Lack of Suppression of Glucagon Contributes to Postprandial Hyperglycemia in Subjects with Type 2 Diabetes Mellitus1
Abstract
We tested the hypothesis that a lack of suppression of glucagon causes postprandial hyperglycemia in subjects with type 2 diabetes. Nine diabetic subjects ingested 50 g glucose on two occasions. On both occasions, somatostatin was infused at a rate of 4.3 nmol/kg x min, and insulin was infused in a diabetic insulin profile. On one occasion, glucagon was also infused at a rate of 1.25 ng/kg x min to maintain portal glucagon concentrations constant (nonsuppressed study day). On the other occasion, glucagon infusion was delayed by 2 h to create a transient decrease in glucagon (suppressed study day). Glucagon concentrations on the suppressed study day fell to about 70 ng/L during the first 2 h, rising thereafter to approximately 120 ng/L. In contrast, glucagon concentrations on the nonsuppressed study day remained constant at about 120 ng/L throughout. The decrease in glucagon resulted in substantially lower (P < 0.001) glucose concentrations on the suppressed compared with the nonsuppressed study days (9.2+/-0.7 vs. 10.9+/-0.8 mmol/L) and a lower (P < 0.001) rate of release of [14C]glucose from glycogen (labeled by infusing [1-14C]galactose). On the other hand, flux through the hepatic UDP-glucose pool (and, by implication, glycogen synthesis), measured using the acetaminophen glucuronide method, did not differ on the two occasions. We conclude that lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes at least in part by acc…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Hyperglucagonemia is a hallmark in type 2 diabetes, promoting hepatic glucose output and exacerbating hyperglycemia.
“Hyperglucagonemia is a hallmark in T2D, promoting hepatic glucose output and exacerbating hyperglycemia [17, 18].”
From Tirzepatide as monotherapy improved markers of beta-cell function and insulin sensitivity in type 2 diabetes (SURPASS-1). (2023) · cites this paper as [18]
Cites
Abnormal Alpha-Cell Function in Diabetes: Response to Carbohydrate and Protein Ingestion
Müller, W. A., Faloona, G. R., Aguilar-Parada, E., & Unger, R. H. (1970) · New England Journal of Medicine · doi:10.1056/nejm197007162830301 · Cited by 626 · see citing works
Contribution of Abnormal Muscle and Liver Glucose Metabolism to Postprandial Hyperglycemia in NIDDM
Mitrakou, A., Kelley, D., Veneman, T., Jenssen, T., Pangburn, T., Reilly, J., & Gerich, J. (1990) · Diabetes · doi:10.2337/diab.39.11.1381 · Cited by 317 · see citing works
Hyperglucagonemia and Blood Glucose Regulation in Normal, Obese and Diabetic Subjects
Sherwin, R. S., Fisher, M., Hendler, R., & Felig, P. (1976) · New England Journal of Medicine · doi:10.1056/nejm197602262940901 · Cited by 252 · see citing works
Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM
Dinneen, S., Alzaid, A., Turk, D., & Rizza, R. (1995) · Diabetologia · doi:10.1007/bf00400639 · Cited by 190 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
The Physiology of Glucagon-like Peptide 1
Holst, J. J. (2007) · Physiological Reviews · doi:10.1152/physrev.00034.2006 · Cited by 3,371 · see citing works
FGF-21 as a novel metabolic regulator
Kharitonenkov, A., Shiyanova, T. L., Koester, A., Ford, A. M., Micanovic, R., Galbreath, E. J., Sandusky, G. E., Hammond, L. J., Moyers, J. S., Owens, R. A., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23606 · Cited by 2,125 · see citing works
Glucagon and regulation of glucose metabolism
Jiang, G., & Zhang, B. B. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00492.2002 · Cited by 905 · see citing works
The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21
Kharitonenkov, A., Wroblewski, V. J., Koester, A., Chen, Y.-F., Clutinger, C. K., Tigno, X. T., Hansen, B. C., Shanafelt, A. B., & Etgen, G. J. (2007) · Endocrinology · doi:10.1210/en.2006-1168 · Cited by 738 · see citing works
Physiology of Proglucagon Peptides: Role of Glucagon and GLP-1 in Health and Disease
Sandoval, D. A., & D'Alessio, D. A. (2015) · Physiological Reviews · doi:10.1152/physrev.00013.2014 · Cited by 498 · see citing works
Reed, J., Bain, S., & Kanamarlapudi, V. (2021) · Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy · doi:10.2147/dmso.s319895 · Cited by 441 · see citing works
