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Reply to Rodgers: The hepatic glucose-mobilizing effect of glucagon is not mediated by cyclic AMP most of the time

Reply to Rodgers: The hepatic glucose-mobilizing effect of glucagon is not mediated by cyclic AMP... Am J Physiol Endocrinol Metab 321: E579, 2021. First published September 6, 2021; doi:10.1152/ajpendo.00304.2021 POINT:COUNTERPOINT Reply to Rodgers: The hepatic glucose-mobilizing effect of glucagon is not mediated by cyclic AMP most of the time Nicolai J. Wewer Albrechtsen Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark A central dogma in glucagon biology is the acute effects of DISCLOSURES glucagon on hepatic glucose production. However, this No conflicts of interest, financial or otherwise, are declared by needs to be put into a physiological context hereof to insulin the author. levels. Dr. Rodgers argues that glucagon effect on glucose production may not be dependent on cyclic AMP “most of AUTHOR CONTRIBUTIONS the time” (1). The main argument made by Dr. Rodgers appears to be a lack of “sufficient” glucagon levels in the por- N.J.W.A. drafted manuscript; edited and revised manuscript; tal vein to induce glucose production from the liver via and approved final version of manuscript. cAMP. Some counterarguments must be considered. First, accurate measurement of glucagon is still after more than REFERENCES 50 years, limited (2). Not only will most glucagon assays used 1. Rodgers RL. The hepatic glucose-mobilizing effect of glucagon is have an inherent specificity challenge but also the lack of not mediated by cyclic AMP most of the time. Am J Physiol and use of assay standards calibrated toward an interna- Endocrinol Metab,2021. doi:10.1152/ajpendo.000171.2021. tional reference value (3) preclude comparisons of absolute 2. Holst JJ, Wewer Albrechtsen NJ. Methods and guidelines for mea- glucagon concentrations. Taken together, we need new stud- surement of glucagon in plasma. Int J Mol Sci 20: 5416, 2019. ies using more accurate glucagon immunoassays of portal doi:10.3390/ijms20215416. levels of glucagon in humans. Finally, as previously shown, 3. Wewer Albrechtsen NJ, Hartmann B, Veedfald S, Windeløv JA, glucagon levels are two to threefold higher in samples that Plamboeck A, Bojsen-Møller KN, Idorn T, Feldt-Rasmussen B, Knop FK, Vilsboll T, Madsbad S, Deacon CF, Holst JJ. have not been subjected to a freeze-thaw cycle (4). Collectively, Hyperglucagonaemia analysed by glucagon sandwich ELISA: non- drawing conclusions merely on portal levels of glucagon may specific interference or truly elevated levels? Diabetologia 57: 1919– not be valid. 1926, 2014. doi:10.1007/s00125-014-3283-z. Finally, glucagon biology is complex and the effect of glu- 4. Wewer Albrechtsen NJ, Bak MJ, Hartmann B, Christensen LW, cagon on glucose production may depend on several factors Kuhre RE, Deacon CF, Holst JJ. Stability of glucagon-like peptide 1 hereof the amount of stored glycogen and the corresponding and glucagon in human plasma. Endocr Connect 4: 50–57, 2015. levels of insulin (the glucagon: insulin ratio). The latter is doi:10.1530/EC-14-0126. 5. Galsgaard KD, Winther-Sørensen M, Pedersen J, Kjeldsen SAS, clear as to when manipulating with glucagon and insulin re- Rosenkilde MM, Wewer Albrechtsen NJ, Holst JJ. Glucose and ceptor signaling (5). amino acid metabolism in mice depend mutually on glucagon and Collectively, it is indisputable that glucagon increases he- insulin receptor signaling. Am J Physiol Endocrinol Metab 316: patic production of cAMP and glucose and if reviewing the E660–E673, 2019. doi:10.1152/ajpendo.00410.2018. arguments made here and elsewhere (6) cAMP appears to be 6. Wewer Albrechtsen NJ. The glucose-mobilizing effect of glucagon a key factor for glucagon receptor signaling and glucose at fasting is mediated by cyclic AMP. Am J Physiol Endocrinol production. Metabol, 2021. doi:10.1152/ajpendo.00172.2021. Correspondence: N. J. Wewer Albrechtsen (nicolai.albrechtsen@sund.ku.dk). Submitted 25 August 2021 / Accepted 31 August 2021 http://www.ajpendo.org 0193-1849/21 Copyright © 2021 the American Physiological Society. E579 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Endocrinology and Metabolism The American Physiological Society

