Losartan Improves Palmitate-Induced Insulin Resistance in 3T3-L1 Adipocytes Through Upregulation of Src Phosphorylation

Abstract

Angiotensin II type 1 receptor blocker losartan has shown strongly anti-insulin resistance properties in vivo and in vitro; however, the underlying mechanisms are poorly understood. In this study, we demonstrate that losartan administration increased phosphorylation of Akt and its downstream Akt substrate of 160 kDa (AS160), enhanced plasma membrane translocation of glucose transporter type 4 (GLUT4), and increased glucose uptake, along with increased Src phosphorylation as well as reduced expression of docking protein 1(DOK1) in palmitate-treated 3T3-L1 adipocytes. The beneficial impacts of losartan on insulin signaling were diminished in Src-deficient 3T3-L1 adipocytes. In addition, suppressed expression of DOK1 by losartan was abolished by Src knockdown. Our results suggest that anti-insulin resistance ability of losartan is mediated by Src/DOK1/Akt pathway.

• References

• 1 Bharati SM, Singh N. Effect of losartan and atenolol on insulin sensitivity in nondiabetic hypertensive patients. J Pharmacol Pharmacother 2016; 7: 80-86
• 2 Jin HM, Pan Y. Angiotensin type-1 receptor blockade with losartan increases insulin sensitivity and improves glucose homeostasis in subjects with type 2 diabetes and nephropathy. Nephrol Dial Transplant 2007; 22: 1943-1949
• 3 Cavusoglu T, Karadeniz T, Cagiltay E et al. The protective effect of losartan on diabetic neuropathy in a diabetic rat model. Exp Clin Endocrinol Diabetes. 2015; 123: 479-484
• 4 Schupp M, Janke J, Clasen R et al. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-γ activity. Circulation 2004; 109: 2054 -2057
• 5 Fogari R, Maffioli P, Mugellini A et al. Effects of losartan and amlodipine alone or combined with simvastatin in hypertensive patients with nonalcoholic hepatic steatosis. Eur J Gastroenterol Hepatol 2012; 24: 164-171
• 6 Pan Y, Qiao QY, Pan LH et al. Losartan reduces insulin resistance by inhibiting oxidative stress and enhancing insulin signaling transduction. Exp Clin Endocrinol Diabetes 2015; 123: 170-177
• 7 Van Epps-Fung M, Williford J, Wells A et al. Fatty acid-induced insulin resistance in adipocytes. Endocrinology 1997; 138: 4338-4345
• 8 Kaburagi Y, Satoh S, Tamemoto H et al. Role of insulin receptor substrate-1 and pp60 in the regulation of insulin-induced glucose transport and GLUT4 translocation in primary adipocytes. J Biol Chem 1997; 272: 25839-25844
• 9 Hosooka T, Noguchi T, Kotani K et al. Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-gamma phosphorylation. Nat Med 2008; 14: 188-193
• 10 Wick MJ, Dong LQ, Hu D et al. Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398 plays distinct roles for binding GTPase-activating protein and Nck and is essential for inhibiting insulin-stimulated activation of Ras and Akt. J Biol Chem 2001; 276: 42843-42850
• 11 Janas JA, Van Aelst L.. Oncogenic tyrosine kinases target Dok-1 for ubiquitin-mediated proteasomal degradation to promote cell transformation. Mol Cell Biol 2011; 31: 2552-2565
• 12 Ogino K, Kato M, Furuse Y et al. Addition of losartan to angiotensin-converting enzyme inhibitors improves insulin resistance in patients with chronic heart failure treated without β-blockers. Circ J 2010; 74: 2346-2352
• 13 Flammer AJ, Hermann F, Wiesli P et al. Effect of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertension. J Hypertens 2007; 25: 785-791
• 14 Mourad AA, Heeba GH, Taye A et al. Comparative study between atorvastatin and losartan on high fat diet-induced type 2 diabetes mellitus in rats. Fundam Clin Pharmacol 2013; 27: 489-497
• 15 Benson SC, Pershadsingh HA, Ho CI et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARγ-modulating activity. Hypertension 2004; 43: 993-1002
• 16 Ishizaka N, Hongo M, Matsuzaki G et al. Effects of the AT(1) receptor blocker losartan and the calcium channel blocker benidipine on the accumulation of lipids in the kidney of a rat model of metabolic syndrome. Hypertens Res 2010; 33: 263-268
• 17 Nishimura H, Sanaka T, Tanihata Y et al. Losartan elevates the serum high-molecular weight-adiponectin isoform and concurrently improves insulin sensitivity in patients with impaired glucose metabolism. Hypertens Res 2008; 31: 1611-1618
• 18 Uchida T, Shimizu M, Sakai Y et al. Effects of losartan on serum total and high-molecular weight adiponectin concentrations in hypertensive patients with metabolic syndrome. Metabolism 2008; 57: 1278-1285
• 19 Aksnes TA, Seljeflot I, Torjesen PA et al. Improved insulin sensitivity by the angiotensin II-receptor blocker losartan is not explained by adipokines, inflammatory markers, or whole blood viscosity. Metabolism 2007; 56: 1470-1477