Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR, and p70S6K protein kinases in lymphocytes of diabetic patients
The expression of the main effector protein kinase Akt of the PI3K signaling pathway and the activities of mTOR
 and p70S6K protein kinases in lymphocytes of patients with diabetes mellitus are determined at the combination
 treatment with insulin and hypoglycemic drugs. It is shown...
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| Cite this: | Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR, and p70S6K protein kinases in lymphocytes of diabetic patients / L.K. Sokolova, V.M. Pushkarev, Yu.B. Belchina, V.V. Pushkarev, T.S. Vatseba, M.D. Tronko // Доповіді Національної академії наук України. — 2018. — № 8. — С. 105-109. — Бібліогр.: 14 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859989071464497152 |
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| author | Sokolova, L.K. Pushkarev, V.M. Belchina, Yu.B. Pushkarev, V.V. Vatseba, T.S. Tronko, M.D. |
| author_facet | Sokolova, L.K. Pushkarev, V.M. Belchina, Yu.B. Pushkarev, V.V. Vatseba, T.S. Tronko, M.D. |
| citation_txt | Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR, and p70S6K protein kinases in lymphocytes of diabetic patients / L.K. Sokolova, V.M. Pushkarev, Yu.B. Belchina, V.V. Pushkarev, T.S. Vatseba, M.D. Tronko // Доповіді Національної академії наук України. — 2018. — № 8. — С. 105-109. — Бібліогр.: 14 назв. — англ. |
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| description | The expression of the main effector protein kinase Akt of the PI3K signaling pathway and the activities of mTOR
and p70S6K protein kinases in lymphocytes of patients with diabetes mellitus are determined at the combination
treatment with insulin and hypoglycemic drugs. It is shown that the Akt expression is reduced in blood mononuclear
cells of patients with diabetes of the 2nd and, to a less extent, type 1. The activities of mTOR and p70S6K are
also reduced in lymphocytes of patients with type 2 diabetes. Possible mechanisms of inhibiting the expression and
activity of protein kinases are discussed.
Визначали експресію основної ефекторної протеїнкінази сигнального шляху PI3K Akt та активність
протеїнкіназ mTOR і p70S6K в лімфоцитах хворих на цукровий діабет при комбінованому лікуванні інсуліном і цукрознижувальними препаратами. Показано, що експресія Akt знижена в мононуклеарах крові
хворих на діабет 2-го і, меншою мірою, 1-го типу. Активність mTOR і p70S6K також знижена в лімфоцитах хворих на діабет 2-го типу. Обговорюються можливі механізми пригнічення експресії і активності
протеїнкіназ.
Определяли экспрессию основной эффекторной протеинкиназы сигнального пути PI3K Akt и активность протеинкиназ mTOR и p70S6K в лимфоцитах больных сахарным диабетом при комбинированном
лечении инсулином и сахароснижающими препаратами. Показано, что экспрессия Akt снижена в мононуклеарах крови больных диабетом 2-го и, в меньшей степени, 1-го типа. Активность mTOR и p70S6K
также снижена в лимфоцитах больных диабетом 2-го типа. Обсуждаются возможные механизмы подавления экспрессии и активности протеинкиназ.
|
| first_indexed | 2025-12-07T16:30:30Z |
| format | Article |
| fulltext |
105ISSN 10256415. Допов. Нац. акад. наук Укр. 2018. № 8
ОПОВІДІ
НАЦІОНАЛЬНОЇ
АКАДЕМІЇ НАУК
УКРАЇНИ
© L.K. Sokolova, V.M. Pushkarev, Yu.B. Belchina, V.V. Pushkarev, T.S. Vatseba, M.D. Tronko, 2018
Type 2 diabetes (T2D) is characterized by a phosphoinositide 3 kinase (PI3K)/Akt signaling
disorder, which leads to a decrease of the glucose uptake and the insulin resistance in peripheral
tissues [1]. mTOR is a serine/threonine protein kinase, which belongs to the PI3Krelated kinase
family and plays a key role in the cell growth regulation, as well as in lipid and glucose metabo
lism. Growth factors and insulin stimulate the mTORC1 complex through the PI3K signaling
pathway. Activated mTORC1 promotes the phosphorylation of ribosomal S6 kinase (p70S6K),
which is involved in fundamental cellular processes, including protein and lipid synthesis, cell
growth, and metabolism [2].
