vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ17.303vavilov-1233Research ArticleТЕСТ-СИСТЕМЫ И БИОИСПЫТАНИЯTEST SYSTEMS AND BIOTESTSПоловые различия молекулярных механизмов чувствительности к инсулину у молодых и взрослых мышей C57BL/6JSex differences of molecular mechanisms of insulin sensitivity in young and adult C57BL/6J miceЯковлеваТ. В.YakovlevaT. V.

Новосибирск.

Novosibirsk.

jakov@bionet.nsc.ruКазанцеваА. Ю.KazantsevaA. Yu.

Новосибирск.

Novosibirsk.

МакароваЕ. Н. MakarovaE. N.

Новосибирск.

Novosibirsk.

БажанН. М.BazhanN. M.

Новосибирск.

Novosibirsk.

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук.РоссияInstitute of Cytology and Genetics SB RAS.Russian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университет.РоссияInstitute of Cytology and Genetics SB RAS; Novosibirsk State University.Russian Federation201723122017217833840Copyright © Яковлева Т.В., Казанцева А.Ю., Макарова Е.Н., Бажан Н.М., 20172017Яковлева Т.В., Казанцева А.Ю., Макарова Е.Н., Бажан Н.М.Yakovleva T.V., Kazantseva A.Y.,  Makarova E.N., Bazhan N.M.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/1233

В патогенезе сахарного диабета 2-го типа важную роль играет снижение чувствительности к инсулину. Существуют половые различия в развитии метаболических нарушений: самцы мышей по сравнению с самками более склонны к развитию с возрастом гиперинсулинемии и к снижению толерантности к глюкозе при содержании на высококалорийной диете. Целью данной работы было исследовать экспрессию генов трансдукции сигнала инсулина у мышей разного пола и возраста. Исследования проводили на мышах линии C57BL/6J. Оценку экспрессии генов трансдукции сигнала инсулина в печени, мышцах и в жировой ткани выполняли методом ПЦР в реальном времени. Показано, что независимо от возраста чувствительность к инсулину у самок выше, чем у самцов, поскольку уровень глюкозы в плазме крови у самок и самцов не различается, тогда как уровень инсулина у самок ниже, чем у самцов. С возрастом у самок повышается толерантность к глюкозе, и в возрасте 30 недель толерантность к глюкозе у самок выше, чем у самцов. Показано, что пол и возраст влияют на уровень экспрессии генов трансдукции сигнала инсулина. В возрасте 10 недель существуют половые различия по уровню мРНК Pik3cd в печени, мРНК Irs1 в мышцах, мРНК Irs1 и Slc2a4 в жировой ткани, в возрасте 30 недель – по уровню мРНК Irs2 и Pik3cd в печени, мРНК Pik3cd и Slc2a4 в мышцах, мРНК Insr и Pik3cd в жировой ткани. В возрасте 10 недель во всех тканях экспрессия генов выше у самок, чем у самцов. В возрасте 30 недель у самок экспрессия генов в печени выше, а в мышцах и жировой ткани ниже, чем у самцов. С возрастом у самцов снижается уровень мРНК Insr в печени и мышцах и мРНК Pik3cd в жировой ткани, повышается уровень мРНК Pik3cd в мышцах. У самок с возрастом снижается уровень мРНК Irs1 в мышцах и мРНК Pik3cd и Slc2a4 в жировой ткани. Таким образом, молекулярной основой половых различий и возрастных изменений чувствительности к инсулину может быть изменение экспрессии генов трансдукции сигнала инсулина в тканях-мишенях.

