Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids
Open accessAbstract
Aims/hypothesis The secretion of glucagon is controlled by blood glucose and inappropriate secretion of glucagon contributes to hyperglycaemia in diabetes. Besides its role in glucose regulation, glucagon regulates amino acid metabolism in hepatocytes by increasing ureagenesis. Disruption of this mechanism causes hyperaminoacidaemia, which in turn increases glucagon secretion. We hypothesised that hepatic insulin resistance (secondary to hepatic steatosis) via defective glucagon signalling/glucagon resistance would lead to impaired ureagenesis and, hence, increased plasma concentrations of glucagonotropic amino acids and, subsequently, glucagon.Methods To examine the association between glucagon and amino acids, and to explore whether this relationship was modified by hepatic insulin resistance, we studied a well-characterised cohort of 1408 individuals with normal and impaired glucose regulation. In this cohort, we have previously reported insulin resistance to be accompanied by increased plasma concentrations of glucagon. We now measure plasma levels of amino acids in the same cohort. HOMA-IR was calculated as a marker of hepatic insulin resistance.Results Fasting levels of glucagonotropic amino acids and glucagon were significantly and inversely associated in linear regression models (persisting after adjustment for age, sex and BMI). Increasing levels of hepatic, but not peripheral insulin resistance (p > 0.166) attenuated the association between glucagon and circulating levels of alanine, glutamine and tyrosine, and was significantly associated with hyperaminoacidaemia and hyperglucagonaemia. A doubling of the calculated glucagon-alanine index was significantly associated with a 30% increase in hepatic insulin resistance, a 7% increase in plasma alanine aminotransferase levels, and a 14% increase in plasma γ-glutamyltransferase levels.Conclusions/interpretation This cross-sectional study supports the existence of a liver-alpha cell axis in humans: glucagon regulates plasma levels of amino acids, which in turn feedback to regulate the secretion of glucagon. With hepatic insulin resistance, reflecting hepatic steatosis, the feedback cycle is disrupted, leading to hyperaminoacidaemia and hyperglucagonaemia. The glucagon-alanine index is suggested as a relevant marker for hepatic glucagon signalling.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F., & Turner, R. C. (1985) · Diabetologia · doi:10.1007/bf00280883 · Cited by 31,502 · see citing works
Newgard, C. B., An, J., Bain, J. R., Muehlbauer, M. J., Stevens, R. D., Lien, L. F., Haqq, A. M., Shah, S. H., Arlotto, M., Slentz, C. A., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.02.002 · Cited by 3,165 · see citing works
Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease
Samuel, V. T., Liu, Z.-X., Qu, X., Elder, B. D., Bilz, S., Befroy, D., Romanelli, A. J., & Shulman, G. I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313478200 · Cited by 1,322 · see citing works
Glucagonocentric restructuring of diabetes: A pathophysiologic and therapeutic makeover
Unger, R. H., & Cherrington, A. D. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60016 · Cited by 670 · see citing works
High-throughput serum NMR metabonomics for cost-effective holistic studies on systemic metabolism
Soininen, P., Kangas, A. J., Würtz, P., Tukiainen, T., Tynkkynen, T., Laatikainen, R., Järvelin, M., Kähönen, M. A. P., Lehtimäki, T. J., Viikari, J. S. A., et al. (2009) · The Analyst · doi:10.1039/b910205a · Cited by 591 · see citing works
α-Cells of the Endocrine Pancreas: 35 Years of Research but the Enigma Remains
Gromada, J., Franklin, I., & Wollheim, C. B. (2007) · Endocrine Reviews · doi:10.1210/er.2006-0007 · Cited by 574 · see citing works
Gelling, R. W., Du, X. Q., Dichmann, D. S., Rømer, J., Huang, H., Cui, L., Obici, S., Tang, B., Holst, J. J., Fledelius, C., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0237106100 · Cited by 563 · see citing works
Self-citationMuscle and Liver Insulin Resistance Indexes Derived From the Oral Glucose Tolerance Test
