diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM12967diaendo-12967Research ArticleОригинальные исследованияOriginal StudiesВлияние терапии современными сахароснижающими препаратами на показатели костного обмена в условиях экспериментальной модели сахарного диабета и овариэктомииModern glucose-lowering treatment effect on bone remodeling in experimental diabetes mellitus and surgical menopausehttps://orcid.org/0000-0001-9836-5427ТимкинаН. В.ТimkinaN. V.

Тимкина Наталья Владимировна; Scopus Author ID: 57222553770

197341, Санкт-Петербург, ул. Аккуратова, д. 2

Natalya V. Timkina; Scopus Author ID: 57222553770

2 Akkuratova street, 197341 Saint Petersburg

n.timkina2014@yandex.ruhttps://orcid.org/0000-0003-4069-0678СеменоваН. Ю.SemenovaN. Yu.

Семенова Наталья Юрьевна - кандидат биологических наук.

Санкт-Петербург

Natalia Yu. Semenova - PhD in Biology.

Saint Petersburg

natyciel87@gmail.comhttps://orcid.org/0000-0003-3300-1280СиманенковаА. В.SimanenkovaA. V.

Симаненкова Анна Владимировна - кандидат медицинских наук.

Санкт-Петербург

Anna V. Simanenkova - MD, PhD.

Saint Petersburg

annasimanenkova@mail.ruhttps://orcid.org/0000-0001-7361-1927ЦинзерлингВ. А.ZinserlingV. A.

Цинзерлинг Всеволод Александрович - доктор медицинских наук, профессор.

Санкт-Петербург

Vsevolod A. Zinserling - MD, PhD, Professor.

Saint Petersburg

Tsinzerling_VA@almazovcentre.ruhttps://orcid.org/0000-0002-6951-7599ВласовТ. Д.VlasovT. D.

Власов Тимур Дмитриевич - доктор медицинских наук, профессор.

Санкт-Петербург

Timur D. Vlasov - MD, PhD, Professor.

Saint Petersburg

tdvlasov@mail.ruhttps://orcid.org/0000-0002-0673-8722БайрамовА. А.BairamovА. A.

Байрамов Алекбер Азизага оглы - доктор медицинских наук.

Санкт-Петербург

Alekber A. Bairamov - MD, PhD.

Saint Petersburg

Bayramov_AA@almazovcentre.ruhttps://orcid.org/0000-0001-8074-2917ХальзоваА. К.KhalzovaA. K.

Хальзова Александра Константиновна

Санкт-Петербург

Aleksandra K. Khalzova

Saint Petersburg

alexbadm200@yandex.ruhttps://orcid.org/0000-0002-0654-2711ШимшилашвилиА. А.ShimshilashviliA. A.

Шимшилашвили Анжелика Азоровна

Санкт-Петербург

Anzhelika A. Shimshilashvili

Saint Petersburg

angelahaha@mail.ruhttps://orcid.org/0000-0003-4929-1534ТимофееваВ. А.ТimofeevaV. A.

Тимофеева Валерия Александровна

Санкт-Петербург

Valeria A. Timofeeva

Saint Petersburg

timoshka.lera@gmail.comhttps://orcid.org/0000-0002-1547-0123КароноваТ. Л.KaronovaT. L.

Каронова Татьяна Леонидовна - доктор медицинских наук, профессор.

Санкт-Петербург

Tatiana L. Karonova - MD, PhD, Professor.

Saint Petersburg

karonova@mail.ruНациональный медицинский исследовательский центр им. В.А. Алмазова; Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. ПавловаРоссияAlmazov National Medical Research Centre; Pavlov First Saint-Petersburg State Medical UniversityRussian FederationНациональный медицинский исследовательский центр им. В.А. Алмазова; Российский институт гематологии и трансфузиологии Федерального медико-биологического агентства РоссииРоссияAlmazov National Medical Research Centre; Russian Scientific Research Institute of Hematology and TransfusiologyRussian FederationНациональный медицинский исследовательский центр им. В.А. АлмазоваРоссияAlmazov National Medical Research CentreRussian FederationПервый Санкт-Петербургский государственный медицинский университет им. акад. И.П. ПавловаРоссияPavlov First Saint-Petersburg State Medical UniversityRussian Federation202315052023262145156Copyright © Тимкина Н.В., Семенова Н.Ю., Симаненкова А.В., Цинзерлинг В.А., Власов Т.Д., Байрамов А.А., Хальзова А.К., Шимшилашвили А.А., Тимофеева В.А., Каронова Т.Л., 20232023Тимкина Н.В., Семенова Н.Ю., Симаненкова А.В., Цинзерлинг В.А., Власов Т.Д., Байрамов А.А., Хальзова А.К., Шимшилашвили А.А., Тимофеева В.А., Каронова Т.Л.Тimkina N.V., Semenova N.Y., Simanenkova A.V., Zinserling V.A., Vlasov T.D., Bairamov А.A., Khalzova A.K., Shimshilashvili A.A., Тimofeeva V.A., Karonova T.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/12967ОБОСНОВАНИЕ

ОБОСНОВАНИЕ. Сахарный диабет (СД) является независимым фактором риска низкотравматичных переломов. Сахароснижающие препараты могут оказывать как положительное, так и отрицательное влияние на костное ремоделирование.

ЦЕЛЬ

ЦЕЛЬ. Изучение параметров костного обмена в условиях экспериментальной модели (хирургическая менопауза в сочетании с СД) при применении современных сахароснижающих препаратов: агониста рецепторов глюкагоноподобного пептида 1 типа лираглутида (ЛИРА) и ингибитора натрий-глюкозного котранспортера 2 типа канаглифлозина (КАНА).

