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\title{Insulin Resistance and Pharmacotherapy Effectiveness in Patients with Long -Term Diabetes Mellitus Type 2}
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             \author[1]{Yulia Andreevna  Sorokina}

             \author[2]{Lovcova Lubov  Valerievna}

             \author[3]{Zanozina Olga  Vladimirovna}

             \author[4]{Urakov Alexander  Livevich}

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\date{\small \em Received: 16 December 2019 Accepted: 4 January 2020 Published: 15 January 2020}

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\begin{abstract}
        


Introduction: With the development of the availability of genetic research, a multiplex approach to determining the pharmacotherapy tactics has become possible, taking into account the individual characteristics of the patient. Nevertheless, the modern tactics of pharmacotherapy "to failure" has been adopted, which over time leads to the intensification of therapy. A personalized approach to the pharmacotherapy of type 2 diabetes mellitus by determining the genotype of endothelial synthase of nitric oxide will predict the effectiveness of metformin monotherapy in the debut of the disease and reduce the risk of decompensation and complications with long-term type 2 diabetes mellitus.The aim of the study was to monitor the effectiveness of metformin pharmacotherapy for long-term type 2 DM, depending on the patient's genotype.

\end{abstract}


\keywords{type 2 diabetes mellitus, monotherapy, methformin, eNOS3 gene polymorphism, insulin resistance.}

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\let\tabcellsep& 	 	 		 \par
of genetic research, a multiplex approach to determining the pharmacotherapy tactics has become possible, taking into account the individual characteristics of the patient. Nevertheless, the modern tactics of pharmacotherapy "to failure" has been adopted, which over time leads to the intensification of therapy. A personalized approach to the pharmacotherapy of type 2 diabetes mellitus by determining the genotype of endothelial synthase of nitric oxide will predict the effectiveness of metformin monotherapy in the debut of the disease and reduce the risk of decompensation and complications with long-term type 2 diabetes mellitus.\par
The aim of the study was to monitor the effectiveness of metformin pharmacotherapy for long-term type 2 DM, depending on the patient's genotype. Materials and methods: A single-center, randomized, prospective study of 200 patients referred for planned hospitalization. The single nucleotide polymorphism of the gene eNOS3, the level of glycated hemoglobin. Homeostatic model 2 (HOMA 2) was applied to evaluate insulin resistance in patients. In consistency with the results, patients were divided into three groups: with the ??, TC and TT genotype.\par
Results and discussion: Patients of the CC genotype group achieved and kept glycated hemoglobin below the target level in 80\% of cases, when metformin was used at a dose of 1700 mg per day. No one of the patients, who representatives of the TC and TT genotypes reached the target values of glycated hemoglobin. Thus, the use of metformin as monotherapy to compensate for carbohydrate metabolism is not enough for TC and TT genotypes, and combination hypoglycemic pharmacotherapy, including insulin therapy, is required.\par
Conclusion: Identification of the presence of a particular eNOS3 gene allele provides the possibility of earlier prescribing appropriate drugs in an individual dose to reduce insulin resistance and likely limit the progression of diabetes mellitus, as well as increase the degree of compensation for carbohydrate metabolism.   
