The Role of Sirtuins in Treatment with Sglt2 Inhibitor in Experimental Type 2 Diabetes with Vascular Damage and Cardiomyopathy

Project no. 24026 · Status: Kapanmış (Yayın bekleniyor) · 2022

Summary

<p><strong>Background:&nbsp;</strong>Diabetes&nbsp;mellitus&nbsp;(DM)&nbsp;is&nbsp;a&nbsp;complicated&nbsp;and&nbsp;chronic&nbsp;endocrine&nbsp;disease&nbsp;characterised&nbsp;by&nbsp;hyperglycaemia&nbsp;caused&nbsp;by&nbsp;decreased&nbsp;insulin&nbsp;secretion&nbsp;or&nbsp;sensitivity.&nbsp;Sodium&nbsp;glucose&nbsp;cotransporter&nbsp;2&nbsp;(SGLT2)&nbsp;inhibitors&nbsp;(empagliflozin,&nbsp;dapagliflozin,&nbsp;kanagliflozin)&nbsp;are&nbsp;a&nbsp;group&nbsp;of&nbsp;antihyperglycaemic&nbsp;drugs&nbsp;recently&nbsp;introduced&nbsp;for&nbsp;the&nbsp;treatment&nbsp;of&nbsp;type&nbsp;2&nbsp;diabetes&nbsp;(T2DM)&nbsp;that&nbsp;reduce&nbsp;blood&nbsp;glucose&nbsp;levels&nbsp;by&nbsp;inhibiting&nbsp;glucose&nbsp;reabsorption&nbsp;from&nbsp;the&nbsp;kidneys.&nbsp;This&nbsp;group&nbsp;of&nbsp;drugs&nbsp;is&nbsp;known&nbsp;to&nbsp;have&nbsp;beneficial&nbsp;effects&nbsp;in&nbsp;preventing&nbsp;cardiomyopathy,&nbsp;the&nbsp;most&nbsp;important&nbsp;complication&nbsp;of&nbsp;T2DM,&nbsp;but&nbsp;the&nbsp;effects&nbsp;of&nbsp;SGLT2&nbsp;inhibitors&nbsp;on&nbsp;vascular&nbsp;damage&nbsp;in&nbsp;diabetic&nbsp;individuals&nbsp;and&nbsp;the&nbsp;mechanism&nbsp;of&nbsp;these&nbsp;effects&nbsp;are&nbsp;not&nbsp;yet&nbsp;known.&nbsp;However,&nbsp;studies&nbsp;show&nbsp;that&nbsp;Sirtuins&nbsp;(1-7)&nbsp;(Silent&nbsp;Information&nbsp;Regulator&nbsp;2&nbsp;Proteins;&nbsp;SIRT)&nbsp;have&nbsp;roles&nbsp;in&nbsp;insulin&nbsp;secretion,&nbsp;glycolysis,&nbsp;mitochondrial&nbsp;biogenesis,&nbsp;fat&nbsp;oxidation&nbsp;and&nbsp;glucogenesis.&nbsp;The&nbsp;aim&nbsp;of&nbsp;this&nbsp;study&nbsp;was&nbsp;to&nbsp;investigate&nbsp;the&nbsp;relationship&nbsp;between&nbsp;sirtuin&nbsp;enzymes&nbsp;and&nbsp;the&nbsp;effects&nbsp;of&nbsp;SGLT2&nbsp;inhibitor&nbsp;empagliflozin&nbsp;on&nbsp;vascular&nbsp;damage,&nbsp;cardiomyopathy&nbsp;and&nbsp;oxidant&nbsp;stress&nbsp;in&nbsp;an&nbsp;experimental&nbsp;type&nbsp;2&nbsp;diabetes&nbsp;model&nbsp;induced&nbsp;by&nbsp;high&nbsp;fat&nbsp;diet&nbsp;(HFD,&nbsp;35%&nbsp;kcal)&nbsp;and&nbsp;low&nbsp;dose&nbsp;streptozotocin&nbsp;(STZ)&nbsp;(35&nbsp;mg/kg,&nbsp;ip).</p><p><strong>Materials&nbsp;and&nbsp;Methods:&nbsp;</strong>Thirty&nbsp;6-week-old&nbsp;male&nbsp;Wistar&nbsp;rats&nbsp;were&nbsp;divided&nbsp;into&nbsp;3&nbsp;groups&nbsp;as&nbsp;control,&nbsp;diabetes&nbsp;and&nbsp;treatment&nbsp;groups.