G·A·B·B·A

Insulin action is associated with the release of the Hepatic Insulin Sensitizing Substance (HISS), which enhances peripheral glucose uptake. In the fed state, HISS release is maximal, decreasing with the duration of fasting. The prandial control of HISS action is mediated through hepatic parasympathetic - derived nitric oxide (NO), and hepatic glutathione (GSH). The current methods used to evaluate insulin sensitivity are only performed in the fasted state. The present thesis focus on the hypothesis that HISS-dependent mechanism exists in humans and can be manipulated.
In humans, a new powerful tool to characterize HISS-dependent insulin action not only in the fasted, but also in the fed state, the Rapid Insulin Sensitivity Test (RIST), was developed. The RIST can be performed with reproducible results, having no intra and inter-variability.
The decreased insulin sensitivity observed in the fasted state is potentiated following a meal, and intravenous atropine administration suppresses this effect. The partial blockade of meal-induced insulin sensitization (MIS), is consistent with the hypothesis that a hepatic parasympathetic “feeding signal” is necessary for hepatic HISS release.
When lean and overweight subjects were submitted to a 24h fasting period, the insulin action per se, was similar in both groups studied. However, when one performed the insulin sensitivity in the fed state, the results present within this thesis have shown that, the lower MIS observed in the overweight subjects is associated with an impairment of the HISS-dependent component. These results indicate the importance of postprandial insulin sensitivity evaluation, and also suggested that the prediabetic state can only be detected in the fed state.
Hyperglucagonemia is associated with type 2 diabetes. It is already known that glucagon leads to a decrease in GSH synthesis and hepatic GSH is crucial for HISS release, therefore the effect of glucagon on HISS-pathway was evaluated. In animals, both a cAMP analog, and glucagon produce a decrease of insulin sensitivity in a dose-dependent manner. The HISS-dependent insulin resistance produced by a NO synthase inhibitor was not aggravated by glucagons. These results suggest that glucagon, leads to reduced insulin sensitivity through a decrease of HISS action, and not via some other action. The two observations together are in support that glucagon acts via cAMP pathway to decrease hepatic GSH levels, leading to an impairment of HISS release. This decrease might be responsible for an earlier stage of insulin release.