\section[{Keywords}]{Keywords}\begin{figure}[htbp]
\noindent\textbf{1}\includegraphics[]{image-2.png}
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 \begin{figure}[htbp]
\noindent\textbf{} \par 
\begin{longtable}{P{0.85\textwidth}}
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 \begin{figure}[htbp]
\noindent\textbf{} \par 
\begin{longtable}{P{0.4584269662921348\textwidth}P{0.18146067415730335\textwidth}P{0.12415730337078651\textwidth}P{0.07640449438202247\textwidth}P{0.009550561797752809\textwidth}}
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\caption{\label{tab_1}? ??? ????? ???????????????. ??????????: ????????? ??????? ???? ??? ????? ?????? ???? eNOS3 ????????????? ??????????? ????? ???????}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{} \par 
\begin{longtable}{P{0.85\textwidth}}
???????? ?????: ???????? ?????? 2 ????,\\
?????????????? ???????, ?????????, ???????????\\
???? eNOS3, ??????????????????????.\\
Abstract-Introduction: With the development of the availability\end{longtable} \par
 
\caption{\label{tab_2}?????????? ??????????? ???????????????? ????????? ???????, ? ????? ?????????? ??????? ??????????? ??????????? ??????.}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{} \par 
\begin{longtable}{P{0.010839850630592545\textwidth}P{0.8337701683928697\textwidth}P{0.00538998097653773\textwidth}}
16 Year 2020 Global Journal of Medical Research Volume XX Issue VIII Version I ( D D D D ) Year 2020 18 Volume XX Issue VIII Version I D D D D ) ( Medical Research Global Journal of\tabcellsep : type 2 diabetes mellitus, monotherapy, methformin, eNOS3 gene polymorphism, insulin resistance. I. ???????? ???????????, ??? ???????? ?????? (?Ð?") ???????? ?????? ?????????????? ????????. ???????? ?????? ????????????? ????????? ???????, ????? 415 ???. ??????? ?? ???? ???? ???????? ?Ð?" 2 ????, ? ?? ??????????????? ????????? ? 2040 ?. ??? ????? ????????? 642 ???. ??? ????, ?? ?????? ?????? 320,5 ???. ????????? ? ?Ð?" 2 ???? ????????? ? ?????? ??????????????? ????????? ?? 20 ?? 64 ??? [1]. ?????????????? ???????? ???????? ????? ? ??????? ?Ð?". ??????????????? ????????????? ???????? ??????????? ? ??????? ???????????????? ?Ð?" ? ?? ??? ??????????? ????? ????????. ????????? ?????????? ?????????????? ?Ð?" ????????: ???????????????? ??????, ???? ????????????? ???????????, ???????????? ????????????? ??? ???????????? ????????????. ? ?????????? ??????????? ??????? ??????????? ?Ð?" ??? ??????? ??????????? ??????? ???????????? ???????????? ???? ????????? ?????????????? ?????? ? ??????????? ??????? ?????????????? ? ?????? ?????????????? ???????????? ???????? (??????? 1) [2]. ? ??????? ?? ?????????? ???? ??????? (MODY, ???????????? ?????? ? ????????? ??????), ?Ð?" 2 ???? ??????????????? ?????????? ???????? ? ??????????? ?????, ??????? ?????????? ?? ?????? ???????? ? ??????? ??????? ???????????, ?? ? ????? ?? ??????????????, ???????? «??????? ????????» [3]. ?? ?????? ?????? ??????? ?????????? ???????????? ????????????? ? ???????????? ??????????????? ?????????? ? ??????????? ?? ??????? ?????, ????????? ? ????????? ?