Blockade of Angiotensin Receptor Ameliorates Insulin Resistance and Suppresses Plasma Leptin in OLETF Rats Supplemented with High Glucose

Abstract

Renin angiotensin system blockade improves insulin resistance (IR); however, the effects of angiotensin receptor blockers (ARB) on plasma leptin in a model of IR are not well defined. We examined the benefits of ARB on IR and leptin in 5 groups of rats: 1) LETO (lean strain control), 2) OLETF, 3) OLETF + 5% glucose water (OLETF HG), 4) OLETF + ARB (10mg/kg/day) and 5) OLETF HG + ARB. Homeostasis Model Assessment of Insulin Resistance (HOMA‐IR) was calculated as an indicator of IR after 6 weeks of treatment. HOMA‐IR increased 3‐fold in OLETF compared to LETO. High glucose increased mean HOMA‐IR 50%, and ARB treatment alleviated IR in OLETF ARB and OLETF HG + ARB. Plasma leptin levels increased over 2‐fold in OLETF (10.7 ± 0.9 ng/mL) compared to LETO (4.3 ± 0.6 ng/mL). ARB (9.7 ± 0.7 ng/mL) was effective in normalizing the increase in plasma leptin associated with HG (21.1±2.5 ng/mL). Plasma leptin positively correlated with IR (HOMA‐IR = 0.71 + 0.94*plasma leptin; R = 0.96; p< 0.01) suggesting that increased plasma leptin contributes to the manifestation of IR in obesity. Preliminary data suggest that increased plasma leptin is not associated with increased phosphorylation (and thus activation) of the leptin receptor in the liver. Furthermore, the data suggest that AT1 activation in conjunction with elevated leptin contributes to the development of IR in a model of metabolic syndrome. Funded by NIH NCMHD 9T37MD001480.