Postprandial insulin resistance in Zucker diabetic fatty rats is associated with parasympathetic-nitric oxide axis deficiencies.

The Zucker diabetic fatty (ZDF) rat is an obesity and type 2 diabetes model. Progression to diabetes is well characterised in ZDF rats, but only in the fasted state. We evaluated the mechanisms underlying postprandial insulin resistance in young ZDF rats. We tested the hypothesis that the overall postprandial action of insulin is affected in ZDF rats as a result of impairment of the hepatic parasympathetic-nitric oxide (PSN-NO) axis and/or glutathione (GSH), resulting in decreased indirect (PSN-NO axis) and direct actions of insulin. Nine-week-old male ZDF rats and lean Zucker rats (LZR, controls) were used. The action of insulin was assessed in the fed state before and after parasympathetic antagonism atropine. Basal hepatic NO and GSH were measured, as well as NO synthase (NOS) and γ-glutamyl-cysteine synthethase (GCS) activity and expression. ZDF rats presented postprandial hyperglycaemia (ZDF, 201.4 ± 12.9 mg/dl; LZR, 107.7 ± 4.3 mg/dl), but not insulinopaenia (ZDF, 5.9 ± 0.8 ng/ml; LZR, 1.5 ± 0.3 ng/ml). Total postprandial insulin resistance was observed (ZDF, 78.6 ± 7.5 mg glucose/kg; LZR, 289.2 ± 24.7 mg glucose/kg), with a decrease in both the direct action of insulin (ZDF, 54.8 ± 7.0 mg glucose/kg; LZR, 173.3 ± 20.5 mg glucose/kg) and the PSN-NO axis (ZDF, 24.5 ± 3.9 mg glucose/kg; LZR, 115.9 ± 19.4 mg glucose/kg). Hepatic NO (ZDF, 117.2 ± 11.4 µmol/g tissue; LZR, 164.6 ± 4.9 µmol/g tissue) and GSH (ZDF, 4.9 ± 0.3 µmol/g; LZR, 5.9 ± 0.2 µmol/g) were also compromised as a result of decreased NOS and GCS activity, respectively. These results suggest a compromise of the mechanism responsible for potentiating insulin action after a meal in ZDF rats. We show that defective PSN-NO axis and GSH synthesis, together with an impaired direct action of insulin, appears to contribute to postprandial insulin resistance in this model.

Hepatic parasympathetic role in insulin resistance on an animal model of hypertension.

The hepatic insulin sensitizing substance (HISS) pathway, which includes the hepatic parasympathetic nerves and hepatic nitric oxide (HNO), has been shown to be crucial to the action of insulin on glucose metabolism. Insulin resistance in essential hypertension has been related to parasympathetic dysfunction; thus, we tested the hypothesis that the HISS pathway is impaired in spontaneously hypertensive rats (SHR) when compared with their normotensive controls, Wistar (WIS) and Wistar Kyoto (WKY) rats. A modified euglycemic clamp quantified insulin sensitivity. Differentiation of the HISS-dependent and HISS-independent components of insulin action was achieved by administration of a muscarinic receptor antagonist (atropine, 3 mg/kg) or of a nitric oxide synthase inhibitor (N(g)-methyl-arginine, 0.73 mg/kg). Both SHR and WKY had lower postprandial total insulin action when compared with WIS (209.1 +/- 13.6 for WKY and 217.8 +/- 19.8 for SHR vs 296.1 +/- 16.9 mg glucose/kg body weight for WIS, P < .05). Furthermore, we observed that this is due to a decrease of the HISS-dependent component of insulin action (154.8 +/- 16.4 for WIS vs 87.1 +/- 14.5 for WKY and 55.9 +/- 15.6 mg glucose/kg body weight for SHR; P < .05 and P < .001, respectively; data concerning the atropine protocol). Blockade of HISS action by inhibition of hepatic nitric oxide synthase with N(g)-methyl-arginine showed similar results to those obtained with atropine, suggesting that they indeed act through the same pathway. In conclusion, our results support our hypothesis that impairment of the HISS pathway is responsible for the development of insulin resistance between WIS and SHR.