Abdul-Ghani, M. A., Matsuda, M., Balas, B., & DeFronzo, R. A. (2006) · Diabetes Care · doi:10.2337/dc06-1519 · Cited by 555 · see citing works
Validation of the insulin sensitivity index (ISI0,120): comparison with other measures
Gutt, M., Davis, C. L., Spitzer, S. B., Llabre, M. M., Kumar, M., Czarnecki, E. M., Schneiderman, N., Skyler, J. S., & Marks, J. B. (2000) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(99)00116-3 · Cited by 464 · see citing works
Færch, K., Torekov, S. S., Vistisen, D., Johansen, N. B., Witte, D. R., Jonsson, A., Pedersen, O., Hansen, T., Lauritzen, T., Sandbæk, A., et al. (2015) · Diabetes · doi:10.2337/db14-1751 · Cited by 321 · see citing works
Glucagon-stimulating activity of 20 amino acids in dogs
Rocha, D. M., Faloona, G. R., & Unger, R. H. (1972) · Journal of Clinical Investigation · doi:10.1172/jci107046 · Cited by 268 · see citing works
GRuttenfor the ADDITION Study Group, Lauritzen, T., Griffin, S. J., Borch‐Johnsen, K., Wareham, N., & Wolffenbuttel, B. H. R. (2000) · International Journal of Obesity · doi:10.1038/sj.ijo.0801420 · Cited by 247 · see citing works
Self-citationGlutamate Is a Positive Autocrine Signal for Glucagon Release
Cabrera, O., Jacques-Silva, M. C., Speier, S., Yang, S.-N., Köhler, M., Fachado, A., Vieira, E., Zierath, J. R., Kibbey, R., Berman, D. M., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.03.004 · Cited by 217 · see citing works
Færch, K., Vistisen, D., Pacini, G., Torekov, S. S., Johansen, N. B., Witte, D. R., Jonsson, A., Pedersen, O., Hansen, T., Lauritzen, T., et al. (2016) · Diabetes · doi:10.2337/db16-0240 · Cited by 217 · see citing works
Self-citationDixon, J., Bhathal, P., & O'Brien, P. (2006) · Obesity Surgery · doi:10.1381/096089206778663805 · Cited by 212 · see citing works
KAZDA, C. M., Ding, Y., Kelly, R. P., Garhyan, P., Shi, C., Lim, C. N., Fu, H., Watson, D. E., Lewin, A. J., Landschulz, W. H., et al. (2015) · Diabetes Care · doi:10.2337/dc15-1643 · Cited by 211 · see citing works
Petersen, K. F., & Sullivan, J. T. (2001) · Diabetologia · doi:10.1007/s001250100006 · Cited by 209 · see citing works
Liver-Specific Disruption of the Murine Glucagon Receptor Produces α-Cell Hyperplasia
Longuet, C., Robledo, A. M., Dean, E. D., Dai, C., Ali, S., McGuinness, I., de Chavez, V., Vuguin, P. M., Charron, M. J., Powers, A. C., et al. (2012) · Diabetes · doi:10.2337/db11-1605 · Cited by 207 · see citing works
Dean, E. D., Li, M., Prasad, N., Wisniewski, S., Deylen, A. V., Spaeth, J. M., Maddison, L. A., Botros, A., Sedgeman, L. R., Bozadjieva-Kramer, N., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.011 · Cited by 207 · see citing works
Hyperglucagonemia and Its Suppression
Raskin, P., & Unger, R. H. (1978) · New England Journal of Medicine · doi:10.1056/nejm197808312990901 · Cited by 197 · see citing works
Glucagon and Amino Acids Are Linked in a Mutual Feedback Cycle: The Liver–α-Cell Axis
Holst, J. J., Wewer Albrechtsen, N. J., Pedersen, J., & Knop, F. K. (2017) · Diabetes · doi:10.2337/db16-0994 · Cited by 187 · see citing works
Self-citationGlucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass
Solloway, M. J., Madjidi, A., Gu, C., Eastham-Anderson, J., Clarke, H. J., Kljavin, N. M., Zavala‐Solorio, J., Kates, L., Friedman, B. A., Brauer, M., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.06.034 · Cited by 186 · see citing works
Albrechtsen, N. J. W., Hartmann, B., Veedfald, S., Windeløv, J. A., Plamboeck, A., Bojsen-Møller, K. N., Idorn, T., Feldt‐Rasmussen, B., Knop, F. K., Vilsbøll, T., et al. (2014) · Diabetologia · doi:10.1007/s00125-014-3283-z · Cited by 185 · see citing works
Self-citationKim, J., Okamoto, H., Huang, Z., Guillermo Anguiano, L., Chen, S., Liu, Q., Cavino, K., Xin, Y., Na, E., Hamid, R., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.006 · Cited by 183 · see citing works
Guzman, C. B., Zhang, X. M., Liu, R., Regev, A., Shankar, S., Garhyan, P., Pillai, S. G., Kazda, C., Chalasani, N., & Hardy, T. A. (2017) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.12958 · Cited by 172 · see citing works
Evidence of Extrapancreatic Glucagon Secretion in Man
Lund, A., Bagger, J. I., Albrechtsen, N. J. W., Christensen, M., Grøndahl, M. F. G., Hartmann, B., Mathiesen, E. R., Hansen, C. P., Storkholm, J. H., van Hall, G., et al. (2015) · Diabetes · doi:10.2337/db15-1541 · Cited by 167 · see citing works
