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Changing the Way We Think About Endothelial Cell Insulin Sensitivity, Nitric Oxide, and the Pathophysiology

Purpose Nitric oxide (NO) mediates vascular endothelial growth factor (VEGF)-induced angiogenesis and vascular hyperpermeability. The underlying mechanisms are not yet clear, in particular whether this defect is caused by a direct effect of diabetes on the activity and the expression of nitric oxide synthases (NOS) or indirectly by an enhanced inactivation of nitric oxide. Cultured murine glomerular endothelial cells exposed to high glucose had similar alterations in eNOS dimerization and phosphorylation. tNOS and ciNOS were assessed by measuring the conversion of [3H]L-arginine to [3H]L-citrulline in the three groups. This new research looked at how the body of a mouse generates NO. These inhibitors are competitive in nature and inhibit both the cytokine-inducible and constitutive isoforms of nitric oxide synthase with nearly identical kinetics. Based on the current evidence, it is reasonable to conclude that early nephropathy in diabetes is associated with increased intrarenal NO production mediated primarily by constitutively released NO (endothelial nitric oxide synthase [eNOS] and neuronal nitric oxide synthase [nNOS]).

Comparison of plasma NO levels between groups were performed by Mann-Whitney test and relationships between SSPG and different variables were analyzed by partial correlations. We have shown that insulin resistance specifically in the endothelium reduces NO bioavailability and increases the generation of potentially toxic levels of free radicals such as superoxide (11,12); this supports the hypothesis that insulin resistance at the level of the endothelium contributes to accelerated vascular disease seen in individuals with type 2 diabetes, and argues for the idea that it is a legitimate therapeutic target to treat diabetes-related atherosclerosis, as suggested by Rask-Madsen et al. Interestingly, NO donor treatment completely removed oxidative stress and nitrosative stress, and restored endothelial NO synthase expression in diabetic renal glomeruli. Results. Finally, in diabetic nephropathy NO deficiency may be associated to that of hydrogen sulfide, another interesting gaseous mediator which is increasingly investigated. nNOS gene deficiency does not protect from development of nerve conduction deficit, sensory neuropathy and intraepidermal nerve fiber loss. Questions remain regarding whether or not enhancing insulin sensitivity in the vascular wall of patients with type 2 diabetes is an appropriate therapeutic strategy.

Conditions with high salt-intake, elevated angiotensin II (Ang II) levels, or increased adenosine A-{1} receptor signaling may stimulate ROS production, and consequently impair renal, cardiovascular and metabolic regulation. By deleting the three isoforms of FoxO specifically in the endothelium, Accili and colleagues generated a model in which the restraining effect of the FoxOs on endothelial insulin signaling is removed. In a study conducted in bovine aortic endothelial cells, King and Johnson (17) reported that the transport of insulin across a cell monolayer is saturable and unidirectional, consistent with receptor-mediated transport. Moreover, negative feedback effects of FoxOs on upstream insulin signaling elements such as Akt can also dampen insulin signaling. If eNOS stimulation rely on partly different mechanisms in men and women under normal physiological conditions, women after menopause would be more susceptible/vulnerable to any additional factors that impair eNOS function and NO bioavailability than men, and this could offer a putative explanation to why the combined effect of T2DM and the Asp298 allele is stronger in women than in men in our survey. In a model of advanced atherosclerosis and metabolic dysfunction (VECKO mice crossed onto an atherosclerosis-prone LDL receptor–deficient (Ldlr−/−) background), the Accili laboratory demonstrated that the deletion of all three FoxO isoforms in the endothelium has a potentially favorable effect on the development of vascular dysfunction and atherosclerosis (17). Suppressed PGI2 (12–15) and/or increased TxA2 or PGH2 (16–19) have been reported in the early stage of diabetes (1,4).

To treat these attacks, researchers are trying to find ways to selectively inhibit the production of nitric oxide where it is harming the body — without decreasing the overall levels of beneficial nitric oxide. By contrast, in this model of metabolic and vascular dysfunction, no beneficial effect on metabolic parameters or glucose homeostasis was shown. As mentioned above in athletes the ATP/ADP ratio and NO have a more positive significant in comparison with others, this due to exercise led to increase in ca +2 and then activation of nitric oxide synthase from a series of signal such as increase in ATP/ADP ratio, NADPH ,… and also decrease in reactive oxygen species(ROS) [ 46 ] (Figure 5 ). Reliable, reproducible quantitative estimation of diabetic macular edema has been realized with advent of spectral domain optical coherence tomography (SD-OCT). Tsuchiya and Accili (16) examined the effect of the deletion of the FoxOs in mouse endothelium against a C57BL/6 background and standard chow diet. Intriguingly, standard chow–fed VECKO mice were glucose intolerant and had reduced insulin sensitivity; the defect in insulin action was identified as being in the liver. As expected, increasing insulin sensitivity in liver endothelial cells by deleting the FoxOs increased eNOS-derived NO.

Surprisingly, NO reduced hepatic insulin sensitivity by tyrosine nitration of the insulin receptor in hepatocytes. Previous studies demonstrated that intrinsic or mitochondrial pathway involve in CM induces renal cells apoptosis [44]. BH4 is both an anti-oxidant and an essential cofactor of eNOS and other members of the monooxygenase family [39]. It should be noted that the effect of FoxO deletion on endothelial cell function in the aorta or other arteries was not examined; it would be interesting to know whether or not—despite insulin resistance and glucose intolerance—FoxO deletion in the endothelium has a favorable effect on endothelial cell function in atherosclerosis-prone vessels (Fig. 1). Diabetes mellitus was considered to be present if the fasting glucose concentration is greater than 126 mg/mL. Negative effect of increased NO on hepatic glucose homeostasis in early insulin resistance and favorable effect on atherosclerosis in more advanced metabolic disease.

So where does the phenotype of the endothelium-specific FoxO-deficient mouse leave us? The new data support insulin sensitization in the vascular endothelium as a useful strategy in advanced vascular disease. The data from mice without the severe insult of hypercholesterolemia are more challenging to reconcile with our current way of thinking about NO and type 2 diabetes. With the important caveat that the effect of different mechanisms of enhancing insulin sensitivity in the endothelium other than the deletion of FoxOs need to be examined, Tsuchiya and Accili (16) show that, in the case of NO and hepatic glucose homeostasis, it is possible to get too much of a good thing. Their results raise the exciting possibility that the hyperinsulinemia of early insulin resistance is a legitimate therapeutic target.

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