Losartan Reduces Insulin Resistance by Inhibiting Oxidative Stress and Enhancing Insulin Signaling Transduction

Abstract

These results suggest that the effect of losartan on insulin resistance is associated with the reduction of oxidative stress and inflammation in patients with type 2 DKD as well as the activation of insulin signal pathway in insulin-resistance 3T3-L1 adipocytes through modulation of PI3K pathway. (Clinical Trials. gov number, NCT 00774904).

TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice

“…Plasma insulin concentration (ng/mL) was determined by radioimmunoassay (Insulin Kit®). Insulin sensitivity was calculated using the HOMA-IR index (Homeostasis Model Assessment) [26], which takes into account insulin and fasting blood glucose levels, using the following mathematical formula: HOMA-IR = fasting insulin × fasting glucose/22.5.…”

Insulin resistance: Review of the underlying molecular mechanisms

“…Elchebly et al (1999),Klaman et al (2000),Koren and Fantus (2007),Sun et al (2007), andYip et al (2010) Inflammatory mediators and adipokines Activation of IKKβ/NF-κB and JNK pathways, serine phosphorylation of IRS-1 in the site of 307, declines GLUT-4 expression, reduces IRS-1 expression via ERK1/2, induce IRS degradation through SOCS1-and SOCS3-dependent mechanismsDe Luca and Olefsky (2008), Fantuzzi (2005), Hundal et al (2002), Peraldi and Spiegelman (1998), Rui et al (2002), Scherer et al (1995), Tilg and Moschen (2008), and Yuan et al (2001) Free radical overload Activates several serine-threonine kinase pathways, i.e., IKKβ/NF-κB and JNK, IRS degradation, suppresses GLUT-4 expression and localization in cell membrane, decreases insulin-induced IRS-1 and PIP-kinase relocation between cytoplasm and microsomes, decreases PKB phosphorylation, serine phosphorylation at site of serine 307 of IRS-1, activates inflammatory responses Elmarakby and Sullivan (2012), Evans et al (2005), Furukawa et al (2017), Houstis et al (2006), Hurrle and Hsu (2017), Moreira et al (2010), and Rahmanto et al (2010) Defects in serine phosphorylation of IRS-1 Decrease in insulin receptor phosphorylation, phosphorylation in serine 307 which blocks signaling Aguirre et al (2002), Beeson et al (2003), Copps and White(2012),Goodyear et al (1995),Hirosumi et al (2002),Ho et al (2016),Kim et al (1999),Pan et al (2015),Smith et al (1999), andTaniguchi et al (2006) Obesity and adipocytes importance Activates the serine-threonine kinase, induces inflammation and impairs insulin signalingKahn and Flier (2000),Kojima and Kangawa (2005),Petersen et al (2002), Pöykkö et al (2003,Purnell et al (2003), andShimomura et al (1999) Accelerated insulin degradation Autoimmune antibodies against insulin or abnormal insulin structure due to mutationKasuga et al (1999),Olatunbosun and Schade (2017), andSchlessinger et al (1980) Mitochondrial dysfunction Induces oxidative stress, impairs insulin signalingCheng et al (2010),Rains and Jain (2011), Sebastián et al (2012), andWestermeier et al (2015) …”

The Role of Reactive Oxygen Species in the Pathogenesis of Adipocyte Dysfunction in Metabolic Syndrome. Prospects of Pharmacological Correction

“…В 2015 г. Y. Pan и соавт. [42] обнаружили, что H 2 O 2 в 2 раза снижала продукцию адипонектина 3T3-L1адипоцитами и способствовала увеличению в 3 раза синтеза TNFα и IL6. Окислительный стресс, вызванный добавлением в среду инкубации 3T3-L1-адипоцитов H 2 O 2 , вызывал увеличение мРНК лептина и IL6 и усиление секреции этих белков адипоцитами.…”

“…Эта гипотеза подтверждается данными клинических наблюдений [54]. Действительно, клинические данные свидетельствуют о положительном влиянии лозартана, антагониста рецепторов ангиотезина II, на течение МС [42]. Установлено, что блокада минералокортикоидных рецепторов эплереноном уменьшает инсулинорезистентность и дисфункцию адипоцитов у мышей линий ob/ob и db/db с дисметаболическим состоянием, сходным с МС [12].…”