Self-citationHyperglycemia of Diabetic Rats Decreased by a Glucagon Receptor Antagonist
Johnson, D. G., Goebel, C. U., Hruby, V. J., Bregman, M. D., & Trivedi, D. B. (1982) · Science · doi:10.1126/science.6278587 · Cited by 166 · see citing works
Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels
Mahendran, Y., Jonsson, A. E., Have, C. T., Allin, K. H., Witte, D. R., Jørgensen, M. E., Grarup, N., Pedersen, O. B., Kilpeläinen, T. O., & Hansen, T. F. (2017) · Diabetologia · doi:10.1007/s00125-017-4222-6 · Cited by 154 · see citing works
Self-citationZhou, C., Dhall, D., Nissen, N. N., Chen, C., & Yu, R. (2009) · Pancreas · doi:10.1097/mpa.0b013e3181b2bb03 · Cited by 144 · see citing works
Amino Acid Deficiency and the Skin Rash Associated with Glucagonoma
Norton, J. A., KAHN, C. R., SCHIEBINGER, R., GORSCHBOTH, C., & BRENNAN, M. F. (1979) · Annals of Internal Medicine · doi:10.7326/0003-4819-91-2-213 · Cited by 137 · see citing works
The effect of alanine on glucagon secretion
Müller, W. A., Faloona, G. R., & Unger, R. H. (1971) · Journal of Clinical Investigation · doi:10.1172/jci106716 · Cited by 130 · see citing works
Isokuortti, E., Zhou, Y., Peltonen, M., Bugianesi, E., Clement, K., Bonnefont-Rousselot, D., Lacorte, J.-M., Gastaldelli, A., Schuppan, D., Schattenberg, J. M., et al. (2017) · Diabetologia · doi:10.1007/s00125-017-4340-1 · Cited by 120 · see citing works
Effects of glucagon on plasma amino acids.
Boden, G., Rezvani, I., & Owen, O. E. (1984) · Journal of Clinical Investigation · doi:10.1172/jci111272 · Cited by 118 · see citing works
Galsgaard, K. D., Winther‐Sørensen, M., Ørskov, C., Kissow, H., Poulsen, S. S., Vilstrup, H., Prehn, C. P., Adamski, J., Jepsen, S. L., Hartmann, B., et al. (2017) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00198.2017 · Cited by 117 · see citing works
Self-citationAlbrechtsen, N. J. W., Junker, A. E., Christensen, M., Hædersdal, S., Wibrand, F., Lund, A. M., Galsgaard, K. D., Holst, J. J., Knop, F. K., & Vilsbøll, T. (2017) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00216.2017 · Cited by 98 · see citing works
Self-citationInsulin and Glucagon: Partners for Life
Holst, J. J., Holland, W. L., Gromada, J., Lee, Y., Unger, R. H., Yan, H., Sloop, K. W., Kieffer, T. J., Damond, N., & Herrera, P. L. (2017) · Endocrinology · doi:10.1210/en.2016-1748 · Cited by 90 · see citing works
Self-citationAlexander, E. K., Robinson, M., Staniec, M., & Dluhy, R. G. (2002) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2002.01660.x · Cited by 87 · see citing works
Junker, A. E., Gluud, L. L., Holst, J. J., Knop, F. K., & Vilsbøll, T. (2016) · Journal of Internal Medicine · doi:10.1111/joim.12462 · Cited by 86 · see citing works
Self-citationConnelly, M. A., Wolak, J. E., & Dullaart, R. P. F. (2017) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2016.0145 · Cited by 85 · see citing works
Stability of glucagon-like peptide 1 and glucagon in human plasma
Albrechtsen, N. J. W., Bak, M. J., Hartmann, B., Christensen, L. W., Kuhre, R. E., Deacon, C. F., & Holst, J. J. (2015) · Endocrine Connections · doi:10.1530/ec-14-0126 · Cited by 79 · see citing works
Self-citationYamada, C., Kondo, M., Kishimoto, N., Shibata, T., Nagai, Y., Imanishi, T., Oroguchi, T., Ishii, N., & Nishizaki, Y. (2014) · Journal of Diabetes Investigation · doi:10.1111/jdi.12323 · Cited by 62 · see citing works
Johansen, N. B., Bjerregaard, A., Jensen, T. M., Philipsen, A., Rasmussen, S. S., Jørgensen, M. E., Simmons, R. K., Lauritzen, T., Sandbæk, A., & Witte, D. R. (2012) · BMC Public Health · doi:10.1186/1471-2458-12-1078 · Cited by 57 · see citing works
Self-citationPancreatic α-cell hyperplasia and hyperglucagonemia due to a glucagon receptor splice mutation
Larger, É., Albrechtsen, N. J. W., Hansen, L., Gelling, R. W., Capeau, J., Deacon, C. F., Madsen, O. D., Yakushiji, F., MEYTS, P. D., Holst, J. J., et al. (2016) · Endocrinology Diabetes and Metabolism Case Reports · doi:10.1530/edm-16-0081 · Cited by 51 · see citing works
Self-citationIncreased amino acid clearance and urea synthesis in a patient with glucagonoma.
