Hepatic glucagon clearance during insulin induced hypoglycemia
Abstract
Studies concerning the importance of glucagon secretion in hypoglycemic counterregulation have assumed that peripheral levels of glucagon are representative of rates of pancreatic glucagon secretion. The measurement of peripheral levels of this hormone, however, may be a poor reflection of secretion rates because of glucagon's metabolism by the liver. Therefore, in order to understand the relationship between pancreatic glucagon secretion and levels of glucagon in the peripheral blood during hypoglycemia, we evaluated hepatic glucagon metabolism during insulin induced hypoglycemia. Four dogs received an insulin infusion to produce glucose levels less than 50 mg/dl for 45 minutes. In response to this, the delivery of glucagon to the liver increased from 36.7±5.9 ng/min in the baseline to 322.6±6.3 ng/min during hypoglycemia. Hepatic glucagon uptake increased proportionally from 13.6±7.2 ng/min to 103.1±28.3 ng/min and the percentage of delivered hormone that was extracted did not change (30.8±13.8% vs 32.9±11.6%). The absolute amount of glucagon metabolized by the liver was dependent on the rate of delivery and was not directly affected by plasma glucose level per se. To directly study the effect of hypoglycemia on hepatic glucagon metabolism, five dogs were given an exogenous infusion of somatostatin followed by an infusion of glucagon and then administered insulin to produce hypoglycemia. The percent of glucagon extracted by the liver (19.5±4.9% and 21.3±6.4%) was not affected by a fall in the plasma glucose level. We conclude 1) Hepatic glucagon uptake is directly dependent on hepatic glucagon delivery during euglycemic and hypoglycemic conditions, 2) the percentage of glucagon extracted by the liver is not changed by the glucose level or rate of glucagon delivery and 3) in an individual animal, peripheral glucagon levels during hypoglycemia may be used as a reflection of the rate of glucagon secretion, just as they are under euglycemic conditions. Key-Words Glucagon Metabolism - Hypoglycemia
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The model includes two parameters with specific physiological meaning: the glucagon clearance from plasma, KGLUCA, mainly due to liver and kidneys, and the sensitivity of glucagon secretion from pancreatic alpha cells to the inhibitory effect of insulin, SGLUCA(t).
“it includes two parameters with specific physiological meaning: the glucagon clearance from plasma, KGLUCA, mainly due to liver and kidneys (32, 33), and the sensitivity of the glucagon secretion from the pancreatic alpha cells to the inhibitory effect of insulin, SGLUCA(t).”
From Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test (2021) · cites this paper as [32]
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Taborsky, G. J. (2010) · Journal of Diabetes Science and Technology · doi:10.1177/193229681000400607 · Cited by 96 · see citing works
Berndt, N., Horger, M., Bulik, S., & Holzhütter, H. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006005 · Cited by 34 · see citing works
Malmgren, S., & Åhrén, B. (2015) · Diabetologia · doi:10.1007/s00125-015-3518-7 · Cited by 34 · see citing works
“Alterations in glucagon clearance could theoretically contribute to a counterregulatory response since nutritional state has been shown to affect glucagon clearance in mice [36]; however, this seems not to be directly affected by low blood glucose during hyperinsulinaemic clamp [37].”
BackgroundAssessment of individual and standardized glucagon kinetics in healthy humans
LAURENTI, M. C., Vella, A. V., Adams, J. D., Wismayer, D. S., Egan, A. M., & Man, C. D. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00488.2020 · Cited by 28 · see citing works
Evidence against important catecholamine compensation for absent glucagon counterregulation
Feo, P. D., Perriello, G., Torlone, E., Fanelli, C. G., Ventura, M. M., Santeusanio, F., Brunetti, P., Gerich, J. E., & Bolli, G. B. (1991) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1991.260.2.e203 · Cited by 27 · see citing works
Morettini, M., Burattini, L., Göbl, C., Pacini, G., Ahrén, B., & Tura, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.611147 · Cited by 27 · see citing works
“It is based on two ordinary differential equations, and it includes two parameters with specific physiological meaning: the glucagon clearance from plasma, KGLUCA, mainly due to liver and kidneys (32, 33), and the sensitivity of the glucagon secretion from the pancreatic alpha cells to the inhibitory effect of insulin…”
BackgroundThe pancreatic-adrenocortical-pituitary clamp technique for study of counterregulation in humans
Feo, P. D., Perriello, G., Ventura, M. M., Brunetti, P., Santeusanio, F., Gerich, J. E., & Bolli, G. B. (1987) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1987.252.4.e565 · Cited by 21 · see citing works
Merino, B., Casanueva-Álvarez, E., Quesada, I., González-Casimiro, C. M., Fernández-Díaz, C. M., Postigo, T., Leissring, M. A., Kaestner, K. H., Perdomo, G., & Cózar‐Castellano, I. (2022) · Diabetologia · doi:10.1007/s00125-022-05729-y · Cited by 18 · see citing works
“First, plasma glucagon levels reflect the balance between glucagon secretion and its clearance in vivo [30] but clearance mechanisms are not present ex vivo.”