Ð?" 2 ???? (PPARG, DIPOR2, ADAMTS9, IRS1, GCKR, KLF14, ADIPOQ), ????????? ? ??????? ????????????? ?????????? (SUR1, GLPR-1), ? ????? ???????? ?? ??????????????? ????????? (MATE ? ???). ?????? ??????? ???????????? ??????? ?????, ??????????? ? ??????????????? ??????????????? ??????? ?????????????? ???????. ????????, ???????? ???? ????????????????? ? ????, ??????????? ?? ???????? ??????????? ???????? [4]. ?? ???? ?????????????? ????? ?????????????? ?Ð?" 2 ???? ?????????? ?????????????? ???????????? ????????? ???????? ??????????? ?????????? ?? ?????????????????? ???????? ? ????????? ?Ð?" ? ??? ?????????? ??????? ? ??????????????? ?????????, ??? ????????? ?????????????? ?????????????, ? ??????????, ????????? ????????????? ????????? ???? ? ????????? ?????????????? ??????? ??????? ????? ??? ?? 1,0 \%, ?? ??????? ????? ???????? ? ??????????? (???????????? ?????????? ???????? ????????? ??? ?????????? ????????????????). ??? ???? ??????????? ????????? ???? ???????? ?bA1c ? 0,5 \% ?? 6 ??????? ?????????? [11]. ?????? ? ???????? ??????? ?????? ????????? ????????? ?????????????? ??????? ?????????? ????, ??? ?????????? ??????? ??????????? ?????????????? ??????????? ??? ???????????? ??????? ?????????? ???????????. ? ????? ? ????, ????? ???????????? ???? ?????????? ????????????? ?????????????? ??????????? ????????? ???????? ?Ð?" 2 ???? ? ??????????? ?? ???????? ????????. II. ????????? ? ?????? Ð?"????? ????????????: ????????????? ????????????? ????????????????? ????????????. ??????????? ?????????? ?? ????????? ????????????? ?????????????? ? ????????? ??????????? ? ??????????? ?? ???????? ???????? ??? ??????????? ? ??????? ???????? ?????????????? ?????????). ???????????????? ??????????? ???? (???) eNOS3 (rs 2070744) ?????????? ??????? ???????????? ?????? ??????? ? ???????? ??????? ??? ????????????? ??????????? ??????? (??? «?????», ??????). Ð?"???????????? ?????????? ?????????? ?? ?????????? ???????????? Bio-Rad ?? ???????????? ???????? (???????). ??????? ?-???????, ????????????? ??? ??????? ??????????? HOMA 2-IR, HOMA 2-B ? HOMA 2-IS ???????????????? ??????, ????????? ? ??????? ??????????????? ???????????????? ????-?????? «Mercodia C-peptide ELISA specific». ??? ?? ???? ?? ?????????????? ????????? ?? ? ?? ?? ?????? ??????? ???????? ?????????????? 2. Hattersle ?.?., Patel ?.?. Precision diabetes: learning from monogenic diabetes. Diabetologia. ???????????. ??? ???? HbA1c ? ????????? ??????? 2017. 60:769-777 DOI 10.1007/s00125-017-4226-2. ?????????? ?? (0,14) ???????, ??? 60,00 [55,00;64,00] Ð?"??????????? ?Ð?" 2 ????, ??? 9,5 [ 6,0;10,25 ] ??????? HbA 1 c, \% Ð?"?????????? HbA 1 c, 6,90 [5,9;7,8] *p=0,029 ??????????????? ?????????????? ????????? ??????? ??????????? ???????? ????????? Ð?"??-4 ????? ?? ??? ????????? ????????????? ??????????, ?????????????? ?????????????? ??? ???? ?????? ??????????????????????. ????????? ??????? ??? ???????? ???????? ? ????????? ???????? ??????? ????????. ?????????? ?????? ??????????????? ? ???, ??? ??? ?? ? ?? ????????? ?????????? ?????????? ? ???????? ??????????? ??? ??????????? ??????????? ?????? ????????????. ???? ???? ????????????? ????????????? ?????????????? ?????????????? ?Ð?" ????? ?????????? 3. ???????? ?.?., ??????? ?.?., ?????? ?.?., ???????? ?.?. Ð?"??????????? ??????????? ? ????????? ? ??????? ?????????? ???????? ???????? 2-?? ????. ??????????? ?????????? ? 2019. 11 (2):57-62. DOI: ????????. 10.17691/stm2019.11.2.08 ??????????????? ??????????????? ??????????????, ? ??? ????? ???????????????. ? ????????? ?? ???????? ????????? ??????????? ?????????