Reduced insulin sensitivity plays an important role in the pathogenesis of type II diabetes. There are sex differences in the development of metabolic disorders. The aim of this work was to investigate the insulin signal transduction gene expression in mice of different sex and age. Male and female C57BL/6J mice were used in our studies. Gene expression was assayed by RT-PCR. It was shown that insulin sensitivity in females was higher than in males regardless of age because the level of glucose in blood plasma of females does not differ from that in males, whereas female insulin levels were lower than male insulin levels. Female glucose tolerance increased with age, and glucose tolerance was higher in females than in males at the age of 30 weeks. It was shown that sex and age affect the expressions of insulin signal transduction genes. It was shown that there are sex differences in the levels of mRNA Pik3cd in the liver, in the levels of mRNA Irs1 in the muscle, in the levels of mRNA Irs1 and Slc2a4 in adipose tissue at the age of 10 weeks, and there are sex differences in the levels of mRNA Irs2 and Pik3cd in the liver, in the levels mRNA Pik3cd and Slc2a4 in the muscle, in the levels mRNA Insr and Pik3cd in adipose tissue at the age of 30 weeks. In young animals, the expression of the genes was higher in females than in males in all tissues. In adult animals, the expression of the genes in the liver was higher in females than in males, the expression of the genes in muscle and adipose tissues were lower in females than in males. In males, the levels of mRNA Insr in the liver and muscles and mRNA Pik3cd in adipose tissue decreased with age, and the level of mRNA Pik3cd in muscles  increased with age. In females, the levels of mRNA Irs1 in muscle and mRNA Pik3cd and Slc2a4 in adipose tissue decreased with age. Thus the molecular basis of sex differences and age-related changes in insulin sensitivity may be a change in expressions of insulin signal transduction genes in the target tissues.

