Glucagon and Cyclic AMP: Time to Turn the Page?

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.

desHis1Glu9-glucagon-[mPEG] and desHis1Glu9(Lys30PAL)-glucagon: Long-acting peptide-based PEGylated and acylated glucagon receptor antagonists with potential antidiabetic activity

“…Subsequent studies confirmed the antagonistic properties of desHis 1 Glu 9 -glucagon-[mPEG] and desHis 1 -Glu 9 (Lys 30 PAL)-glucagon on glucagon-mediated biological action, by demonstrating that these compounds significantly inhibited glucagon induced elevations of cAMP generation and insulin release. Antagonistic effects on cAMP production were more prominent than corresponding actions on insulin secretion, suggesting that alternative signalling pathways may be involved in glucagon-mediated elevations of insulin secretion from BRIN BD11 cells (Rodgers, 2012). However, these data do accord with the supposition that the desHis 1 Glu 9 -glucagon derivatives are able to bind to, but not activate, the glucagon receptor (Unson et al, 1989).…”

Physiological and Pathophysiological Control of Glucagon Secretion by Pancreatic α-Cells

“…It might involve the stimulation of phospholipase C (via Gq and/or Gi/o (Xu and Xie (2009)) leading to IP 3 production. However, some investigators have attributed this effect to a cAMPdependent potentiation of the action of IP 3 -producing agents (Mayo et al 2003;Jelinek et al 1993;Wakelam et al 1986;Rodgers 2012;Wang et al 2012;Authier and Desbuquois 2008;Aromataris et al 2006;Hansen et al 1998;Pecker and Pavoine 1996). Experiments on cell lines expressing the glucagon receptor have shown that stimulation of IP 3 production requires high glucagon concentrations (Xu and Xie 2009).…”

Lack of glucagon receptor signaling and its implications beyond glucose homeostasis

“…cAMP activates signaling pathways that cause an increase in gluconeogenesis, glycogenolysis, and fatty acid oxidation. In addition, glucagon controls glucose, energy, and lipid metabolism at least in part via AC/cAMP-independent signals including p38MAPK, IP3/DAG/Ca, peroxisome proliferator-activated receptor alpha (PPARa), and fibroblast growth factor 21 (FGF21)-dependent pathways (Berglund et al 2010, Rodgers 2012, Cyphert et al 2014.…”