Type 2 diabetes mellitus (T2D) is a progressive disease with a steady decrease in the function
of pancreatic βcells, which ultimately determines the inevitability of insulin therapy. Insulin
therapy together with oral hypoglycemic agents is offered in the ADA guide for managing pa
tients with T2D [3].
We study effects of combined therapy of the firstline hypoglycemic drug metformin (MF)
with insulin and gliclazide (diabeton MR) upon the expression of main effector kinase Akt of
PI3K pathway and the activity of its downstream kinases mTOR and p70S6K.
МЕДИЦИНА
doi: https://doi.org/10.15407/dopovidi2018.08.105
UDC 616.379008.64002:577.2
L.K. Sokolova, V.M. Pushkarev, Yu.B. Belchina,
V.V. Pushkarev, T.S. Vatseba, M.D. Tronko
V.P. Komisarenko Institute of Endocrinology and Metabolism of the NAMS of Ukraine, Kiev
Email: pushkarev.vm@gmail.com
Effect of combined treatment with insulin,
metformin, and gliclazide on the expression
and activity of Akt, mTOR, and p70S6K protein
kinases in lymphocytes of diabetic patients
Presented by Corresponding Member of the NAS of Ukraine M.D. Tronko
The expression of the main effector protein kinase Akt of the PI3K signaling pathway and the activities of mTOR
and p70S6K protein kinases in lymphocytes of patients with diabetes mellitus are determined at the combination
treatment with insulin and hypoglycemic drugs. It is shown that the Akt expression is reduced in blood mononuclear
cells of patients with diabetes of the 2nd and, to a less extent, type 1. The activities of mTOR and p70S6K are
also reduced in lymphocytes of patients with type 2 diabetes. Possible mechanisms of inhibiting the expression and
activity of protein kinases are discussed.
Keywords: Akt, mTOR, p70S6K, diabetes mellitus, metformin, insulin, gliclazide.
106 ISSN 10256415. Dopov. Nac. akad. nauk Ukr. 2018. № 8
L.K. Sokolova, V.M. Pushkarev, Yu.B. Belchina, V.V. Pushkarev, T.S. Vatseba, M.D. Tronko
Materials and methods. The study was conducted in the diabetology department of the In
stitute. All patients signed the informed consent to conduct further diagnostic and research stu
dies with biomaterials. Immediately after collection, blood was centrifuged using Histopaque
1077 (Sigma, USA), the lymphocytes collected were washed and frozen at −80 °C until use.
The cells were lysed in an extraction buffer with inhibitors of proteases and phosphatases.
The protein concentration in the lysate was determined, using the Novagen (USA) BCA pro
tein assay kit.
Reagents. Polyclonal antibodies to Akt/PKB PH domain, phosphomTOR (Ser2448), phos
phop70 S6 Kinase 1/2 (Thr412/Thr397) were from Millipore Corp. (USA). Horseradish per
oxidase conjugated second antibodies were from the Sigma (USA). Complexes of proteins with
antibodies were visualized, using ECL reagent (Amersham Life Science, UK).
Preparation of cell lysates and Western blot analysis were performed as previously described
[4]. Total cell lysates were boiled in a sample buffer (100 mM TrisHCl, 4 % sodium dodecyl sul
fate, 0.2 % bromophenol blue, 20 % glycerol, 10 % dithiothreitol) and separated by SDSPAGE
12.5 % gels. ~30 µg of protein were applied per each lane. Proteins were transferred onto nitrocel
lulose membranes with 0.2 µm pores (Millipore Corp., USA) by semidry blotting. Membranes
were blocked with Trisbuffered saline (TBS)/0.1 % Tween 20 containing 5 % nonfat dry milk or
5 % BSA and incubated with primary antibodies, at 4 °C overnight. After washing three times
with TBS/0.1 % Tween 20, the blots were incubated with horseradish peroxidaseconjugated
speciesspecific secondary antibody for 1 h at ambient temperature and then again washed three
times. Complexes were visualized, using ECL reagents (Amersham, Life Science, UK). Developed
Xray film was scanned using GelPro 3.1 software and normalized by the protein amount of the
sample and βactin amount in each lane.
