Abstract
Numerous animal and clinical investigations have pointed to a potential role of the renin-angiotensin system (RAS) in the development of insulin resistance and diabetes in conditions of expanded fat mass. However, the mechanisms underlying this association remain unclear. We used a transgenic mouse model overexpressing renin in the liver (RenTgMK) to examine the effects of chronic activation of RAS on adiposity and insulin sensitivity. Hepatic overexpression of renin resulted in constitutively elevated plasma angiotensin II (four- to six-fold increase vs. wild-type, WT). Surprisingly, RenTgMK mice developed glucose intolerance despite low levels of adiposity and insulinemia. The transgenics also had lower plasma triglyceride levels. Glucose intolerance in transgenic mice fed a low-fat diet was comparable to that observed in high-fat fed WT mice. These studies demonstrate that overexpression of renin and associated hyperangiotensinemia impair glucose tolerance in a diet-dependent manner and further support a consistent role of RAS in the pathogenesis of diabetes and insulin resistance, independent of changes in fat mass.
Highlights
The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, fluid, and electrolyte balance (Schmieder et al, 2007)
We report here that elevated circulating angiotensin II (Ang II) due to renin overexpression leads to glucose intolerance, which is further exacerbated by high-fat feeding
We hypothesized that chronic systemic RAS activation via transgenic renin overexpression in the liver would lead to glucose intolerance and systemic insulin resistance
Summary
The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, fluid, and electrolyte balance (Schmieder et al, 2007). Angiotensinogen (AGT), the precursor peptide of this system, undergoes successive enzymatic cleavages by renin and angiotensin converting enzyme (ACE) to yield angiotensin I (Ang I) and angiotensin II (Ang II) respectively. The latter is the main bioactive peptide of this system, which acts via two G-protein coupled receptors, namely angiotensin Type (AT1) and Type-2 (AT2) receptors, to exert its physiological effects. Because AT1 activation by Ang II leads to elevation of blood pressure, ACE inhibitors (ACEI) and AT1 blockers (ARB) are pharmacologically used as anti-hypertensive agents (Schmieder et al, 2007). Chronic RAS overactivation via Ang II infusion (Ogihara et al, 2002) leads to glucose intolerance and insulin resistance in rodents, further supporting a role of RAS overactivation in the pathogenesis of insulin resistance
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