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Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39.
Abstract
Glucagon-like peptide 1(7-36) amide (GLP-1) is postulated to be the major physiological incretin in humans, but evidence is indirect. We report the first studies examining the physiological role of GLP-1 in the postprandial state in humans using the GLP-1 antagonist exendin 9-39. Exendin 9-39 completely blocked GLP-1-induced glucose-stimulated insulin release from perifused human islets of Langerhans. In healthy fasted volunteers, intravenous infusion of exendin 9-39 at 500 pmol x kg(-1) x min(-1) in the hyperglycemic state abolished the insulinotropic effect of a physiological dose of GLP-1 and fully reversed the glucose-lowering effect of GLP-1. Nine healthy subjects consumed a 150-g oral glucose tolerance test and were infused with 500 pmol x kg(-1) x min(-1) exendin 9-39 or saline. Exendin 9-39 increased the peak postprandial glucose level (exendin 9-39, 8.67 +/- 0.35 vs. saline, 7.67 +/- 0.35 mmol/l, P < or = 0.005) and increased postprandial plasma glucose incremental area under the curve by 35% (exendin 9-39, 152 +/- 19 vs. saline, 113 +/- 16 mmol x min x l(-1), P < or = 0.05). This could be explained as partly secondary to the blockade of glucose-induced suppression of glucagon and maybe also to an increased rate of gastric emptying. Thus, in humans exendin 9-39 acts as an antagonist of GLP-1 both in vitro and in vivo. When infused alone, exendin 9-39 causes a deterioration in postprandial glycemic control, suggesting that GLP-1 may be important for maintenance of normal postprandial glucose homeostasis in humans.
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“This peptide is known to impair oral glucose tolerance, resulting in a greater glucose AUC compared to saline (8).”
From Assessment of the incretin effect in healthy subjects: concordance between clamp and OGTT methods (2023) · cites this paper as [8]
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The biology of incretin hormones
Drucker, D. J. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.01.004 · Cited by 2,210
Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1
Drucker, D. J. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.001 · Cited by 2,170
“The physiological importance of endogenous GLP-1 is illustrated by studies employing the GLP-1R antagonist exendin(9–39), which increased glycemic excursion following oral glucose ingestion in human subjects (Edwards et al., 1999).”
BackgroundConsumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity
Bray, G. A., Nielsen, S. J., & Popkin, B. M. (2004) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/79.4.537 · Cited by 1,990
“Along with 2 peptides, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 released from the gastrointestinal tract, circulating glucose increases insulin release from the pancreas (13, 14).”
BackgroundZander, M., Madsbad, S., Madsen, J. L., & Holst, J. J. (2002) · The Lancet · doi:10.1016/s0140-6736(02)07952-7 · Cited by 1,297
New drug targets for type 2 diabetes and the metabolic syndrome
Moller, D. E. (2001) · Nature · doi:10.1038/414821a · Cited by 1,012
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients
Toft-Nielsen, M.-B., Damholt, M. B., Madsbad, S., Hilsted, L. M., Hughes, T. E., Michelsen, B. K., & Holst, J. J. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.8.7750 · Cited by 869
The role of incretins in glucose homeostasis and diabetes treatment
Kim, W., & Egan, J. M. (2008) · Pharmacological Reviews · doi:10.1124/pr.108.000604 · Cited by 824
“Removal of GLP-1 action, whether by Ex-9-39 or by its immunoneutralization, causes increases in both fasting and postprandial glycemia and reduces glucose-stimulated insulin release in both animals and humans (Kolligs et al., 1995; Wang et al., 1995; D’Alessio et al., 1996; Edwards et al., 1999; Baggio et al., 2000).”
BackgroundKisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males
Dhillo, W. S., Chaudhri, O. B., Patterson, M., Thompson, E. L., Murphy, K. G., Badman, M. K., McGowan, B. M., Amber, V., Patel, S., Ghatei, M. A., et al. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1468 · Cited by 656
Self-citationThe role of gut hormones in glucose homeostasis
Drucker, D. J. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30076 · Cited by 628
Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans
Holst, J. J., & Gromada, J. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00545.2003 · Cited by 611
“Furthermore, experiments with the same antagonist in humans have suggested that GLP-1 may be essential for normal glucose tolerance (14).”
BackgroundGlucagon-like Peptide-1 Receptor Signaling Modulates β Cell Apoptosis
Li, Y., Hansotia, T., Yusta, B., Ris, F., Halban, P. A., & Drucker, D. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209423200 · Cited by 589
Enhancing Incretin Action for the Treatment of Type 2 Diabetes
Drucker, D. J. (2003) · Diabetes Care · doi:10.2337/diacare.26.10.2929 · Cited by 581
“Comparable studies with exendin(9-39) in humans have demonstrated the essential role of GLP-1 action for glucose control via regulation of glucagon and insulin secretion (89,90).”
BackgroundSteinert, R. E., Feinle-Bisset, C., Asarian, L., Horowitz, M., Beglinger, C., & Geary, N. (2017) · Physiological Reviews · doi:10.1152/physrev.00031.2014 · Cited by 578
“Exendin(9–39) also stimulates PYY(3–36) secretion, which may slow gastric emptying and contribute to these variable results (41, 230, 665, 670, 721, 843).”