половые различиятолерантность к глюкозечувствительность к инсулинумРНКInsrIrs1/2Pik3cdSlc2a2/4real- time ПЦРмыши линии C57BL/6Jsex differencesglucose toleranceinsulin sensitivitymRNAInsrIrs1/2Pik3cdSlc2a2/4real-time PCRmouse C57BL/6JReferencesAkoum S.E., Lamontagne V., Cloutier I., Tanguay J.F. Nature of fatty acids in high fat diets differentially delineates obesity-linked metabolic syndrome components in male and female C57BL/6J mice. Diabetol. Metab. Syndr. 2011;3:34. DOI 10.1186/1758-5996-3-34.Akoum S.E., Lamontagne V., Cloutier I., Tanguay J.F. Nature of fatty acids in high fat diets differentially delineates obesity-linked metabolic syndrome components in male and female C57BL/6J mice. Diabetol. Metab. Syndr. 2011;3:34. DOI 10.1186/1758-5996-3-34.Anisimov V.N., Popovich I.G., Zabezhinski M.A., Egormin P.A., Yurova M.N., Semenchenko A.V., Tyndyk M.L., Panchenko A.V., Trashkov A.P., Vasiliev A.G., Khaitsev N.V. Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin. Cell Cycle. 2015;14(1):46-55. DOI 10.4161/15384101.2014.973308.Anisimov V.N., Popovich I.G., Zabezhinski M.A., Egormin P.A., Yurova M.N., Semenchenko A.V., Tyndyk M.L., Panchenko A.V., Trashkov A.P., Vasiliev A.G., Khaitsev N.V. Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin. Cell Cycle. 2015;14(1):46-55. DOI 10.4161/15384101.2014.973308.Barzilai N., Huffman D.M., Muzumdar R.H., Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012;61(6):1315-1322. DOI 10.2337/db11-1300.Barzilai N., Huffman D.M., Muzumdar R.H., Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012;61(6):1315-1322. DOI 10.2337/db11-1300.Copps K.D., White M.F. Regulation of insulin sensitivity by serine/ threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia. 2012;55(10):2565-2582. DOI 10.1007/ s00125-012-2644-8.Copps K.D., White M.F. Regulation of insulin sensitivity by serine/ threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia. 2012;55(10):2565-2582. DOI 10.1007/ s00125-012-2644-8.Dakin R.S., Walker B.R., Seckl J.R., Hadoke P.W., Drake A.J. Estrogens protect male mice from obesity complications and influence glucocorticoid metabolism. Int. J. Obes. (Lond). 2015;39(10):1539-1547. DOI 10.1038/ijo.2015.102.Dakin R.S., Walker B.R., Seckl J.R., Hadoke P.W., Drake A.J. Estrogens protect male mice from obesity complications and influence glucocorticoid metabolism. Int. J. Obes. (Lond). 2015;39(10):1539-1547. DOI 10.1038/ijo.2015.102.Ganz M., Csak T., Szabo G. High fat diet feeding results in gender specific steatohepatitis and inflammasome activation. World J. Gastroenterol. 2014;20(26):8525-8534. DOI 10.3748/wjg.v20.i26.8525.Ganz M., Csak T., Szabo G. High fat diet feeding results in gender specific steatohepatitis and inflammasome activation. World J. Gastroenterol. 2014;20(26):8525-8534. DOI 10.3748/wjg.v20.i26.8525.Grove K.L., Fried S.K., Greenberg A.S., Xiao X.Q., Clegg D.J. A microarray analysis of sexual dimorphism of adipose tissues in high-fat-diet-induced obese mice. Int. J. Obes. (Lond). 2010;34(6):989-1000. DOI 10.1038/ijo.2010.12.Grove K.L., Fried S.K., Greenberg A.S., Xiao X.Q., Clegg D.J. A microarray analysis of sexual dimorphism of adipose tissues in high-fat-diet-induced obese mice. Int. J. Obes. (Lond). 2010;34(6):989-1000. DOI 10.1038/ijo.2010.12.Hinder L.M., O'Brien P.D., Hayes J.M., Backus C., Solway A.P., Sims-Robinson C., Feldman E.L. Dietary reversal of neuropathy in a murine model of prediabetes and the metabolic syndrome. Dis. Model. Mech. 2017;10:717-725. DOI 10.1242/dmm.028530.Hinder L.M., O'Brien P.D., Hayes J.M., Backus C., Solway A.P., Sims-Robinson C., Feldman E.L. Dietary reversal of neuropathy in a murine model of prediabetes and the metabolic syndrome. Dis. Model. Mech. 2017;10:717-725. DOI 10.1242/dmm.028530.Macotela Y., Boucher J., Tran T.T., Kahn C.R. Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes. 2009;58(4):803-812. DOI 10.2337/db08-1054.Macotela Y., Boucher J., Tran T.T., Kahn C.R. Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes. 2009;58(4):803-812. DOI 10.2337/db08-1054.Markofski M.M., Dickinson J.M., Drummond M.J., Fry C.S., Fujita S., Gundermann D.M., Glynn E.L., Jennings K., Paddon-Jones D., Rei-dy P.T., Sheffield-Moore M., Timmerman K.L., Rasmussen B.B., Volpi E. Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women. Exp. Gerontol. 2015;65:1-7. DOI 10.1016/j.exger.2015.02.015.Markofski M.M., Dickinson J.M., Drummond M.J., Fry C.S., Fujita S., Gundermann D.M., Glynn E.L., Jennings K., Paddon-Jones D., Rei-dy P.T., Sheffield-Moore M., Timmerman K.L., Rasmussen B.B., Volpi E. Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women. Exp. Gerontol. 