Almdal, T. P., Heindorff, H., Bardram, L., & Vilstrup, H. (1990) · Gut · doi:10.1136/gut.31.8.946 · Cited by 49 · see citing works
Inability of Some Commercial Assays to Measure Suppression of Glucagon Secretion
Albrechtsen, N. J. W., Veedfald, S., Plamboeck, A., Deacon, C. F., Hartmann, B., Knop, F. K., Vilsbøll, T., & Holst, J. J. (2015) · Journal of Diabetes Research · doi:10.1155/2016/8352957 · Cited by 49 · see citing works
Self-citationFactors affecting the stability of L-glutamine in solution
Khan, K., & Elia, M. (1991) · Clinical Nutrition · doi:10.1016/0261-5614(91)90037-d · Cited by 47 · see citing works
Glucagon secretion in relation to insulin sensitivity in healthy subjects
Åhrén, B. (2005) · Diabetologia · doi:10.1007/s00125-005-0056-8 · Cited by 40 · see citing works
The Amino Acid-Induced Secretion of Glucagon
Assan, R., Marre, M., & Gormley, M. (1983) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-69019-8_2 · Cited by 25 · see citing works
Glucagon receptor gene mutations with hyperglucagonemia but without the glucagonoma syndrome
Miller, H. C. (2015) · World Journal of Gastrointestinal Surgery · doi:10.4240/wjgs.v7.i4.60 · Cited by 25 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
NAFLD as a Continuum: From Obesity to Metabolic Syndrome and Diabetes
Godoy-Matos, A. F., Silva Júnior, W. S., & Valerio, C. M. (2020) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-020-00570-y · Cited by 643 · see citing works
Lipid metabolism in MASLD and MASH: From mechanism to the clinic
Carli, F., Della Pepa, G., Sabatini, S., Vidal Puig, A., & Gastaldelli, A. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101185 · Cited by 147 · see citing works
100 years of glucagon and 100 more
Wewer Albrechtsen, N. J., Holst, J. J., Cherrington, A. D., Finan, B., Gluud, L. L., Dean, E. D., Campbell, J. E., Bloom, S. R., Tan, T. M.-M., Knop, F. K., et al. (2023) · Diabetologia · doi:10.1007/s00125-023-05947-y · Cited by 117 · see citing works
Self-citationNutrition in Patients with Type 2 Diabetes: Present Knowledge and Remaining Challenges
Petroni, M. L., Brodosi, L., Marchignoli, F., Sasdelli, A. S., Caraceni, P., Marchesini, G., & Ravaioli, F. (2021) · Nutrients · doi:10.3390/nu13082748 · Cited by 116 · see citing works
EJE PRIZE 2018: A gut feeling about glucagon
Knop, F. K. (2018) · European Journal of Endocrinology · doi:10.1530/eje-18-0197 · Cited by 47 · see citing works
Self-citationMorettini, 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
Role of peptide hormones in the adaptation to altered dietary protein intake
Rose, A. J. (2019) · Nutrients · doi:10.3390/nu11091990 · Cited by 15 · see citing works
- Authors
- Wewer Albrechtsen, N. J., Færch, K., Jensen, T. M., Witte, D. R., Pedersen, J., Mahendran, Y., Jonsson, A. E., Galsgaard, K. D., Winther-Sørensen, M., Torekov, S. S., Lauritzen, T., Pedersen, O., Knop, F. K., Hansen, T., Jørgensen, M. E., Vistisen, D., & Holst, J. J.
- Affiliations
- Steno Diabetes Center Copenhagen (DK)
- Aarhus University (DK)
- University of Copenhagen (DK)
- University of Southern Denmark (DK)
- Corresponding author
- Holst, Jens J.
- ORCID
- Venue
- Diabetologia
- Published
- 2018-01-05
- Volume
- 61
- Issue
- 3
- Pages
- 671-680
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2781547740
- Cited by
- 119
- References
- 49
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 15 · 2023: 13 · 2022: 21 · 2021: 18 · 2020: 13 · 2019: 12 · 2018: 4
- FWCI
- 12.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- European Foundation for the Study of Diabetes (74550801)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- hepatic insulin resistance, glucagon, hyperglucagonaemia, urea synthesis, hepatic steatosis, alanine, glutamine, tyrosine, prediabetes, alanine aminotransferase, gamma-glutamyl transferase
- MeSH terms
- Aged, Alanine, Amino Acids, Cross-Sectional Studies, Female, Glucagon, Glucose Tolerance Test, Humans, Insulin Resistance, Liver, Male, Middle Aged, Magnetic Resonance Spectroscopy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
