The Crosstalk Between Insulin and Renin-Angiotensin-Aldosterone Signaling Systems and its Effect on Glucose Metabolism and Diabetes Prevention
Giovanna Muscogiuri, Alberto O. Chavez, Amalia Gastaldelli, Lucia Perego, Devjit Tripathy, Mario J. Saad, Licio Velloso and Franco Folli
Affiliation: Department of Medicine, Diabetes Division, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Essential hypertension is an insulin resistant state. Early insulin signaling steps are impaired in essential hypertension and a large body of data suggests that there is a crosstalk at multiple levels between the signal transduction pathways that mediate insulin and angiotensin II actions. At the extracellular level the angiotensin converting enzyme (ACE) regulates the synthesis of angiotensin II and bradykinin that is a powerful vasodilator. At early intracellular level angiotensin II acts on JAK-2/IRS1-IRS2/PI3-kinase, JNK and ERK to phosphorylate serine residues of key elements of insulin signaling pathway therefore inhibiting signaling by the insulin receptor. On another level angiotensin II inhibits the insulin signaling inducing the regulatory protein SOCS 3. Angiotensin II acting through the AT1 receptor can inhibit insulininduced nitric oxide (NO) production by activating ERK 1/2 and JNK and enhances the activity of NADPH oxidase that leads to an increased reactive oxygen species generation. From the clinical standpoint, the inhibition of the renin angiotensin system improves insulin sensitivity and decreases the incidence of Type 2 Diabetes Mellitus (T2DM). This might represent an alternative approach to prevent type 2 diabetes in patients with hypertension and metabolic syndrome, (i.e. insulin resistant patients). This review will discuss: a) the molecular mechanisms of the crosstalk between the insulin and angiotensin II signaling systems b) the results of clinical studies employing drugs targeting the renin-angiotensin IIaldosterone systems and their role in glucose metabolism and diabetes prevention.
Keywords: Insulin, Renin-Angiotensin-Aldosterone, Glucose Metabolism, Diabetes, hypertension, angiotensin converting enzyme (ACE), renin-angiotensin Iialdosterone systems
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