Abstract

It is well established that glucagon can stimulate adipose lipolysis, myocardial contractility, and hepatic glucose output by activating a GPCR and adenylate cyclase (AC) and increasing cAMP production. It is also widely reported that activation of AC in all three tissues requires pharmacological levels of the hormone, exceeding 0.1 nM. Extensive evidence is presented here supporting the view that cAMP does not mediate metabolic actions of glucagon on adipose, heart, or liver in vivo. Only pharmacological levels stimulate AC, adipose lipolysis, or cardiac contractility. Physiological concentrations of glucagon (below 0.1 nM) duplicate metabolic effects of insulin on the heart by activating a PI3K-dependent signal without stimulating AC. In the liver, glucagon can enhance gluconeogenesis and glucose output - by increasing the expression of PEPCK or inhibiting the activity of PK - at pharmacological concentrations by activating AC coupled to a low-affinity GPCR, but also at physiological concentrations by activating a high affinity receptor without generating cAMP. Plausible AC/cAMP-independent signals mediating the increase in gluconeogenesis include p38 MAPK (PEPCK expression) and IP3/DAG/Ca(2+) (PK activity). None of glucagon's physiological effects can be explained by activation of spare receptors or amplification of the AC/cAMP signal. In a new model proposed here, glucagon antagonizes insulin on the liver but mimics insulin on the heart without activating AC. Confirmation of the model would have broad implications, applicable not only to the general field of metabolic endocrinology but also to the specific role of glucagon in the pathogenesis and treatment of diabetes.

Links

Publisher Full Text

Authors

Rodgers RL

Institution

Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA. rrodgers@uri.edu

Source

Current diabetes reviews 8:5 2012 Sep pg 362-81

MeSH

Adipose Tissue
Biological Transport
Cyclic AMP
Female
Glucagon
Humans
Insulin
Insulin Resistance
Liver
Male
Myocardium
Phosphoenolpyruvate Carboxykinase (ATP)
Pyruvate Kinase
Signal Transduction

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

22587514