2015;65:1-7. DOI 10.1016/j.exger.2015.02.015.Oh Y.S., Lee T.S., Cheon G.J., Jang I.S., Jun H.S., Park S.C. Modulation of insulin sensitivity and caveolin-1 expression by orchidectomy in a nonobese type 2 diabetes animal model. Mol. Med. 2011;17(1-2): 4-11. DOI 10.2119/molmed.2009.00105.Oh Y.S., Lee T.S., Cheon G.J., Jang I.S., Jun H.S., Park S.C. Modulation of insulin sensitivity and caveolin-1 expression by orchidectomy in a nonobese type 2 diabetes animal model. Mol. Med. 2011;17(1-2): 4-11. DOI 10.2119/molmed.2009.00105.Pettersson U.S., Walden T.B., Carlsson P.O., Jansson L., Phillipson M. Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS ONE. 2012;7(9):e46057. DOI 10.1371/journal.pone. 0046057.Pettersson U.S., Walden T.B., Carlsson P.O., Jansson L., Phillipson M. Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS ONE. 2012;7(9):e46057. DOI 10.1371/journal.pone. 0046057.Radavelli-Bagatinil S., Blair A.R., Proietto J., Spritzer P.M., Andriko-poulos S. The New Zealand obese mouse model of obesity insulin resistance and poor breeding performance: evaluation of ovarian structure and function. J. Endocrinol. 2011;209:307-315. DOI 10.1530/JOE-11-0022.Radavelli-Bagatinil S., Blair A.R., Proietto J., Spritzer P.M., Andriko-poulos S. The New Zealand obese mouse model of obesity insulin resistance and poor breeding performance: evaluation of ovarian structure and function. J. Endocrinol. 2011;209:307-315. DOI 10.1530/JOE-11-0022.Sairam M.R., Wang M., Danilovich N., Javeshghani D., Maysinger D. Early obesity and age-related mimicry of metabolic syndrome in female mice with sex hormonal imbalances. Obesity (Silver Spring). 2006;14(7):1142-1154. DOI 10.1038/oby.2006.131.Sairam M.R., Wang M., Danilovich N., Javeshghani D., Maysinger D. Early obesity and age-related mimicry of metabolic syndrome in female mice with sex hormonal imbalances. Obesity (Silver Spring). 2006;14(7):1142-1154. DOI 10.1038/oby.2006.131.Sakamuri A., Pitla S., Putcha U.K., Jayapal S., Pothana S., Vada-kattu S.S., Konapalli N.R., Sakamuri S.S., Ibrahim A. Transient decrease in circulatory testosterone and homocysteine precedes the development of metabolic syndrome features in fructose-fed Sprague Dawley rats. J. Nutr. Metab. 2016; Article ID 7510840. DOI 10.1155/2016/7510840.Sakamuri A., Pitla S., Putcha U.K., Jayapal S., Pothana S., Vada-kattu S.S., Konapalli N.R., Sakamuri S.S., Ibrahim A. Transient decrease in circulatory testosterone and homocysteine precedes the development of metabolic syndrome features in fructose-fed Sprague Dawley rats. J. Nutr. Metab. 2016; Article ID 7510840. DOI 10.1155/2016/7510840.Senthil Kumar S.P., Shen M., Spicer E.G., Goudjo-Ako A.J., Stumph J.D., Zhang J., Shi H. Distinct metabolic effects following short-term exposure of different high-fat diets in male and female mice. Endocr. J. 2014;61(5):457-470.Senthil Kumar S.P., Shen M., Spicer E.G., Goudjo-Ako A.J., Stumph J.D., Zhang J., Shi H. Distinct metabolic effects following short-term exposure of different high-fat diets in male and female mice. Endocr. J. 2014;61(5):457-470.Shelley P., Martin-Gronert M.S., Rowlerson A., Poston L., Heales S.J., Hargreaves I.P., McConnell J.M., Ozanne S.E., Fernandez-Twinn D.S. Altered skeletal muscle insulin signaling and mitochondrial complex II-III linked activity in adult offspring of obese mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009;297(3):R675-R681. DOI 10.1152/ajpregu.00146.2009.Shelley P., Martin-Gronert M.S., Rowlerson A., Poston L., Heales S.J., Hargreaves I.P., McConnell J.M., Ozanne S.E., Fernandez-Twinn D.S. Altered skeletal muscle insulin signaling and mitochondrial complex II-III linked activity in adult offspring of obese mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009;297(3):R675-R681. DOI 10.1152/ajpregu.00146.2009.Spruss A., Henkel J., Kanuri G., Blank D., Puschel G.P., Bischoff S.C., Bergheim I. Female mice are more susceptible to nonalcoholic fatty liver disease: sex-specific regulation of the hepatic AMP-activated protein kinase-plasminogen activator inhibitor 1 cascade, but not the hepatic endotoxin response. Mol. Med. 2012;18(1):1346-1355. DOI 10.2119/molmed.2012.00223.Spruss A., Henkel J., Kanuri G., Blank D., Puschel G.P., Bischoff S.C., Bergheim I. Female mice are more susceptible to nonalcoholic fatty liver disease: sex-specific regulation of the hepatic AMP-activated protein kinase-plasminogen activator inhibitor 1 cascade, but not the hepatic endotoxin response. Mol. Med. 2012;18(1):1346-1355. DOI 10.2119/molmed.2012.00223.Tripathy D., Carlsson A.L., Lehto M., Isomaa B., Tuomi T., Groop L. Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state. Diabetologia. 2000;43(12): 1476-1483. DOI 10.1007/s0012500515508.Tripathy D., Carlsson A.L., Lehto M., Isomaa B., Tuomi T., Groop L. Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state. Diabetologia. 2000;43(12): 1476-1483. DOI 10.1007/s0012500515508.

The authors declare that there are no conflicts of interest present.