МАТЕРИАЛЫ И МЕТОДЫ

МАТЕРИАЛЫ И МЕТОДЫ. В начале эксперимента крысам-самкам стока Wistar производилась двусторонняя овариэктомия (ОЭ). Для моделирования СД вводился раствор никотинамида и стрептозотоцина, предварительно животные получали высокожировой корм. Были сформированы следующие группы: «ОЭ+CД» (самки после ОЭ с СД без терапии, n=4), «ОЭ+СД+КАНА» (самки после ОЭ с СД на терапии КАНА, n=4), «ОЭ+СД+ЛИРА» (самки с СД после ОЭ на терапии ЛИРА, n=5). Период лечения или наблюдения составил 8 нед. Перед эвтаназией производился забор крови из каудальной вены для определения показателей фосфорно-кальциевого обмена и маркеров костного ремоделирования (кальций общий, фосфор неорганический, фактор роста фибробластов-23, остеокальцин, склеростин, остеопротегерин (ОПГ), лиганд активатора рецептора ядерного фактора каппа-В (RANKL)). После эвтаназии проводилось гистоморфометрическое исследование костей.

РЕЗУЛЬТАТЫ

РЕЗУЛЬТАТЫ. Лечение как КАНА, так и ЛИРА значимо не повлияло на показатели фосфорно-кальциевого обмена и концентрацию склеростина и остеокальцина. Вместе с тем уровень ОПГ был наиболее высоким в группе «ОЭ+СД» (9,1 [7,81; 10,045] пмоль/л), различия были значимы как по сравнению с группой «ОЭ+СД+КАНА» (2,33 [1,84; 5,84] пмоль/л, p=0,003), так и по сравнению с группой «ОЭ+СД+ЛИРА» (1,7 [1; 2] пмоль/л, p=0,003). Различий в уровне ОПГ, а также в соотношении ОПГ/RANKL между животными, получающими терапию сахароснижающими препаратами, не было. При применении КАНА отмечено меньшее количество костных балок в зоне эпифиза бедра по сравнению с животными без лечения (р=0,042). При применении ЛИРА изменений гистоархитектоники костной ткани зафиксировано не было.

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. Показатели костного обмена не отличаются при применении КАНА и ЛИРА. Однако применение КАНА ассоциировано со снижением количества костных балок эпифизарной области бедренной кости.

BACKGROUND

BACKGROUND: Diabetes mellitus (DM) is an independent risk factor for low-traumatic fractures. On the other hand, hypoglycemic drugs can have both positive and negative effects on bone remodeling.

THE AIM

THE AIM: Тo investigate bone metabolism parameters during surgical menopause and experimental DM under the treatment with glucagon-like peptide receptor agonist type 1 (arGLP-1) liraglutide (LIRA) and sodium-glucose cotransporter type 2 inhibitor (iSGLT-2) canagliflozin (CANA).

MATERIALS AND METHODS

MATERIALS AND METHODS: Female Wistar rats have been subjected to bilateral ovariectomy at the beginning of the experiment. Diabetes mellitus (DM) was modelled using a high-fat diet and streptozotocin+nicotinamide. Four weeks after the following groups were formed: “OE+DM” (females after ovariectomy with DM and without any therapy, n=4) «OE+DM+CANA» (females after ovariectomy with DM under treatment with CANA, n=4), «OE+DM+LIRA» (females after ovariectomy with DM under treatment LIRA, n=5). The treatment or observation period were continuing for 8 weeks. Calcium, phosphorus and bone turnover markers (fibroblast growth factor-23 (FGF-23), osteocalcin, sclerostin, osteoprotegerin (OPG), nuclear factor-kappa-B receptor activator ligand (RANKL), were measured in the end of experiment. Bone histomorphometry was performed after euthanasia.

RESULTS

RESULTS: Treatment with both CANA and LIRA did not significantly affect the phosphorus-calcium metabolism, sclerostin and osteocalcin concentrations. At the same time, the level of OPG was the highest in «OE+DM ‘’ group (9.1 [7.81; 10.045] pmol/l). The differences were significant compared with «OE+DM+CANA’’ (2, 33 [1.84; 5.84] pmol/l, p = 0.003) and «OE+DM+LIRA» (1.7 [1; 2] pmol/l, p = 0.003) groups. There were no differences in OPG levels between animals treated with different drugs. Similarly, the OPG/RANKL ratio was similarly reduced with both types of treatment. In “OE+DM+CANA’’ group the bone trabeculae number of   the femur epiphysis (p=0.042) were decreased in comparison to «OE+DM» group. LIRA did not change the histoarchitectonic parameters.

CONCLUSION

CONCLUSION: Bone metabolism markers did not differ when using as canagliflozin as liraglutide. Besides, canagliflosin can lead to the activation of bone resorption, which is expressed in the femur epiphyseal trabeculae number decreasing.

сахарный диабетменопаузаостеопорозкостное ремоделированиеингибиторы натрий-глюкозного котранспортера 2 типаагонисты рецепторов глюкагоноподобного пептида 1 типаdiabetes mellitusmenopausеosteoporosisbone remodelingsodium-glucose transporter 2 inhibitorsglucagon-like peptide-1 receptor agonistsИсследование выполнено в рамках государственного задания № 122041900088-1 «Персонифицированный подход в выборе сахароснижающей терапии у больных СД 2 типа, основанный на нейропротективных и остеопротективных свойствах препаратов». Подана заявка на оформление патента «Способ экспериментального моделирования сахарного диабета 2 типа в сочетании с менопаузой у самок крыс стока Wistar», регистрационный № 2022133307ReferencesKanis JA. Assessment of osteoporosis at the primary health-care level. UK: World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, Technical Report; 2007.Kanis JA. Assessment of osteoporosis at the primary health-care level. 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The authors declare that there are no conflicts of interest present.