Abstract-Angiotensin II has been shown to contribute to the pathogenesis of insulin resistance; however, the mechanism is not well understood. The present study was undertaken to investigate the potential effect of an angiotensin II type-1 (AT 1 ) receptor blocker, valsartan, to improve insulin resistance and to explore the signaling basis of cross-talk of the AT 1 receptor-and insulin-mediated signaling in type 2 diabetic KK-Ay mice. 3 H]DG uptake and superoxide production in skeletal muscle of KK-Ay mice. Moreover, we observed that valsartan treatment exaggerated the insulin-induced phosphorylation of IRS-1, the association of IRS-1 with the p85 regulatory subunit of phosphoinositide 3 kinase (PI 3-K), PI 3-K activity, and translocation of GLUT4 to the plasma membrane. It also reduced tumor necrosis factor-␣ (TNF-␣) expression and superoxide production in skeletal muscle of KK-Ay mice. Specific AT 1 receptor blockade increases insulin sensitivity and glucose uptake in skeletal muscle of KK-Ay mice via stimulating the insulin signaling cascade and consequent enhancement of GLUT4 translocation to the plasma membrane. Key Words: angiotensin II Ⅲ insulin Ⅲ glucose Ⅲ diabetes mellitus T he renin-angiotensin system plays an important role in the regulation of cardiovascular and fluid volume homeostasis, and in the control of various hormone secretion, tissue growth and neuronal activity. Angiotensin (Ang) II seems to be involved in the pathogenesis of hypertension and insulin resistance, although few studies have examined the relationship between the two. Insulin resistance occurs in a wide variety of pathological states and is commonly associated with obesity, type 2 diabetes, accelerated atherosclerosis, and hypertension. 1,2 Shimamoto et al demonstrated that the insulin sensitivity of fructose-fed rats is improved by treatment with an Ang II receptor blocker (ARB), olmesartan, caused by changes in muscle fiber composition and a decrease in tumor necrosis factor (TNF)-␣ expression in skeletal muscle. 3,4 Henriksen et al 5 reported that an ARB, irbesartan, either acutely or chronically, improves glucose tolerance in the obese Zucker rat, at least in part through enhancement of skeletal muscle glucose transport, and the effect of chronic Ang II receptor antagonism on skeletal muscle glucose uptake is associated with an increase in GLUT4 protein expression. Recent large clinical trials revealed that angiotensin II receptor blockade by losartan was associated with a lower risk of development of diabetes. 6 However, it remains unclear whether Ang II has a direct effect on the insulin-mediated pathway of glucose metabolism in addition to changes in local blood flow in insulinsensitive organs such as skeletal muscle.Recent studies have suggested that Ang II might negatively modulate insulin-mediated actions by regulating multiple levels of the insulin signaling cascade such as the insulin receptor, insulin receptor substrate (IRS), and phosphatidylinositol 3-kinase (PI 3-K). 7-9 Therefore, we examined the possibility tha...

These results suggest that the stimulation of the AT(2) receptor after AT(1) blockade is important in the improvement of the inflammatory vascular injury.

Abstract-Improvement of insulin resistance by ACE inhibitors has been suggested; however, this mechanism has not been proved. We postulated that activation of the bradykinin-nitric oxide (NO) system by an ACE inhibitor enhances glucose uptake in peripheral tissues by means of an increase in translocation of glucose transporter 4 (GLUT4), resulting in improvement of insulin resistance. Administration of an ACE inhibitor, temocapril, significantly decreased plasma glucose and insulin concentrations in type 2 diabetic mouse KK-Ay. Mice treated with temocapril showed a smaller plasma glucose increase after glucose load. We demonstrated that temocapril treatment significantly enhanced 2-[ 3 H]-deoxy-D-glucose (2-DG) uptake in skeletal muscle but not in white adipose tissue. Administration of a bradykinin B2 receptor antagonist, Hoe140, or an NO synthase inhibitor, L-NAME, attenuated the enhanced glucose uptake by temocapril. Moreover, we observed that translocation of GLUT4 to the plasma membrane was significantly enhanced by temocapril treatment without influencing insulin receptor substrate-1 phosphorylation. In L6 skeletal muscle cells, 2-DG uptake was increased by temocaprilat, and Hoe140 inhibited this effect of temocaprilat but not that of insulin. These results suggest that temocapril would improve insulin resistance and glucose intolerance through increasing glucose uptake, especially in skeletal muscle at least in part through enhancement of the bradykinin-NO system and consequently GLUT4 translocation. Key Words: angiotensin-converting enzyme Ⅲ bradykinin Ⅲ glucose Ⅲ insulin resistance Ⅲ nitric oxide T he earliest defect in the development of type 2 diabetes is insulin resistance, 1,2 characterized by decreased glucose transport and metabolism in muscle and adipocytes. 3,4 Glucose is cleared from the bloodstream by a family of facilitative transporters (glucose transporters, GLUTs). The glucose transporter GLUT4 mediates insulin-stimulated glucose uptake in adipocytes and muscle by rapidly moving from intracellular storage sites to the plasma membrane. In insulinresistant states such as obesity and type 2 diabetes, GLUT4 expression is decreased in adipose tissue but preserved in muscle. 5,6 Insulin-resistant states are often associated with hypertension, and the effects of antihypertensive drugs on insulin resistance have been highlighted. Accumulated data indicate that ACE inhibitors have either no adverse effect on glucose control or insulin sensitivity 7-10 or may even improve them. [11][12][13][14][15][16][17][18][19][20] The variability of results between studies may relate to differences in experimental design, the degree of glycemia or insulin resistance, potassium balance, and the dose or duration of ACE inhibitor treatment, among others. The actions of ACE inhibitors are due in part to the decrease in angiotensin II formation and accumulation of kinins, and the resulting increase in nitric oxide (NO) production may also play a role.Kishi et al 21 proposed that bradykinin directly stimulates GLUT4 t...