&nbsp;Diabetes&nbsp;and&nbsp;treatment&nbsp;group&nbsp;rats&nbsp;were&nbsp;fed&nbsp;high-fat&nbsp;diet&nbsp;(HFD,&nbsp;35%&nbsp;kcal)&nbsp;for&nbsp;4&nbsp;weeks&nbsp;and&nbsp;then&nbsp;induced&nbsp;with&nbsp;low-dose&nbsp;streptozotocin&nbsp;(STZ)&nbsp;(35&nbsp;mg/kg,&nbsp;ip)&nbsp;to&nbsp;create&nbsp;a&nbsp;type&nbsp;2&nbsp;diabetes&nbsp;model.&nbsp;In&nbsp;order&nbsp;to&nbsp;examine&nbsp;the&nbsp;endothelial&nbsp;structure&nbsp;disrupted&nbsp;in&nbsp;diabetes,&nbsp;cumulative&nbsp;ACh&nbsp;(10<sup>-9</sup>-10<sup>-4</sup>&nbsp;M),&nbsp;SLB&nbsp;(10<sup>-9</sup>-10<sup>-5</sup>&nbsp;M)&nbsp;and&nbsp;NTG&nbsp;(10<sup>-9</sup>-3x10<sup>-5</sup>&nbsp;M)&nbsp;relaxation&nbsp;responses&nbsp;were&nbsp;obtained&nbsp;after&nbsp;pre-contraction&nbsp;with&nbsp;Fen&nbsp;(10<sup>-6</sup>&nbsp;M)&nbsp;in&nbsp;the&nbsp;presence/absence&nbsp;of&nbsp;NO&nbsp;inhibitor&nbsp;L-NAME&nbsp;(10<sup>-4</sup>&nbsp;M)&nbsp;to&nbsp;determine&nbsp;endothelium-dependent&nbsp;and&nbsp;smooth&nbsp;muscle-induced&nbsp;relaxation&nbsp;responses&nbsp;in&nbsp;the&nbsp;aorta&nbsp;of&nbsp;rats.&nbsp;At&nbsp;the&nbsp;same&nbsp;time,&nbsp;contraction&nbsp;responses&nbsp;were&nbsp;obtained&nbsp;cumulatively&nbsp;with&nbsp;Fen&nbsp;(10<sup>-9</sup>-10<sup>-4</sup>&nbsp;M)&nbsp;and&nbsp;5-HT&nbsp;(10<sup>-9</sup>-3x10<sup>-5</sup>&nbsp;M).&nbsp;The&nbsp;expression&nbsp;levels&nbsp;of&nbsp;SIRT-1/-6&nbsp;enzymes,&nbsp;Troponin-I,&nbsp;GRP78&nbsp;proteins,&nbsp;MMP-2/-9&nbsp;activity&nbsp;levels&nbsp;and&nbsp;tissue&nbsp;inhibitors&nbsp;(TIMP-1/-2)&nbsp;protein&nbsp;levels&nbsp;were&nbsp;measured&nbsp;in&nbsp;isolated&nbsp;heart&nbsp;tissues.&nbsp;In&nbsp;addition,&nbsp;changes&nbsp;in&nbsp;the&nbsp;morphology&nbsp;of&nbsp;the&nbsp;heart&nbsp;tissue&nbsp;deteriorated&nbsp;in&nbsp;diabetes&nbsp;following&nbsp;empagliflozin&nbsp;treatment&nbsp;are&nbsp;seen&nbsp;histopathologically.</p><p><strong>Results:</strong>&nbsp;Empagliflozin&nbsp;treatment&nbsp;improved&nbsp;the&nbsp;impaired&nbsp;vascular&nbsp;responses&nbsp;(ACh&nbsp;relaxation,&nbsp;5-HT&nbsp;contraction,&nbsp;NTG)&nbsp;in&nbsp;diabetes.&nbsp;Histological&nbsp;analyses&nbsp;showed&nbsp;that&nbsp;the&nbsp;collagen&nbsp;deposition&nbsp;around&nbsp;the&nbsp;blood&nbsp;vessels&nbsp;observed&nbsp;in&nbsp;the&nbsp;diabetes&nbsp;group&nbsp;was&nbsp;not&nbsp;observed&nbsp;in&nbsp;the&nbsp;empagliflozin-treated&nbsp;group,&nbsp;disorganized&nbsp;myofibrils&nbsp;decreased&nbsp;in&nbsp;the&nbsp;heart&nbsp;tissues&nbsp;after&nbsp;empagliflozin&nbsp;treatment,&nbsp;and&nbsp;cardiomyocytes&nbsp;had&nbsp;normal&nbsp;cytoplasm&nbsp;and&nbsp;nucleus&nbsp;structure.