Reply to Rodgers: The hepatic glucose-mobilizing effect of glucagon is not mediated by cyclic AMP most of the time

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ISSN
0193-1849
eISSN
1522-1555
DOI
10.1152/ajpendo.00304.2021
Publisher site
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Abstract

Am J Physiol Endocrinol Metab 321: E579, 2021. First published September 6, 2021; doi:10.1152/ajpendo.00304.2021 POINT:COUNTERPOINT Reply to Rodgers: The hepatic glucose-mobilizing effect of glucagon is not mediated by cyclic AMP most of the time Nicolai J. Wewer Albrechtsen Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark A central dogma in glucagon biology is the acute effects of DISCLOSURES glucagon on hepatic glucose production. However, this No conflicts of interest, financial or otherwise, are declared by needs to be put into a physiological context hereof to insulin the author. levels. Dr. Rodgers argues that glucagon effect on glucose production may not be dependent on cyclic AMP “most of AUTHOR CONTRIBUTIONS the time” (1). The main argument made by Dr. Rodgers appears to be a lack of “sufficient” glucagon levels in the por- N.J.W.A. drafted manuscript; edited and revised manuscript; tal vein to induce glucose production from the liver via and approved final version of manuscript. cAMP. Some counterarguments must be considered. First, accurate measurement of glucagon is still after more than REFERENCES 50 years, limited (2). Not only will most glucagon assays used 1. Rodgers RL. The hepatic glucose-mobilizing effect of glucagon is have an inherent specificity challenge but also the lack of not mediated by cyclic AMP most of the time. Am J Physiol and use of assay standards calibrated toward an interna- Endocrinol Metab,2021. doi:10.1152/ajpendo.000171.2021. tional reference value (3) preclude comparisons of absolute 2. Holst JJ, Wewer Albrechtsen NJ. Methods and guidelines for mea- glucagon concentrations. Taken together, we need new stud- surement of glucagon in plasma. Int J Mol Sci 20: 5416, 2019. ies using more accurate glucagon immunoassays of portal doi:10.3390/ijms20215416. levels of glucagon in humans. Finally, as previously shown, 3. Wewer Albrechtsen NJ, Hartmann B, Veedfald S, Windeløv JA, glucagon levels are two to threefold higher in samples that Plamboeck A, Bojsen-Møller KN, Idorn T, Feldt-Rasmussen B, Knop FK, Vilsboll T, Madsbad S, Deacon CF, Holst JJ. have not been subjected to a freeze-thaw cycle (4). Collectively, Hyperglucagonaemia analysed by glucagon sandwich ELISA: non- drawing conclusions merely on portal levels of glucagon may specific interference or truly elevated levels? Diabetologia 57: 1919– not be valid. 1926, 2014. doi:10.1007/s00125-014-3283-z. Finally, glucagon biology is complex and the effect of glu- 4. Wewer Albrechtsen NJ, Bak MJ, Hartmann B, Christensen LW, cagon on glucose production may depend on several factors Kuhre RE, Deacon CF, Holst JJ. Stability of glucagon-like peptide 1 hereof the amount of stored glycogen and the corresponding and glucagon in human plasma. Endocr Connect 4: 50–57, 2015. levels of insulin (the glucagon: insulin ratio). The latter is doi:10.1530/EC-14-0126. 5. Galsgaard KD, Winther-Sørensen M, Pedersen J, Kjeldsen SAS, clear as to when manipulating with glucagon and insulin re- Rosenkilde MM, Wewer Albrechtsen NJ, Holst JJ. Glucose and ceptor signaling (5). amino acid metabolism in mice depend mutually on glucagon and Collectively, it is indisputable that glucagon increases he- insulin receptor signaling. Am J Physiol Endocrinol Metab 316: patic production of cAMP and glucose and if reviewing the E660–E673, 2019. doi:10.1152/ajpendo.00410.2018. arguments made here and elsewhere (6) cAMP appears to be 6. Wewer Albrechtsen NJ. The glucose-mobilizing effect of glucagon a key factor for glucagon receptor signaling and glucose at fasting is mediated by cyclic AMP. Am J Physiol Endocrinol production. Metabol, 2021. doi:10.1152/ajpendo.00172.2021. Correspondence: N. J. Wewer Albrechtsen (nicolai.albrechtsen@sund.ku.dk). Submitted 25 August 2021 / Accepted 31 August 2021 http://www.ajpendo.org 0193-1849/21 Copyright © 2021 the American Physiological Society. E579

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AJP - Endocrinology and MetabolismThe American Physiological Society

Published: Oct 1, 2021

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