Objective-Previous studies suggest that nitric oxide (NO) may modulate insulin-induced uptake of glucose in insulin-sensitive tissues. Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase (NOS). We hypothesized that a reduction in endogenous ADMA would increase NO synthesis and thereby enhance insulin sensitivity. Methods and Results-To test this hypothesis we used a transgenic mouse in which we overexpressed human dimethylarginine dimethylaminohydrolase (DDAH-I). The DDAH-I mice had lower plasma ADMA at all ages (22 to 70 wk) by comparison to wild-type (WT) littermates. With a glucose challenge, WT mice showed a prompt increase in ADMA, whereas DDAH-I mice had a blunted response. Furthermore, DDAH-I mice had a blunted increase in plasma insulin and glucose levels after glucose challenge, with a 50% reduction in the insulin resistence index, consistent with enhanced sensitivity to insulin. In liver, we observed an increased Akt phosphorylation in the DDAH-I mice after i.p. glucose challenge. Incubation of skeletal muscle from WT mice ex vivo with ADMA (2 mol/L) markedly suppressed insulin-induced glycogen synthesis in fast-twitch but not slow-twitch muscle. Conclusions-These findings suggest that the endogenous NOS inhibitor ADMA reduces insulin sensitivity, consistent with previous observations that NO plays a role in insulin sensitivity.
Background-Platelet adhesion on components of the extracellular matrix and platelet activation by those components are crucial for the arrest of posttraumatic bleeding, but they can also harm tissue by occluding diseased vessels. Recent studies have shown that the activation of platelets by collagen is mediated through the same pathway used by immune receptors, with an immunoreceptor tyrosine-based activation motif on the Fc receptor ␥ chain (FcR␥) playing a pivotal role. Methods and Results-We examined the role of collagen-stimulated platelets in the development of injury-induced neointimal formation by using mice deficient in FcR␥. The left femoral arteries of 8-to 12-week-old FcR␥-deficient mice (nϭ16) and C57BL/6 (wild-type) mice (nϭ16) were injured by a straight spring wire (0.35-mm diameter). Segments of the injured and uninjured femoral arteries were excised at 7 days and 28 days after the vascular injury. Arterial segments were examined by immunohistochemistry and electron microscopy. Two hours after injury, electron microscopy showed marked decreases in platelet adhesion and neutrophil attachment to the vascular wall surface in FcR␥-knockout mice compared with wild-type mice. At 7 days after injury, staining with anti-neutrophil antibody showed fewer neutrophils in FcR␥-knockout mice than in wild-type mice. Computer-aided morphometry performed to measure the neointimal area, intima/media ratio, and stenotic area at 28 days after injury showed a significantly smaller ratio and area in FcR␥-knockout mice than in wild-type mice (for neointimal area, 16 635Ϯ1406 versus 31 483Ϯ2309 m 2 , respectively; for intima/media ratio, 1.25Ϯ0.40 versus 2.68Ϯ0.04, respectively; and for stenotic area, 26.8Ϯ2.1% versus 49.3Ϯ4.1%, respectively). Conclusions-These
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