The glucose-mobilizing effect of glucagon at fasting is mediated by cyclic AMP
2021; American Physiological Society; Volume: 321; Issue: 4 Linguagem: Inglês
10.1152/ajpendo.00172.2021
ISSN1522-1555
Autores Tópico(s)Metabolism, Diabetes, and Cancer
ResumoPoint: CounterpointThe glucose-mobilizing effect of glucagon at fasting is mediated by cyclic AMPNicolai J. Wewer AlbrechtsenNicolai J. Wewer AlbrechtsenDepartment of Clinical Biochemistry, Rigshospitalet & Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, DenmarkDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkPublished Online:11 Oct 2021https://doi.org/10.1152/ajpendo.00172.2021This is the final version - click for previous versionMoreSectionsPDF (924 KB)Download PDFDownload PDFPlus ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail Glucagon is a fascinating peptide hormone. Since the discovery of a “glucose stimulatory factor” from the pancreas (1), the physiological role of glucagon continues to be investigated and highly debated (2–5). This is exemplified by glucagon’s role in glucose control (5). From randomized clinical trials with glucagon receptor antagonists, we know that glucagon is a powerful regulator of fasting glucose in humans (6, 7) as previously demonstrated in preclinical studies (8, 9). However, the role of glucagon in postprandial glycemic control appears less clear, as those same studies did not observe any additional improvements in postprandial glucose once changes in fasting glucose had been considered. The main arguments made in this article are that 1) cyclic adenosine monophosphate (cAMP) mediates glucagon glucose regulatory effects in (short-term) fasted conditions and 2) glucagon role in postprandial metabolism is to regulate amino acid metabolism [termed the liver-α cell axis (2)] and second to circumvent the potential hypoglycemic effects of an amino acid-induced hyperinsulinemia (Fig. 1). These arguments are placed in a context of glucagon resistance, and a new physiological terminology was observed in patients with type 2 diabetes and nonalcoholic fatty liver disease (10).Figure 1.Glucagon receptor signaling, cAMP, and metabolic diseases. The figure illustrates glucagon receptor signaling in a hepatocyte including both cAMP dependent and independent aspects. cAMP directly activates protein kinase A (PKA) that may together with cAMP or through receptor-mediated downstream signals increases ureagenesis directly (nontranscriptional) and transcriptionally (amino acid transporters). On short term, glucagon increases glycogenolysis and thereby increasing hepatic glucose production through nontranscriptional mechanism(s) but may through transcriptional activation of CREB also affect molecules necessary for gluconeogenesis as well as glycogenolysis. In fatty liver disease and diabetes, the effects of glucagon on hepatic amino acid metabolism are disrupted causing unbalancing signaling at both transcriptional and nontranscriptional levels. This causes hyperaminoacidemia with prevalence of glucagonotropic amino acids resulting in hyperglucagonemia. cAMP levels will increase in parallel with increased glucagon in plasma causing increased glucose production via glycogenolysis and importantly through gluconeogenesis. cAMP, cyclic adenosine monophosphate.Download figureDownload PowerPointThe observation by Raskin et al. (11) of a paradoxically hypersecretion of glucagon in response to orally ingested glucose in individuals with diabetes did in fact initiate the hypothesis that increased glucagon contributes to diabetes. These findings of hyperglucagonemia in the context of T2D have been replicated in dozens of studies (12). But, is the hyperglucagonemia observed during an OGTT in diabetes linked to glucagon’s role in postprandial glucose homeostasis? I do not think so. The emerging concept of glucagon resistance proposed (13) in patients with type 2 diabetes and fatty liver disease may be explained by differential glucagon receptor signaling pathways. Exemplified as cAMP as the driver of fasting glucose and non-cAMP dependent mechanism(s) regulating substrate-dependent hepatic amino acid catabolism (e.g., CPS1 (14)). Glucagon resistance (the differential signaling pathways of glucose