Glucagon, cyclic AMP, and hepatic glucose mobilization: A half-century of uncertainty

For at least 50 years, the prevailing view has been that the adenylate cyclase (AC)/cyclic AMP (cAMP)/protein kinase A pathway is the predominant signal mediating the hepatic glucose-mobilizing actions of glucagon. A wealth of evidence, however, supports the alternative, that the operative signal most of the time is the phospholipase C (PLC)/inositol-phosphate (IP3)/calcium/calmodulin pathway. The evidence can be summarized as follows: (1) The consensus threshold glucagon concentration for activating AC ex vivo is 100 pM, but the statistical hepatic portal plasma glucagon concentration range, measured by RIA, is between 28 and 60 pM; (2) Within that physiological concentration range, glucagon stimulates the PLC/IP3 pathway and robustly increases glucose output without affecting the AC/cAMP pathway; (3) Activation of a latent, amplified AC/cAMP pathway at concentrations below 60 pM is very unlikely; and (4) Activation of the PLC/IP3 pathway at physiological concentrations produces intracellular effects that are similar to those produced by activation of the AC/cAMP pathway at concentrations above 100 pM, including elevated intracellular calcium and altered activities and expressions of key enzymes involved in glycogenolysis, gluconeogenesis, and glycogen synthesis. Under metabolically stressful conditions, as in the early neonate or exercising adult, plasma glucagon concentrations often exceed 100 pM, recruiting the AC/cAMP pathway and enhancing the activation of PLC/IP3 pathway to boost glucose output, adaptively meeting the elevated systemic glucose demand. Whether the AC/cAMP pathway is consistently activated in starvation or diabetes is not clear. Because the importance of glucagon in the pathogenesis of diabetes is becoming increasingly evident, it is even more urgent now to resolve lingering uncertainties and definitively establish glucagon's true mechanism of glycemia regulation in health and disease.