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.

Understanding postprandial glucose clearance by peripheral organs: the role of the hepatic parasympathetic system.

The hepatic parasympathetic system is one of the major contributors for preserving insulin sensitivity in the postprandial state. Postprandial hepatic vagal control of whole-body glucose clearance and its effect on specific organs remains unknown. Our hypothesis is that, in the postprandial state, the hepatic parasympathetic nerves (HPN) are responsible for a considerable part of extra-hepatic tissue glucose clearance. Two groups of 9-week-old Sprague-Dawley rats were studied, comparing sham-operated versus hepatic parasympathetic denervated animals. Insulin sensitivity was evaluated in the postprandial state by the rapid insulin sensitivity test (RIST). [(3) H]2-deoxy-d-glucose was administered during the RIST. Plasma glucose rate of the disappearance and clearance by skeletal muscle, adipose tissue, liver, pancreas, heart and kidney of this radioisotope was measured. The postprandial denervated group showed a decrease insulin sensitivity of 41.4 ± 5.2%. This group of animals showed a decrease in the rate of plasma [(3) H]2-deoxy-d-glucose disappearance and skeletal muscle, heart and kidney glucose clearance by 45%, 35% and 67%, respectively. These studies show that the major contributor of postprandial whole-body glucose clearance was skeletal muscle; in the range 69-38%, depending on HPN integrity. The results obtained in the present study indicate that HPN are crucial for postprandial action of insulin through a mechanism that is essential for maintenance of skeletal muscle, heart and kidney glucose clearance. These results suggest that hepatic parasympathetic dysfunction could lie at the genesis of type 2 diabetes complications, namely insulin resistance, nephropathy and cardiomyopathy.