vs. amino acid catabolism) results in 1) hyperaminoacidemia (due to impaired glucagon induced ureagenesis), 2) hyperglucagonemia (due to impaired glucagon-induced amino acid trapping and ureagenesis), and 3) increased glucose production (due to the differential glucagon sensitivity of cAMP and non-cAMP-mediated mechanisms) (Fig. 1) (10, 14, 15).So how does glucagon regulate fasting blood glucose? As the textbooks of physiology espouse, glucagon increases hepatic glucose production by increasing glycogenolysis and gluconeogenesis. The latter appears to be increased in patients with diabetes, potentially as a result of the reduced insulin:glucagon ratio and insulin resistance (16). Glucagon’s acute effect on glucose production obviously depends on the amount of stored glycogen and, hence, is related to the extent of a carbohydrate rich diet (17). Given that glucagon increases blood glucose within minutes, the molecular actions mediated in this setting must be nontranscriptional, whereas the effect on gluconeogenesis is more complex and involves both transcriptional and nontranscriptional mechanisms. Regarding the acute effects of glucagon on blood glucose, the activation of glucagon receptor signaling increases intracellular levels of the second messenger cAMP that, via several downstream effectors (protein kinase A = phosphorylation), activates glycogen phosphorylase kinase and inhibits glycogen synthase, thereby tipping the balance toward increased glycogenolysis and decreased glycolysis and glycogenesis (Fig. 1). This, in turn, results in increased intracellular levels of glucose 1-phosphate and thereby increased hepatic glucose production. Glucagon-stimulated glucose-6-phosphotase catalytic subunit may as well depend on cAMP but not on gene expression, as demonstrated in vivo (in clamped dogs) and using HEPG2 cells (18). Given that gluconeogenesis is substrate-dependent, and that glucagon does not provide substrates (e.g., muscle-derived amino acids), other mechanisms, including catecholamines and cortisol, may be necessary for long-term fasting or when glycogen storage is insufficient. Glucagon may affect glucose production by calcium signaling; however, at least in isolated hepatocytes from fed rats, the effects on gluconeogenesis appear largely independent of calcium (19), whereas others have claimed calcium to be a more important driver the glucagon induce glucose production (20).The discovery of second messengers, like cAMP, was proposed 50 years ago (21) and cAMP was later shown to mediate the actions of catecholamines and glucagon on glycogen metabolism and hence hepatic glucose production (22, 23). The downstream signaling pathways of cAMP are complex and may each play a specific role in the biological effects of altered levels of cAMP (24). A prevailing consensus is that after glucagon has bound to its cognate receptor, a conformational change occur which results in the activation of the G α s proteins and the production of cAMP via adenylate cyclase. Glucagon may also indirectly increase cAMP by the inhibition of phosphodiesterase (25). It has for decades been known that glucagon receptor activation increases cAMP production (21, 26), and indeed, cAMP appears to be the principal metabolite of hepatocyte activation after the administration of glucagon in the perfused rat liver (14). Glucagon-induced cAMP production can be detected in vitro after just 30 s of incubation and typically peaks at 5 min (27). A glucagon concentration of 1 × 10−10 M (100 pmol/L) is required to increase the hepatic production of glucose. However, circulating glucagon levels (measured in the peripheral blood) are typically between 5 and 50 pmol/L (28), depending on fasted versus fed conditions (in particularly during protein rich meals). So how can glucagon mediate its effect on glucose production if cAMP levels/glucose production is only first observed at 100 pmol/L? Several factors need to be accounted for. First, let us have a look at portal versus peripheral levels of glucagon. Concentrations of glucagon in the portal vein reflect the inherent difference in splenic versus systemic blood, and are threefold higher than what is measured in the periphery. Secondly, glucagon is extremely