Degn, K. B., Juhl, C. B., Sturis, J., Jakobsen, G., Brock, B., Chandramouli, V., Rungby, J., Landau, B. R., & Schmitz, O. (2004) · Diabetes · doi:10.2337/diabetes.53.5.1187 · Cited by 427 · see citing works
The New Biology and Pharmacology of Glucagon
Müller, T. D., Finan, B., Clemmensen, C., DiMarchi, R. D., & Tschöp, M. H. (2017) · Physiological Reviews · doi:10.1152/physrev.00025.2016 · Cited by 419 · see citing works
Graaf, C. D., Donnelly, D., Wootten, D., Lau, J., Sexton, P. M., Miller, L. J., Ahn, J.-M., Liao, J., Fletcher, M. M., Yang, D., et al. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.011395 · Cited by 403 · see citing works
Dunning, B. E., & Gerich, J. E. (2007) · Endocrine Reviews · doi:10.1210/er.2006-0026 · Cited by 369 · see citing works
Jørgensen, N. B., Jacobsen, S. H., Dirksen, C., Bojsen-Møller, K. N., Naver, L., Hvolris, L., Clausen, T. R., Wulff, B. S., Worm, D., Lindqvist Hansen, D., et al. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00073.2012 · Cited by 313 · see citing works
Physiologic action of glucagon on liver glucose metabolism
Ramnanan, C. J., Edgerton, D. S., Kraft, G., & Cherrington, A. D. (2011) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01454.x · Cited by 293 · see citing works
Hare, K. J., Vilsbøll, T., Asmar, M., Deacon, C. F., Knop, F. K., & Holst, J. J. (2010) · Diabetes · doi:10.2337/db09-1414 · Cited by 276 · see citing works
Islet α cells and glucagon--critical regulators of energy homeostasis
Campbell, J. E., & Drucker, D. J. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.51 · Cited by 266 · see citing works
The role of dysregulated glucagon secretion in type 2 diabetes
D'Alessio, D. (2011) · Diabetes, Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01449.x · Cited by 238 · see citing works
Minireview: Glucagon in the Pathogenesis of Hypoglycemia and Hyperglycemia in Diabetes
Cryer, P. E. (2012) · Endocrinology · doi:10.1210/en.2011-1499 · Cited by 242 · see citing works
Conarello, S. L., Jiang, G., Mu, J., Li, Z., Woods, J., Zycband, E., Ronan, J., Liu, F., Roy, R. S., Zhu, L., et al. (2006) · Diabetologia · doi:10.1007/s00125-006-0481-3 · Cited by 224 · see citing works
Anti-obesity therapy: from rainbow pills to polyagonists
Müller, T. D., Clemmensen, C., Finan, B., DiMarchi, R. D., & Tschöp, M. H. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014803 · Cited by 199 · see citing works
The Role of Glucagon in the Pathophysiology and Treatment of Type 2 Diabetes
Hædersdal, S., Lund, A., Knop, F. K., & Vilsbøll, T. (2018) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2017.12.003 · Cited by 162 · see citing works
Regulated Exocytosis of GABA-containing Synaptic-like Microvesicles in Pancreatic β-cells
Braun, M., Wendt, A., Birnir, B., Broman, J., Eliasson, L., Galvanovskis, J., Gromada, J., Mulder, H., & Rorsman, P. (2004) · The Journal of General Physiology · doi:10.1085/jgp.200308966 · Cited by 130 · see citing works
de Heer, J., & Holst, J. J. (2007) · Diabetes · doi:10.2337/db06-0738 · Cited by 115 · see citing works
Kelly, R. P., Garhyan, P., Raddad, E., Fu, H., Lim, C. N., Prince, M. J., Pinaire, J. A., Loh, M. T., & Deeg, M. A. (2015) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.12446 · Cited by 110 · see citing works
Højberg, P. V., Zander, M., Vilsbøll, T., Knop, F. K., Krarup, T., Vølund, A., Holst, J. J., & Madsbad, S. (2008) · Diabetologia · doi:10.1007/s00125-008-0943-x · Cited by 89 · see citing works
Obesity dysregulates fasting-induced changes in glucagon secretion
Stern, J. H., Smith, G. I., Chen, S., Unger, R. H., Klein, S., & Scherer, P. E. (2019) · Journal of Endocrinology · doi:10.1530/joe-19-0201 · Cited by 84 · see citing works
Pancreatic α-Cell Dysfunction in Type 2 Diabetes: Old Kids on the Block
Moon, J. S., & Won, K. C. (2015) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2015.39.1.1 · Cited by 61 · see citing works
Blockade of Na+ Channels in Pancreatic α-Cells Has Antidiabetic Effects
Dhalla, A. K., Yang, M., Ning, Y., Kahlig, K. M., Krause, M., Rajamani, S., & Belardinelli, L. (2014) · Diabetes · doi:10.2337/db13-1562 · Cited by 53 · see citing works
Lee, C. J., Mao, H., Thieu, V. T., Landó, L. F., & Thomas, M. K. (2023) · Journal of the Endocrine Society · doi:10.1210/jendso/bvad056 · Cited by 48 · see citing works
“Hyperglucagonemia is a hallmark in T2D, promoting hepatic glucose output and exacerbating hyperglycemia [17, 18].”