&nbsp;Cardiac&nbsp;troponin-I,&nbsp;an&nbsp;important&nbsp;marker&nbsp;of&nbsp;diabetic&nbsp;cardiomyopathy,&nbsp;and&nbsp;GRP78&nbsp;protein&nbsp;levels,&nbsp;a&nbsp;marker&nbsp;of&nbsp;ER&nbsp;stress,&nbsp;were&nbsp;found&nbsp;to&nbsp;be&nbsp;significantly&nbsp;decreased&nbsp;with&nbsp;empagliflozin&nbsp;treatment.&nbsp;On&nbsp;the&nbsp;other&nbsp;hand,&nbsp;the&nbsp;level&nbsp;of&nbsp;fibrosis&nbsp;occurring&nbsp;in&nbsp;cardiomyopathy&nbsp;was&nbsp;examined&nbsp;and&nbsp;the&nbsp;fact&nbsp;that&nbsp;the&nbsp;activity&nbsp;of&nbsp;MMP-2,&nbsp;one&nbsp;of&nbsp;the&nbsp;matrix&nbsp;metalloproteinases,&nbsp;increased&nbsp;statistically&nbsp;in&nbsp;the&nbsp;diabetic&nbsp;group&nbsp;compared&nbsp;to&nbsp;the&nbsp;control&nbsp;group,&nbsp;and&nbsp;this&nbsp;increase&nbsp;was&nbsp;statistically&nbsp;significantly&nbsp;decreased&nbsp;with&nbsp;empagliflozin&nbsp;treatment,&nbsp;supporting&nbsp;the&nbsp;protective&nbsp;effect&nbsp;of&nbsp;empagliflozin&nbsp;against&nbsp;cardiomyopathy.&nbsp;The&nbsp;relationship&nbsp;between&nbsp;sirtuin&nbsp;enzymes,&nbsp;which&nbsp;is&nbsp;the&nbsp;aim&nbsp;of&nbsp;the&nbsp;study,&nbsp;and&nbsp;the&nbsp;cardioprotective&nbsp;effects&nbsp;of&nbsp;empagliflozin&nbsp;was&nbsp;investigated,&nbsp;and&nbsp;the&nbsp;increase&nbsp;in&nbsp;the&nbsp;decreased&nbsp;SIRT-1&nbsp;expression&nbsp;in&nbsp;diabetes&nbsp;with&nbsp;empagliflozin&nbsp;treatment&nbsp;suggested&nbsp;that&nbsp;there&nbsp;may&nbsp;be&nbsp;a&nbsp;potential&nbsp;correlation&nbsp;between&nbsp;them.</p><p><strong>Conclusion:</strong>&nbsp;The&nbsp;fact&nbsp;that&nbsp;empagliflozin&nbsp;treatment&nbsp;can&nbsp;improve&nbsp;vascular&nbsp;damage&nbsp;in&nbsp;diabetes&nbsp;and&nbsp;empagliflozin&nbsp;is&nbsp;a&nbsp;promising&nbsp;agent&nbsp;in&nbsp;the&nbsp;prevention&nbsp;and&nbsp;treatment&nbsp;of&nbsp;cardiomyopathy,&nbsp;and&nbsp;the&nbsp;decreased&nbsp;SIRT1&nbsp;expression&nbsp;in&nbsp;diabetes&nbsp;is&nbsp;reversible&nbsp;with&nbsp;empagliflozin,&nbsp;suggesting&nbsp;that&nbsp;empagliflozin&nbsp;may&nbsp;be&nbsp;related&nbsp;to&nbsp;SIRT&nbsp;enzymes.&nbsp;However,&nbsp;it&nbsp;is&nbsp;understood&nbsp;that&nbsp;more&nbsp;research&nbsp;on&nbsp;the&nbsp;molecular&nbsp;mechanism&nbsp;is&nbsp;needed&nbsp;to&nbsp;understand&nbsp;this&nbsp;relationship.</p>

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