-???????? ????? ? ???????? ??????? ???????????????????? ? ?????????????????????? (??), ???????? ????-?????? ?? ???????????? ??????????? [13], ?? ???? ???? ?? ???????? ???????????????? ?????????????? ??, ??? ??????? ????????? ? ?????????? HOMA2, ? ?????????? ????????? ????????? ??????? ????-??????. ? ?? ????? ??? ? ????????? ? ??????, ????????, ???????????? ?????? ?????????? ?? ???????????????????? ?? ??????????? ? ?????? ???? ??-?? ???????????? 4. Rotroff D.M. et al. Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes Diabetes. 2018;67:1428-1440 5. Ð?"???? ?.?., ??????????? ?.?., ???????? Ð?".?., ?????????? ?.?., ?????????? ?.?., ?????? ?.?., ??????? Ð?".?., ???????? ?.?. ??????? 2: ?????????? ?????????????????????? ? ????????? ? ?????????? ?????????? ??? ?????????? ?Ð?" 2 ???? Atlas. 8th ed. Brussels: IDF, 2017. ?????????? HbA1c ????????? ? ??????? ????????? ??? ???????????? ?? ????????? ????????? ?????????? ?????????? ???????????. ??????????????-???????????? ?????????????? ???? ????????, ??? ????? ??????????? ?????????? ???????? ?????????, ??? ? ???????????, ??? ? ? ?????????? ? ??????? ???????????. ??? ???? ? ????? ????????? ??????? ???????????? ????????????? ???????? (?b? 1 ?>8\%), ? ??????????? ??????? ???? ???????? ??????? ?? ???? ?? ????? ??????????? ?????????? ?Ð?" [5]. ??????? ????? ?????? ?????????? ?????? ??????????? ???????? ???????? ?????????? ?????????????????? ?????????. ?? ??????? ?????????? ?Ð?" ?????????? 57\% ?????? ??????????? ??????, ????? ??? ?? ???? ??????????????? ??????? -????? 10\% [6]. ????? ???????????? ?????? ? ?????????????? ????? ??????? ??? ????????? ??????? «?? ???????». ?? ????, ? ???????????? ? ??????????????, ? ??????????? ?? ????????? ?????? ?????????? ??????????? ??????????? ?????? ??????????? ?? ??? ???? ?????????????? ? ??????????? ????????? ?? ???? 1 ???? ? ????? ? ? ????????? ??????? ?? ?????????????? ?? ???????, ??? ????? 6 ???????. ? ???? ??? ????? ??????? ????????? ?????????????? ?Ð?" 2 ????, ??????? ????? ?? ??????????? ??????????, ??? ???????? ?????????? ???????????? ???????, ????????? ????????????? ? ?????? ????????? ??? ?Ð?" ?????????? ?????????? [7]. ? ????? ? ????, ?????? ???????? ??????????? ??????????????? ????????????? ?????????????? ?Ð?" 2 ???? ??? ?? ????? ??????????? ?? ???????. ? ???? ????? ??? ?????????? ?????? ??????????????? ????????????? ??????? ??????? ?Ð?" 2 ???? ??????????? ? ??????????? ???? 1700 ?? ? ????? ??? ?????????? ??? ? ???????? ???????????, ??????? ??????? ?? ??????????? ???????? ?????????????? ??????? ?????? ????? (eNOS3) ? ????????? ? ?????? ??????????? ? ?????????????????? ????????? ???????? ? ????? ???????? ?????????????. ????? ???? ??? ????????? ???, ??? ????????? ???????? ????????? ?????? ????? (NO) [8] ? ???????? NO-????????? ?????????? ??????? [9]. ???????????, ??? ????? ??? ?????? ?????????? ?????????? ? ???? 1700 ??/????? ? ???? ????????? ? ????????? ?? ??????????? ??????????? ???????? ???????????????? ?? 1\% ? ?????????? ??? ??????? ???????? [10]. ? ????????? ? ?????????? ?? ? ?? ?? ??? ?????? ?????????????? ??????????? ???????? ???????? ?????? ???????? ? ?????????????? ??????????? ?????????????, ? ??? ??????????????? ?? 6 ??????? ????? ?? ??????? ????????? ?????????????????? ???????? ???????? HbA1c ?? 