The results of the study are presented as M ± SD, n = 3. To compare the data groups, Student’s
ttest was used. Values of P � 0.05 were considered as significant.
Results and their discussion. The patients were divided into groups: the control group (1)
consisted of healthy individuals who did not have diabetes mellitus, representative by age, 2 —
patients with type 1 diabetes on insulin therapy, 3 — patients with type 2 diabetes on combination
therapy receiving original metformin and gliclazide, 4 — patients with T2D receiving metformin
as a hypoglycemic therapy and insulin, 5 — patients on combination therapy — original metform
in and insulin.
Expression of Akt is reduced in lymphocytes of patients with diabetes, both 1st (T1D) and
2nd (T2D) types. However, the amount of protein kinase in lymphocytes of patients with T1D
who received insulin is higher than in patients with T2D (Fig., a). In turn, in patients with T2D,
who received metformin and pharmasulin, the expression of Akt is slightly higher than in patients
taking original metformin with gliclazide and original metformin with insulin.
Decrease in the activation of Akt in patients with T2D is natural and associated with the
impaired insulin signal transduction from insulin receptor substrates (IRS1/2) to PI3K as a
result of the substrate inhibitory phosphorylation by various protein kinases, including mTOR
and p70S6K [1]. A decrease in the expression, however, probably reflects a deeper change in sig
naling mechanisms as a result of the prolonged pathological process. This can be evidenced by
the fact that samples 3 and 5 are taken from patients with 15 and 21 years average of the disease
duration, respectively, while sample 4 is from a patient with an 8year disease (see Fig., a, 3, 5).
107ISSN 10256415. Допов. Нац. акад. наук Укр. 2018. № 8
Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR...
20 % decrease in the Akt quantity in patients with T1D (see Fig., a, 2), apparently, can be ex
plained by the suppression of the insulin signaling due to a decrease in the hormone amount.
The mTOR activity is significantly reduced in patients with diabetes (see Fig., b) that may be
due to the inhibition of activity and, possibly, the expression of Akt that activates mTOR in
response to insulin. As in the case of Akt, the duration of the disease may affect the activity of
this protein kinase (see Fig., b, 4).
As was shown earlier, metformin activates AMPK in lymphocytes of patients with T2D [5],
and this may be the reason for an mTOR activity decrease, because AMPK inhibits mTOR through
phosphorylation and activation of mTOR inhibitor — TSC2 (tuberous sclerosis 2) and phos
phorylation of RAPTOR (Regulatoryassociated protein of mTOR), which causes its binding to
proteins 1433 [6].
Given a decrease in the mTOR activity, it can be assumed that not only the expression, but
also the activity of Akt in lymphocytes is suppressed, since mTORC2 activates Akt, by phos
phorylating it on Ser473 [7]. The activity of PDK1, which phosphorylates Akt at another acti
vating site Thr308, can also be reduced in diabetes by the interruption of the insulin signal trans
duction via IRS.
mTORC1 and mTORC2 have been implicated in integrating signals from growth factors,
energy status, oxygen, and amino acids with the rate of autophagy, and regulation of protein
synthesis. Growth factors and insulin activate both complexes through PI3K/PTEN/Akt signal
ing network. In addition, amino acids activate mTORC1 via small Gproteins such as Rag family
of GTPases and GTPbound Ras homolog enriched in brain (Rheb) on the lysosomal membrane
[8]. Because mTORC1 is a key nutrient sensor, integrating diverse extra and intracellular cues
to downstream signaling pathways in response to the nutrient availability, it is natural that this
signaling is dysregulated in diabetes [9].
