Abstract
Glucagon levels are often moderately elevated in diabetes. It is known that glucagon leads to a decrease in hepatic glutathione (GSH) synthesis that in turn is associated with decreased postprandial insulin sensitivity. Given that cAMP pathway controls GSH levels we tested whether insulin sensitivity decreases after intraportal (ipv) administration of a cAMP analog (DBcAMP), and investigated whether glucagon promotes insulin resistance through decreasing hepatic GSH levels.Insulin sensitivity was determined in fed male Sprague-Dawley rats using a modified euglycemic hyperinsulinemic clamp in the postprandial state upon ipv administration of DBcAMP as well as glucagon infusion. Glucagon effects on insulin sensitivity was assessed in the presence or absence of postprandial insulin sensitivity inhibition by administration of L-NMMA. Hepatic GSH and NO content and plasma levels of NO were measured after acute ipv glucagon infusion. Insulin sensitivity was assessed in the fed state and after ipv glucagon infusion in the presence of GSH-E. We founf that DBcAMP and glucagon produce a decrease of insulin sensitivity, in a dose-dependent manner. Glucagon-induced decrease of postprandial insulin sensitivity correlated with decreased hepatic GSH content and was restored by administration of GSH-E. Furthermore, inhibition of postprandial decrease of insulin sensitivity L-NMMA was not overcome by glucagon, but glucagon did not affect hepatic and plasma levels of NO. These results show that glucagon decreases postprandial insulin sensitivity through reducing hepatic GSH levels, an effect that is mimicked by increasing cAMP hepatic levels and requires physiological NO levels. These observations support the hypothesis that glucagon acts via adenylate cyclase to decrease hepatic GSH levels and induce insulin resistance. We suggest that the glucagon-cAMP-GSH axis is a potential therapeutic target to address insulin resistance in pathological conditions.
Highlights
The prandial status modulates the physiology of whole-body insulin-stimulated glucose disposal which reaches a maximum after a meal and decreases by about 55% after a 24h fasting period [1, 2]
We found that increasing doses of ipv DBcAMP (n = 8) lead to decrease peripheral insulin sensitivity (DBcAMP 0.01mg/kg: from 172.3±6.3mg glucose/kg bw to 125.7±8.3mg glucose/kg bw, p
These results indicate that intraportal infusion of DBcAMP induced a state of insulin resistance suggesting that cyclic adenosine 5’-monophosphate (cAMP) play a role in regulating whole-body glucose homeostasis
Summary
The prandial status modulates the physiology of whole-body insulin-stimulated glucose disposal which reaches a maximum after a meal and decreases by about 55% after a 24h fasting period [1, 2]. Maximal postprandial insulin sensitivity requires signals provided by the hepatic parasympathetic nerves (HPN) [1] and it was recently demonstrated that HPN controls postprandial plasma glucose clearance by skeletal muscle, heart, and kidney [3]. The HPN-NO signal maximizes postprandial insulin sensitivity in presence of optimal levels of hepatic glutathione (GSH) [5]. We have shown that hepatic GSH levels increase in the postprandial state and that co-administration of NO and GSH during fasting induces maximal postprandial insulin sensitivity [5]. Together these data strongly suggest that GSH and HPN-NO interplay in the liver to achieve maximal peripheral postprandial insulin action. It is well known that cAMP is a negative regulator of hepatic GSH production [6,7,8,9,10,11] but it remains unknown whether this action impacts on postprandial insulin sensitivity
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