0,5-1\% [11]. ??????? ????????, ??? ??? ??????????? ????????? ???????? ???????? ??? ?????????????????? ??????????? ??????? ???????? ?????????????? ??????????? ?????????? ????? 7\%. ???? ???????? ?????????????? ????????? ?????????? ?????? ??????????? ????????????????? ?????? ???????. ???????? ????? ???????????? ???????? ????????? ? ???????????????? ???? eNOS3, ???????? ?? ????????? ?????????? ????????????? ? ?????? ????? ????? ??????????. ????????? ?????????? ??????? U ???????? ?????-?????. ???????? ????? ?????????? ???????? ??????????? ? ??????? ???????? ??????????. ?????????? ???????????? ? ????: ??????? [25\% ????????;75\% ????????]. ?????? ??????????? ???????????????? ?????? 2 (????2) ????????? ? ??????? ??????????????????? ??????????, ?????????????? ??????????? ?????????????, ?????? 2.2.3 [12]. III. ?????????? ? ?????????? Ð?"????? ????????? ? ?????????? ??? eNOS3 ??, ?? ? ?? ???? ??????????? ?? ????, ????????, ???????????? ?Ð?" 2 ????, ??????? ????????????? ??????????? ? ????????????? ??????????, ????????????? ??????????????. ??? ??????? ???????????? ?Ð?" 2 ???? 10 ??? ? ????????????? ????????? ??????? ?????????? ?????????????? ??????????? ???????? 7,5\%. ??? ???? ????? ????????? ? ????????? ?? ???????? ? ?????????? ??????? ?????????????? ??????????? ???? ???? ???????? 80\% ??????? ??? ?????????? ?????????? ? ???? 1700 ?? ? ????? ? ??????? ????????? ???????????? ??????????? ? ??????????????? ???????????? ??? ???????. ?????????? ????????? ???????? ? ???????? ??????????????, ??????????? ? ???????????????, ??????? ?? ????????? ? ??????? ????? ??????? ??????? ????????? ??????????? ? ?????? ?????????? (??????? 1). Ð?"?????? (??????? ?????????????) ?? (0,45) ?? (0,41) 59,50 [55,00;66,00] 65,50 [58,00;69,00] 10,2 [ 10,0;13,25 ] 10,0 [5,0;14,5 ] 7,5 8,61 [8,0;9,5] 8,5 [7,6;10,20] ????????? ?????????? ?????? ?????????? ??????????????-2 ??????? ??????????? ? ????????? ???????? ????????? Ð?"??-4 ????????? ?????????? ?????? ?????????? ????????? ???????? 1. International Diabetes Federation. IDF Diabetes ????????? Ð?"??-4 ?????????? ??????? ??????????? ? [14]. ??????????????-2 ?????????? ????????????? ??????? ??, ?????????? ??? ????????????? ????????? ??????? «?? ???????». ??????????? ???? ???????????????? ?????? ?????? 2 (????2), ????????? ?????????????? ????????? ??????? ????-?????? (\%B) ? ???????????????? ? ???????? (\%S), ? ????????? ?? ?????????? ??????????? ?????????, ? ????? ??????? ?????????????? ?????????????????????? (??). ? ????????? ? ?? ?????????, ???????? ?? ??????? ?????????? ???????????????? ????-??????, ?????? ?????????????? ?? (HOMA2-IR) ??????? ? ??????? ? ?????????????? ?????? ?????????. ??? ????? ????????????????? ? ???, ???, ???????? ?? ??????????? ??????????? ??????????? ??????, ????????? ????-?????? ? ????????? ? ?? ????????? ????????, ?? ????????????? (??????? 2). ? ??????????? ??????????? (Me [25p;75p]) ?????????? Ð?"?????? (??????? ?????????????) ?? (0,14) ?? (0,45) ?? (0,41) HOMA 2-IR (??????? ?????????????? ??) 3,5 [1,86;3,64] 3,79 [1,13;4,14] 4,47 [2,34;5,25] HOMA ????????????????????????? ??????? ??????????? ???????? ????????? ? ???????? ???????? 2 ????: ?????????? ??????????? ??????????????? ??????????????? ??????????????????? ???????????? ???????-?Ð?" 2. ???????? ??????. 