mTORC1 plays additional roles in the metabolic regulation through the p70S6K1/2media
ted phosphorylation of the CAD enzyme complex to stimulate pyrimidine biosynthesis, ATF4
Effects of combined therapy of the firstline hypoglycemic drug metformin with insulin and gliclazide upon
the expression of main effector kinase of PI3K pathway — Akt, and activity of its downstream kinases mTOR
and p70S6K. 1 — control group; 2 — patients with type 1 diabetes on insulin therapy; 3 — patients with type 2
diabetes on combination therapy receiving original metformin and gliclazide; 4 — patients with T2D receiv ing
generic metformin and insulin; 5 — patients on combination therapy – original metformin and insulins. M ± SD,
n = 3. Akt: * — difference between control and other group significant; + — significant difference between group
2 and 3—5; ^ — significant difference between group 4 and 3, 5 (P < 0.05). mTOR: * — difference between con
trol and other group significant; + — significant difference between group 4 and 3, 5 (P < 0.05). S6K: * — dif
ference between control and group 3—5 significant (P < 0.05)
108 ISSN 10256415. Dopov. Nac. akad. nauk Ukr. 2018. № 8
L.K. Sokolova, V.M. Pushkarev, Yu.B. Belchina, V.V. Pushkarev, T.S. Vatseba, M.D. Tronko
dependent stimulation of the mitochondrial tetrahydrofolate cycle to enhance the purine bio
synthesis [10], and stimulation of lipid and sterol biosynthesis through the activation of sterol
regulatory binding element proteins [11]. p70S6K is an AGC kinase of the RSK family that is
required for the cell growth and G1 cell cycle progression. It is phosphorylated and activated by
mTOR in mitogenic pathways downstream of PI3K. p70S6K phosphorylates the S6 protein of
the 40S ribosomal subunit and is involved in the translational control of 5’ oligopyrimidine tract
mRNAs. Activity is controlled by multiple phosphorylation events located within the catalytic,
linker, and pseudosubstrate domains. Mouse knockout shows an increased insulin senstivity,
resulting in the protection against dietinduced obesity [7]. mTORC1–S6K1 mediates various
extrinsic signals that regulate the cell growth and metabolism. Activation of mTORC1–S6K1
signaling by nutrients has received broad attention because of its implication in obesity and in
sulin resistance. Phosphorylation of IRS1 at sites Ser307 and Ser636/Ser639, which antagonize
the IRS1 signaling, is elevated in animal models of obesity and in muscle from type 2 diabetic
patients. S6K1 might have the major role in the insulin resistance under conditions of nutrient
overload [5, 12].
The activity of p70S6K1/2 was reduced only in patients with T2D (see Fig., c, 3—5), which
can be explained by the decreased activities of PI3K and mTOR, phosphorylating S6K in the
main activating sites of Thr412 and Thr389. The high activity of this kinase in patient T1D can
be associated with its activation by other protein kinases [13] or more likely with the absence of
an inhibitory effect on mTOR of adenosine monophosphateactivated protein kinase (AMPK),
which is activated by metformin [14].
Conclusions. 1. Expression of Akt is reduced in lymphocytes of patients with diabetes of
both types.
2. Activity of mTOR and its downstream kinase S6K in lymphocytes of patients with T2D
is reduced and may reflect the effectiveness of hypoglycemic drugs.
3. Expression of Akt and the mTOR activity can be associated with the duration of the
disease.
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adenosine monophosphateactivated protein kinase in lymphocytes under the action of hypoglycemic drugs.
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10. BenSahra, I., Hoxhaj, G., Ricoult, S. J., Asara, J. M. & Manning, B. D. (2016). mTORC1 induces purine
synthesis through control of the mitochondrial tetrahydrofolate cycle. Science, 351, pp. 728733.
11. Jones, R. G. & Pearce, E. J. (2017). MenTORing immunity: mTOR signaling in the development and func
tion of tissueresident immune cells. Immunity. 46, No. 5, pp. 730742. doi: https://doi.org/10.1016/j.
