CF (2009) Nitric oxide and potassium channels mediate GM1 ganglioside-induced vasorelaxation. Naunyn Schmiedebergs Arch Pharmacol 380:487-495. https://doi.org/10.1007/s00210-009-0469-x
Dieterle V, Herzer S, Gröne H-J, Jennemann R, Nordström V (2020) Ganglioside deficiency in hypothalamic POMC neurons promotes body weight gain. Int J Obes 44:510-524. https://doi.org/10.1038/s41366-019-0388-y
Eleftheriou P, Geronikaki A, Petrou A (2019) PTP1b Inhibition, A Promising Approach for the Treatment of Diabetes Type II. Curr Top Med Chem 19:246-263. https://doi.org/10.2174/1568026619666190201152153
Villamar-Cruz O, Loza-Mejía MA, Arias-Romero LE, Camacho-Arroyo I (2021) Recent advances in PTP1B signaling in metabolism and cancer. Biosci Rep 41:BSR20211994. https://doi.org/10.1042/BSR20211994
Cao L, Wang Z, Wan W (2018) Suppressor of Cytokine Signaling 3: Emerging Role Linking Central Insulin Resistance and Alzheimer's Disease. Front Neurosci 12:417. https://doi.org/10.3389/fnins.2018.00417
Linossi EM, Calleja DJ, Nicholson SE (2018) Understanding SOCS protein specificity. Growth Factors 36:104-117. https://doi.org/10.1080/08977194.2018.1518324
Banks AS, Li J, McKeag L, Hribal ML, Kashiwada M, Accili D, Rothman PB (2005) Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans. J Clin Invest 115:2462-2471. https://doi.org/10.1172/JCI23853
Saltiel AR (2021) Insulin signaling in health and disease. J Clin Invest 131:e142241. https://doi.org/10.1172/JCI142241
Petersen MC, Shulman G (2018) Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev 98:2133-2223. https://doi.org/10.1152/physrev.00063.2017
Sopasakis V, Liu P, Suzuki R, Kondo T, Winnay J, Tran TT, Asano T, Smyth G, Sajan M, Farese RV, Kahn C R, Zhao JJ (2010) Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. Cell Metab 11:220-230. https://doi.org/10.1016/j.cmet.2010.02.002
Morales-Ruiz M, Cejudo-Martín P, Fernández-Varo G, Tugues S, Ros J, Angeli P, Rivera F, Arroyo V, Rodés J, Sessa WC, Jiménez W (2003) Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats. Gastroenterology 125:522-531. https://doi.org/10.1016/s0016-5085(03)00909-0
Morales-Ruiz M, Santel A, Ribera J, Jiménez W (2017) The Role of Akt in Chronic Liver Disease and Liver Regeneration. Semin Liver Dis 37:11-16. https://doi.org/10.1055/s-0036-1597819
Bala A, Roy S, Das D, Marturi V, Mondal C, Patra S, Haldar PK, Samajdar G (2021) Role of Glycogen synthase kinase-3 in the etiology of Type 2 Diabetes Mellitus: A review. Curr Diabetes Rev. Jul 29. https://doi.org/10.2174/1573399817666210730094225. Epub ahead of print.
Tormos AM, Taléns-Visconti R, Nebreda A R, Sastre J (2013) p38 MAPK: a dual role in hepatocyte proliferation through reactive oxygen species. Free Radic Res 47:905-916. https://doi.org/10.3109/10715762.2013.821200
Thornton TM, Pedraza-Alva G, Deng B, Wood CD, Aronshtam A, Clements JL, Sabio G, Davis RJ, Matthews DE, Doble B, Rincon M (2008) Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science 320:667-670. https://doi.org/10.1126/science.1156037
Sakurai T, He G, Matsuzawa A, Yu GY, Maeda S, Hardiman G, Karin M (2008) Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14:156-165. https://doi.org/10.1016/j.ccr.2008.06.016
Rius-Pérez S, Tormos AM, Pérez S, Finamor I, Rada P, Valverde ÁM, Nebreda AR, Sastre J, Taléns-Visconti R (2019) p38α deficiency restrains liver regeneration after partial hepatectomy triggering oxidative stress and liver injury. Sci Rep 9:3775. https://doi.org/10.1038/s41598-019-39428-3
Revunov E, Johnström P, Arakawa R, Malmquist J, Jucaite A, Defay T, Takano A, Schou M (2020) First Radiolabeling of a Ganglioside with a Positron Emitting Radionuclide: In Vivo PET Demonstrates Low Exposure of Radiofluorinated GM1 in Non-human Primate Brain. ACS Chem Neurosci. 11:1245-1249. https://doi.org/10.1021/acschemneuro.0c00161