sensitive to preanalytical handling ex vivo, with up to 50% of measurable glucagon being simply “lost” after a single freeze-thaw cycle, which can rise to around a 90% loss if samples are stored at an inappropriate temperature (29). Therefore, employing a conservative estimation, portal levels of glucagon are probably 10 times higher than what measured in peripheral blood, meaning that liver exposure to glucagon concentrations in the range of 50 to 500 pmol/L is entirely feasible (30). This is indeed a key argument for the idea that the glucagon mediates its effect on glucose production via cAMP under physiological conditions. Secondly, this argument is supported by the studies of the commonly used glucose-lowering compound, metformin. Metformin has been shown to reduce hepatic glucose production, partly by antagonizing AMPK, but importantly, also by impairing glucagon-induced glucose production, by reducing cAMP levels (31, 32).In summary, glucagon mediates its effect on glycemia in the fasted state by downstream signaling pathways of cAMP, whereas nutrients, in particular proteins, together with glucagon constitute a physiological interplay (the liver-α cell axis) that fine tunes amino acid metabolism in both fasted and postprandial state by signaling independent to that of glucose production/cAMP and thereby evoking the possibility of biased signaling pathways of glucagon explaining the emerging terminology of glucagon receptor resistance toward amino acid metabolism but not glucose (10).GRANTSN. J. Wewer Albrechtsen was supported by a Future Leader Award from EFSD/Novo Nordisk Fonden (NNF) (NNF14CC0001) and an NNF Excellence Emerging Investigator Grant—Endocrinology and Metabolism (application No. NNF19OC0055001).DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSN.J.W.A. conceived and designed research; N.J.W.A. performed experiments; N.J.W.A. analyzed data; N.J.W.A. interpreted results of experiments; N.J.W.A. edited and revised manuscript; N.J.W.A. approved final version of manuscript.REFERENCES1. Kimball CP, Murlin JR. Aqueous extracts of pancreas: III. Some precipitation reactions of insulin. J Biol Chem 58: 337–346, 1923. doi:10.1016/S0021-9258(18)85474-6.Crossref | Google Scholar2. Albrechtsen NJW, Kuhre RE, Pedersen J, Knop FK, Holst JJ. The biology of glucagon and the consequences of hyperglucagonemia. Biomark Med 10: 1141–1151, 2016. doi:10.2217/bmm-2016-0090. Crossref | PubMed | ISI | Google Scholar3. 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Previous Back to Top Next FiguresReferencesRelatedInformationRelated articlesReply to Wewer Albrechtsen: The glucose-mobilizing effect of glucagon at fasting is mediated by cyclic AMP 11 Oct 2021American Journal of Physiology-Endocrinology and MetabolismThe hepatic glucose-mobilizing effect of glucagon is not mediated by cyclic AMP most of the time 11 Oct 2021American Journal of Physiology-Endocrinology and MetabolismCited ByOn measurements of glucagon secretion in healthy, obese, and Roux-en-Y gastric bypass operated individuals using sandwich ELISA22 December 2021 | Scandinavian Journal of Clinical and Laboratory Investigation, Vol. 82, No. 1Physiological significance of bistable circuit design in metabolic homeostasis: role of integrated insulin-glucagon signalling network25 January 2022 | Molecular Biology Reports, Vol. 9Reply to Wewer Albrechtsen: The glucose-mobilizing effect of glucagon at fasting is mediated by cyclic AMPRobert L. Rodgers11 October 2021 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 321, No. 4Reply to Rodgers: The hepatic glucose-mobilizing effect of glucagon is not mediated by cyclic AMP most of the timeNicolai J. Wewer Albrechtsen11 October 2021 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 321, No. 4 More from this issue > Volume 321Issue 4October 2021Pages E571-E574 Crossmark Copyright & PermissionsCopyright © 2021 the American Physiological Society.https://doi.org/10.1152/ajpendo.00172.2021PubMed34369821History Received 6 May 2021 Accepted 21 July 2021 Published online 11 October 2021 Published in print 1 October 2021 Keywordsamino acidscampglucagonglucoseglycogenolysisPDF download Metrics Downloaded 903 times
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