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12. Lee, D. F., Kuo, H. P., Chen, C. T., Wei, Y., Chou, C. K., Hung, J. Y., Yen, C. J. & Hung, M. C. (2008). IKKbeta
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Received 23.04.2018
Л.К. Соколова, В.М. Пушкарьов, Ю.Б. Бєльчина,
В.В. Пушкарьов, Т.С. Вацеба, М.Д. Тронько
ДУ “Інститут ендокринології та обміну речовин ім. В.П. Комісаренка НАМН України”, Київ
Email: pushkarev.vm@gmail.com
ВПЛИВ КОМБІНОВАНОГО ЛІКУВАННЯ ІНСУЛІНОМ, МЕТФОРМІНОМ
ТА ГЛІКЛАЗИДОМ НА ЕКСПРЕСІЮ І АКТИВНІСТЬ ПРОТЕЇНКІНАЗ Akt,
mTOR І p70S6K У ЛІМФОЦИТАХ ХВОРИХ НА ЦУКРОВИЙ ДІАБЕТ
Визначали експресію основної ефекторної протеїнкінази сигнального шляху PI3K — Akt та активність
протеїнкіназ mTOR і p70S6K в лімфоцитах хворих на цукровий діабет при комбінованому лікуванні ін
суліном і цукрознижувальними препаратами. Показано, що експресія Akt знижена в мононуклеарах крові
хворих на діабет 2го і, меншою мірою, 1го типу. Активність mTOR і p70S6K також знижена в лімфоци
тах хворих на діабет 2го типу. Обговорюються можливі механізми пригнічення експресії і активності
протеїнкіназ.
Ключові слова: Akt, mTOR, p70S6K, цукровий діабет, метформін, інсулін, гліклазид.
Л.К. Соколова, В.М. Пушкарев, Ю.Б. Бельчина,
В.В. Пушкарев, Т.С. Вацеба, Н.Д. Тронько
ГУ “Институт эндокринологии и обмена веществ им. В.П. Комиссаренко НАМН Украины”, Киев
Email: pushkarev.vm@gmail.com
ВЛИЯНИЕ КОМБИНИРОВАННОГО ЛЕЧЕНИЯ ИНСУЛИНОМ, МЕТФОРМИНОМ
И ГЛИКЛАЗИДОМ НА ЭКСПРЕССИЮ И АКТИВНОСТЬ ПРОТЕИНКИНАЗ Akt,
mTOR И p70S6K В ЛИМФОЦИТАХ БОЛЬНЫХ САХАРНЫМ ДИАБЕТОМ
Определяли экспрессию основной эффекторной протеинкиназы сигнального пути PI3K — Akt и ак тив
ность протеинкиназ mTOR и p70S6K в лимфоцитах больных сахарным диабетом при комбиниро ванном
лечении инсулином и сахароснижающими препаратами. Показано, что экспрессия Akt снижена в моно
нуклеарах крови больных диабетом 2го и, в меньшей степени, 1го типа. Активность mTOR и p70S6K
также снижена в лимфоцитах больных диабетом 2го типа. Обсуждаются возможные механизмы по дав
ления экспрессии и активности протеинкиназ.
Ключевые слова: Akt, mTOR, p70S6K, сахарный диабет, метформин, инсулин, гликлазид.