BackgroundNeely, B. A., Carlin, K. P., Arthur, J. M., McFee, W. E., & Janech, M. G. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00132 · Cited by 14 · see citing works
“In pigs, the clearance of glucagon largely occurs through elimination via the kidney and in dogs the fraction of glucagon extracted by the liver is only approximately 20% (58) suggesting that renal clearance, not hepatic clearance is the main sink.”
BackgroundThe relationship between insulin and glucagon concentrations in non‐diabetic humans
LAURENTI, M. C., Arora, P., Man, C. D., Andrews, J. C., Rizza, R. A., Matveyenko, A. V., Bailey, K. R., Cobelli, C., & Vella, A. V. (2022) · Physiological Reports · doi:10.14814/phy2.15380 · Cited by 7 · see citing works
Mechanisms of Hyperinsulinemia and Hyperglucagonemia after Liver Transplantation
Sika, M., Blair, K. T., Jabbour, K., Williams, P. E., Donovan, K. L., Drougas, J. G., Becker, Y. T., Bradley, A. L., Buren, D. H. V., Flakoll, P. J., et al. (1997) · Journal of Surgical Research · doi:10.1006/jsre.1997.5119 · Cited by 5 · see citing works
Nomura, S., Ikegami, H., Wada, H., et al. (2014) · PubMed · Cited by 5 · see citing works
Nonlinear Mixed Effects Modeling of Glucagon Kinetics in Healthy Subjects
Faggionato, E., LAURENTI, M. C., Vella, A. V., & Man, C. D. (2023) · IEEE Transactions on Biomedical Engineering · doi:10.1109/tbme.2023.3262974 · Cited by 5 · see citing works
“Compared to insulin, the degree of glucagon extraction seems smaller [3] and independent of the glycemic state [4], thus, neglecting the hepatic extraction might be an acceptable”
Glucagon and Glucagon‐like Peptide Production and Degradation
Kieffer, T. J., Hussain, M. A., & Habener, J. F. (2001) · Comprehensive physiology · doi:10.1002/cphy.cp070208 · Cited by 4 · see citing works
Actions physiologiques du glucagon
Kraft, G., & Cherrington, A. D. (2011) · Médecine des Maladies Métaboliques · doi:10.1016/s1957-2557(11)70205-x · Cited by 1 · see citing works
Glucagon and Glucagon‐like Peptide Production and Degradation
Kieffer, T. J., Hussain, M. A., & Habener, J. F. (2001) · Comprehensive physiology · doi:10.1002/j.2040-4603.2001.tb01454.x
- Authors
- Herold, K., & Jaspan, J.
- Affiliations
- University of Chicago (US)
- ORCID
- Herold, K.
- Venue
- Hormone and Metabolic Research
- Publisher
- Georg Thieme Verlag KG
- Published
- 1986-07
- Volume
- 18
- Issue
- 07
- Pages
- 431-435
- ISSN
- 0018-5043 (ISSN-L)
- 1439-4286
- OpenAlex
- W2084209921
- Cited by
- 16
- References
- 0
- Citations by year
- 2023: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2018: 1 · 2015: 1 · 2014: 1 · 2013: 1
- FWCI
- 0.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hormone and Metabolic Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- insulin-induced hypoglycemia, hypoglycemic counterregulation, somatostatin
- MeSH terms
- Animals, Blood Glucose, Dogs, Glucagon, Hypoglycemia, Insulin, Liver
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