2016. 19(6): doi: 10.14341/DM8146 6. Ð?"???? ?.?., ??????????? ?.?., ???????? Ð?".?., ?????? ?.?., ?????????? ?.?., ??????? ?.?., ??????????? ?.?., ?????? ?.Ð?"., ????? ?.?. ?????? ????????? ??????? ????????? ??????? 2 ???? ? ?????????? ?????????: ?????????? ??????????? ??????????????? ??????????????? ?????????????????????????? ???????????? ???????-?Ð?"2. ???????? ??????. 2017. 20(6):403-419. doi: 10.14341/DM9278 7. ????????? ?????????????????? ??????????? 2-B (?????????????? ????????? ??????? ????-??????, \% ?? ???????????) 93,2 [67, 88;177,2] *?=0,0078 54,3 [35,7;65,5 ] 46,9 [29,7;74,85] HOMA 2-IS (???????????????? ? ????????, \% ?? ??????????) 34,7333 [27,5;53,8] 26,4 [24,1;88,8] 31,45[19,05;42,65] ??????????. ? -??????? ?????????????? ??????????. IV. ??????????. ????? ???????, ?? ?????? ?????????????, ????????????? ?????????? ??????? ???????? ????????? ????????, ?? ? ?????????????? ?????????? ??????????????????????, ? ??? ????? ?????????? ???????????? ???? eNOS3. ????????? ??????? ???? ??? ????? ?????? ??????? ???????????? ???? ????????????? ??????????? ?????? ??????? ???????? ????????. ??? ????????? ?.?. Ð?"?????, ?.?. ??????????, ?.?. ????????. 8-? ??????. ?.: ?? ?????; 2018. 8. ???????? ?.?., ?????????? ?.?., ????????? ?.?., ????? ?.?. ???? ?????????? ??? ?????? ?????? ????? ? ????????? ??????????? ?????? ? ????????? ? ???????? ???????? 2 ????. ???????? ??????. 2013. 16(3):41-45 9. Alvim R.O. et al. General aspects of muscle glucose uptake. Anais da Academia Brasileira de Ciências. 2015. 87(1): 351-368 (Annals of the Brazilian Academy of Sciences) [In Portugal] 10. ?????? ?? ??????????? RU ?2626670 ?2, 2017 ???????? ?.?., ???????? ?.?., ??????? ?. ?., ??????? ?. ?. ?????? ??????????????? ??????????? ????? ??????? ?????????? ??????????????? ?????????? ????????????? ??????? ??????? ???????? ?????????????????????? ???????? ?????? ?????? ?????????? ?Ð?" 2 ???? ? ???????????? ??????? ????????????????? ?????????, ? ????????????? ???????????? ?????????????? ?????????????? -? ?????????????? ???? ??? ???????? ???????? 2 ????. ?????????????????????? ? ?????????? ??????????? 11. ????????? ?????????????????? ??????????? ???????????????? ????????? ???????, ? ????? ?????????? ??????? ??????????? ??????????? ?????? ?????? ??????? ???????? ????????.\tabcellsep 17 Year 2020 Global Journal of Medical Research Volume XX Issue VIII Version I ( D D D D )\end{longtable} \par
  {\small\itshape [Note: ??????????: HbA 1????????????? ??????????; ???????? ?????????????? ??????????; Ð?"?????????????????????.B © 2020 Global Journals Insulin Resistance and Pharmacotherapy Effectiveness in Patients with Long -Term Diabetes Mellitus Type 2 ??????? 1: ?????????????? ????? ? ??????? ?????????????? ??????????? ? ??????????? ?? ???????? ????????? ??? ?????????? ?Ð?" 2 ???? ? ??????????? ??????????? (Me [25p;75p])]} 
\caption{\label{tab_3}}\end{figure}
 			\footnote{B © 2020 Global Journals Insulin Resistance and Pharmacotherapy Effectiveness in Patients with Long -Term Diabetes Mellitus Type 2} 			\footnote{© 2020 Global Journals Insulin Resistance and Pharmacotherapy Effectiveness in Patients with Long -Term Diabetes Mellitus Type 2} 		 		\backmatter  			  				\begin{bibitemlist}{1}
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