Response to Role of Renin-Angiotensin System Blockades in Reciprocal Relationship Between Insulin Resistance and Endothelial Dysfunction
We greatly appreciate comments from Koh et al1 saying that results from our recent study2 provide evidence for a close relationship among endothelial function, insulin resistance, and the renin-angiotensin system (RAS) through inflammatory actions in humans. Our results suggest that the interaction between free fatty acids and RAS may certainly be one piece of a jigsaw puzzle in terms of pathophysiology of atherosclerosis associated with obesity. As substantial experimental evidence suggests, RAS blockade is expected to suppress “the vicious synergy” between endothelial dysfunction and insulin resistance, and our results may partly explain how the RAS blockade works in such vascular and metabolic dysregulation. We should not be too optimistic, however, because prevention of type 2 diabetes mellitus by RAS blockade in patients with glucose intolerance was not necessarily successful.3 Blockade of RAS by valsartan significantly reduced the risk of new onset of diabetes mellitus, but the magnitude of the effect was much smaller than expected.4 Elevated plasma free fatty acid levels, which increase the risk for the development of type 2 diabetes mellitus, reportedly cause insulin resistance and β-cell dysfunction. Although we have shown that RAS blockade prevents adverse effects of free fatty acids on endothelium and leukocytes, roles of RAS in such free fatty acid–induced metabolic lipotoxity remain unknown. We need further clinical research to figure out what RAS blockade can do and cannot do in obesity-related cardiovascular and metabolic impairment.
Koh KK, Sakuma I, Quon MJ. Role of renin-angiotensin system blockades in reciprocal relationship between insulin resistance and endothelial dysfunction. Hypertension. 2010; 56: e169.
Azekoshi Y, Yasu T, Watanabe S, Tagawa T, Abe S, Yamakawa K, Uehara Y, Momomura S, Urata H, Ueda S. Free fatty acid causes leukocyte activation and resultant endothelial dysfunction through enhanced angiotensin II production in mononuclear and polymorphonuclear cells. Hypertension. 2010; 56: 136–142.
NAVIGATOR Study Group, McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B, Hua TA, Belenkov Y, Boolell M, Buse JB, Buckley BM, Chacra AR, Chiang FT, Charbonnel B, Chow CC, Davies MJ, Deedwania P, Diem P, Einhorn D, Fonseca V, Fulcher GR, Gaciong Z, Gaztambide S, Giles T, Horton E, Ilkova H, Jenssen T, Kahn SE, Krum H, Laakso M, Leiter LA, Levitt NS, Mareev V, Martinez F, Masson C, Mazzone T, Meaney E, Nesto R, Pan C, Prager R, Raptis SA, Rutten GE, Sandstroem H, Schaper F, Scheen A, Schmitz O, Sinay I, Soska V, Stender S, Tamás G, Tognoni G, Tuomilehto J, Villamil AS, Vozár J, Califf RM. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010; 362: 1477–1490.