|
| id | nasplib_isofts_kiev_ua-123456789-143441 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1025-6415 |
| language | English |
| last_indexed | 2025-12-07T16:30:30Z |
| publishDate | 2018 |
| publisher | Видавничий дім "Академперіодика" НАН України |
| record_format | dspace |
| spelling | Sokolova, L.K. Pushkarev, V.M. Belchina, Yu.B. Pushkarev, V.V. Vatseba, T.S. Tronko, M.D. 2018-11-02T16:19:01Z 2018-11-02T16:19:01Z 2018 Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR, and p70S6K protein kinases in lymphocytes of diabetic patients / L.K. Sokolova, V.M. Pushkarev, Yu.B. Belchina, V.V. Pushkarev, T.S. Vatseba, M.D. Tronko // Доповіді Національної академії наук України. — 2018. — № 8. — С. 105-109. — Бібліогр.: 14 назв. — англ. 1025-6415 DOI: doi.org/10.15407/dopovidi2018.08.105 https://nasplib.isofts.kiev.ua/handle/123456789/143441 616.379008.64002:577.2 The expression of the main effector protein kinase Akt of the PI3K signaling pathway and the activities of mTOR
 and p70S6K protein kinases in lymphocytes of patients with diabetes mellitus are determined at the combination
 treatment with insulin and hypoglycemic drugs. It is shown that the Akt expression is reduced in blood mononuclear
 cells of patients with diabetes of the 2nd and, to a less extent, type 1. The activities of mTOR and p70S6K are
 also reduced in lymphocytes of patients with type 2 diabetes. Possible mechanisms of inhibiting the expression and
 activity of protein kinases are discussed. Визначали експресію основної ефекторної протеїнкінази сигнального шляху PI3K Akt та активність
 протеїнкіназ mTOR і p70S6K в лімфоцитах хворих на цукровий діабет при комбінованому лікуванні інсуліном і цукрознижувальними препаратами. Показано, що експресія Akt знижена в мононуклеарах крові
 хворих на діабет 2-го і, меншою мірою, 1-го типу. Активність mTOR і p70S6K також знижена в лімфоцитах хворих на діабет 2-го типу. Обговорюються можливі механізми пригнічення експресії і активності
 протеїнкіназ. Определяли экспрессию основной эффекторной протеинкиназы сигнального пути PI3K Akt и активность протеинкиназ mTOR и p70S6K в лимфоцитах больных сахарным диабетом при комбинированном
 лечении инсулином и сахароснижающими препаратами. Показано, что экспрессия Akt снижена в мононуклеарах крови больных диабетом 2-го и, в меньшей степени, 1-го типа. Активность mTOR и p70S6K
 также снижена в лимфоцитах больных диабетом 2-го типа. Обсуждаются возможные механизмы подавления экспрессии и активности протеинкиназ. en Видавничий дім "Академперіодика" НАН України Доповіді НАН України Медицина Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR, and p70S6K protein kinases in lymphocytes of diabetic patients Вплив комбінованого лікування інсуліном, метформіном та гліклазидом на експресію і активність протеїнкіназ Akt, mTOR і p70s6K у лімфоцитах хворих на цукровий діабет Влияние комбинированного лечения инсулином, метформином и гликлазидом на экспрессию и активность протеинкиназ Аkt, mTOR и p70s6k в лимфоцитах больных сахарным диабетом Article published earlier |
| spellingShingle | Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR, and p70S6K protein kinases in lymphocytes of diabetic patients Sokolova, L.K. Pushkarev, V.M. Belchina, Yu.B. Pushkarev, V.V. Vatseba, T.S. Tronko, M.D. Медицина |
| title | Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR, and p70S6K protein kinases in lymphocytes of diabetic patients |
| title_alt | Вплив комбінованого лікування інсуліном, метформіном та гліклазидом на експресію і активність протеїнкіназ Akt, mTOR і p70s6K у лімфоцитах хворих на цукровий діабет Влияние комбинированного лечения инсулином, метформином и гликлазидом на экспрессию и активность протеинкиназ Аkt, mTOR и p70s6k в лимфоцитах больных сахарным диабетом |
| title_full | Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR, and p70S6K protein kinases in lymphocytes of diabetic patients |
| title_fullStr | Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR, and p70S6K protein kinases in lymphocytes of diabetic patients |
| title_full_unstemmed | Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR, and p70S6K protein kinases in lymphocytes of diabetic patients |
| title_short | Effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of Akt, mTOR, and p70S6K protein kinases in lymphocytes of diabetic patients |
| title_sort | effect of combined treatment with insulin, metformin, and gliclazide on the expression and activity of akt, mtor, and p70s6k protein kinases in lymphocytes of diabetic patients |
| topic | Медицина |
| topic_facet | Медицина |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/143441 |
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