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
Kazierad, D. J., Bergman, A., Tan, B., Erion, D. M., Somayaji, V., Lee, D. S., & Rolph, T. (2016) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.12672 · Cited by 44 · see citing works
Glucagon in type 2 diabetes: Friend or foe?
Caruso, I., Marrano, N., Biondi, G., Genchi, V. A., D'Oria, R., Sorice, G. P., Perrini, S., Cignarelli, A., Natalicchio, A., Laviola, L., et al. (2023) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3609 · Cited by 35 · see citing works
GIP’s involvement in the pathophysiology of type 2 diabetes
Christensen, M. B., Gasbjerg, L. S., Heimbürger, S. M., Stensen, S., Vilsbøll, T., & Knop, F. K. (2020) · Peptides · doi:10.1016/j.peptides.2019.170178 · Cited by 35 · see citing works
Involvement of steatosis-induced glucagon resistance in hyperglucagonaemia
Suppli, M. P., Lund, A., Bagger, J. I., Vilsbøll, T., & Knop, F. K. (2016) · Medical Hypotheses · doi:10.1016/j.mehy.2015.10.029 · Cited by 35 · see citing works
Frias, J. P., De Block, C., Brown, K., Wang, H., Thomas, M. K., Zeytinoglu, M., & Maldonado, J. M. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae038 · Cited by 31 · see citing works
Yang, G.-R., Zhao, X.-L., Jin, F., Shi, L.-H., & Yang, J.-K. (2015) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.386 · Cited by 29 · see citing works
Adams, J. D., Egan, A. M., Laurenti, M. C., Schembri Wismayer, D., Bailey, K. R., Cobelli, C., Dalla Man, C., & Vella, A. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00284.2021 · Cited by 10 · see citing works
Roh, S., Koiwa, K., Sato, K., Ohtani, Y., Takahashi, T., & Katoh, K. (2014) · Animal Science Journal · doi:10.1111/asj.12142 · Cited by 7 · see citing works
A New Role for Glucagon: From Secondary Hormone to Key Player
De Fano, M., Malara, M., Rucco, S., Manco, M., Fanelli, C. G., Bolli, G. B., & Porcellati, F. (2025) · Nutrition, Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2025.104233 · Cited by 1 · see citing works
Faggionato, E., Tonello, A., Laurenti, M. C., Vella, A., & Dalla Man, C. (2025) · American Journal of Physiology - Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00172.2025
Self-citation
- Authors
- Shah, P., Vella, A., Basu, A., Basu, R., Schwenk, W. F., & Rizza, R. A.
- Affiliations
- Mayo Clinic (US)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2000-11
- Volume
- 85
- Issue
- 11
- Pages
- 4053-4059
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2025993954
- Cited by
- 368
- References
- 4
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 9 · 2022: 8 · 2021: 16 · 2020: 17 · 2019: 14 · 2018: 17 · 2017: 15 · 2016: 23 · 2015: 22 · 2014: 29 · 2013: 20 · 2012: 18
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK050456, DK50456, DK 29953)
- National Center for Research Resources (RR-00585, M01RR000585)
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- glucagon, postprandial hyperglycemia, type 2 diabetes, glucagon suppression, glycogenolysis, liver glycogen, hepatic glycogen synthesis, somatostatin, insulin
- MeSH terms
- Insulin Secretion, Blood Glucose, C-Peptide, Diabetes Mellitus, Type 2, Female, Galactose, Glucagon, Glycogen, Humans, Hyperglycemia, Infusions, Intravenous, Insulin, Male, Middle Aged, Human Growth Hormone, Postprandial Period
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
