Key result
INT-747 upregulated hepatic DDAH1 expression and enhanced insulin sensitivity, reducing the Insulin Resistance index by up to 23.6% in high-salt fed Dahl rats, though it did not lower blood pressure.
Why the study?
Does INT-747 improve blood pressure and insulin sensitivity in high-salt fed Dahl rats?
Does INT-747 improve blood pressure and insulin sensitivity in high-salt fed Dahl rats?
Effect estimate: 23.6% reduction
p-value: p=<0.05
In a Dahl rat model of salt-sensitive hypertension, the FXR agonist INT-747 improved insulin sensitivity and preserved DDAH expression but did not lower blood pressure.
May support FXR agonism for insulin resistance in salt-sensitive models; leaves open blood pressure effects and human translation.
AIMS: Genetic and pharmacological studies have shown that impairment of the nitric oxide (NO) synthase (NOS) pathway is associated with hypertension and insulin-resistance (IR). In addition, inhibition of NOS by the endogenous inhibitor, asymmetric dimethylarginine (ADMA), may also result in hypertension and IR. On the other hand, overexpression of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that metabolizes ADMA, in mice is associated with lower ADMA, increased NO and enhanced insulin sensitivity. Since DDAH carries a farnesoid X receptor (FXR)-responsive element, we aimed to upregulate its expression by an FXR-agonist, INT-747, and evaluate its effect on blood pressure and insulin sensitivity. METHODS AND RESULTS: In this study, we evaluated the in vivo effect of INT-747 on tissue DDAH expression and insulin sensitivity in the Dahl rat model of salt-sensitive hypertension and IR (Dahl-SS). Our data indicates that high salt (HS) diet significantly increased systemic blood pressure. In addition, HS diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls. CONCLUSION: Our study may provide the basis for a new therapeutic approach for IR by modulating DDAH expression and/or activity using small molecules.
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Ghebremariam et al. (2013) studied Salt-sensitive hypertension and insulin resistance (n=54). INT-747 vs. Vehicle (1% methylcellulose) was evaluated on Insulin Resistance (IR) index (23.6% reduction, p=<0.05). INT-747 upregulated hepatic DDAH1 expression and enhanced insulin sensitivity, reducing the Insulin Resistance index by up to 23.6% in high-salt fed Dahl rats, though it did not lower blood pressure.
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