BackgroundDing, X., Saxena, N. K., Lin, S., Gupta, N., & Anania, F. A. (2006) · Hepatology · doi:10.1002/hep.21006 · Cited by 557
Biological actions and therapeutic potential of the glucagon-like peptides
Drucker, D. J. (2002) · Gastroenterology · doi:10.1053/gast.2002.31068 · Cited by 509
Nauck, M. A., & Meier, J. J. (2016) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(15)00482-9 · Cited by 503
Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers
Edwards, C. M. B., Stanley, S. A., Davis, R. P., Brynes, A. E., Frost, G. S., Seal, L., Ghatei, M. A., & Bloom, S. R. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.1.e155 · Cited by 468
“We had previously infused the exendin-4 fragment, exendin(9–39), at 1,0003 the concentration of exendin-4 infused here, without side effects (10).”
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“Basedonstudiesusing GLP-1Rknockout (GLP-1R / ) mice and in vitro receptor blockade in islets from these mice, a GLP-1 receptor appears to be involved in, and necessary for, the incretin/insulinotropic actions of exenatide and GLP1, and the hepatic portal glucose sensor actions of GLP-1 [3,35–38].”
BackgroundIncretins, insulin secretion and Type 2 diabetes mellitus
Vilsbøll, T., & Holst, J. J. (2004) · Diabetologia · doi:10.1007/s00125-004-1342-6 · Cited by 456
“Furthermore, experiments with the same antagonist in humans have suggested that GLP-1 might be essential for normal glucose tolerance [41].”
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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
“However, exendin9–39 is a selective, competitive GLP-1R antagonist that blocksGLP-1–mediated insulin secretion in vitro and in vivo and impairs glucose tolerance in response to endogenous and exogenous GLP-1 in humans and a variety of rodent models (Schirra et al., 1998; Edwards et al., 1999).”
BackgroundGhrelin increases food intake in obese as well as lean subjects
Druce, M. R., Wren, A., Park, A. J., Milton, J. E., Patterson, M., Frost, G. S., Ghatei, M. A., Small, C. J., & Bloom, S. R. (2005) · International Journal of Obesity · doi:10.1038/sj.ijo.0803001 · Cited by 406
Self-citationMinireview: The Glucagon-Like Peptides
Drucker, D. J. (2001) · Endocrinology · doi:10.1210/endo.142.2.7983 · Cited by 419
Breton, J., Tennoune, N., Lucas, N., Francois, M., Legrand, R., Jacquemot, J., Goichon, A., Guérin, C., Peltier, J., Pestel-Caron, M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.10.017 · Cited by 321
“A differential effect of E. coli proteins from the Exp phase to stimulate GLP-1, may possibly reflect an incretin role of GLP-1 in glycemic control (Edwards et al., 1999).”
Vahl, T. P., Tauchi, M., Durler, T. S., Elfers, E. E., Fernandes, T. M., Bitner, R. D., Ellis, K. S., Woods, S. C., Seeley, R. J., Herman, J. P., et al. (2007) · Endocrinology · doi:10.1210/en.2006-0153 · Cited by 318
The structure and function of the glucagon‐like peptide‐1 receptor and its ligands
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“These two shorter peptides are equipotent (Ørskov et al., 1993) and are the major physiological incretin in humans (Edwards et al., 1999); hence, these N-terminally truncated peptides are the forms implied by the generic term ‘GLP-1’ throughout this review.”
BackgroundExtrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure
Hansotia, T., Maida, A., Flock, G., Yamada, Y., Tsukiyama, K., Seino, Y., & Drucker, D. J. (2007) · Journal of Clinical Investigation · doi:10.1172/jci25483 · Cited by 290
Jørgensen, N. B., Dirksen, C., Bojsen-Møller, K. N., Jacobsen, S. H., Worm, D., Hansen, D. L., Kristiansen, V. B., Naver, L., Madsbad, S., & Holst, J. J. (2013) · Diabetes · doi:10.2337/db13-0022 · Cited by 282
“This was accomplished by pharmacologically blocking the GLP-1 receptor (GLP-1R) during a liquid meal tolerance test before and after surgery using exendin(9-39) (Ex-9; Bachem AG, Bubendorf, Switzerland), a specific GLP-1R antagonist (16).”
MethodOxyntomodulin Inhibits Food Intake in the Rat
Dakin, C. L., Gunn, I., Small, C. J., Edwards, C. M. B., Hay, D. L., Smith, D. M., Ghatei, M. A., & Bloom, S. R. (2001) · Endocrinology · doi:10.1210/endo.142.10.8430 · Cited by 282
Self-citationSchirra, J., Nicolaus, M., Roggel, R., Katschinski, M., Storr, M., Woerle, H. J., & Göke, B. (2005) · Gut · doi:10.1136/gut.2004.059741 · Cited by 275
Obesity in Type 1 Diabetes: Pathophysiology, Clinical Impact, and Mechanisms
Corbin, K. D., Driscoll, K. A., Pratley, R. E., Smith, S. R., Maahs, D. M., Mayer-Davis, E. J., & Advancing Care for Type 1 Diabetes and Obesity Network (ACT1ON) (2018) · Endocrine Reviews · doi:10.1210/er.2017-00191 · Cited by 262
Gut microbiota and diabetes: from pathogenesis to therapeutic perspective
Burcelin, R., Sérino, M., Chabo, C., Blasco‐Baqué, V., & Amar, J. (2011) · Acta Diabetologica · doi:10.1007/s00592-011-0333-6 · Cited by 270
“A major consequence is the rapid change in enteroendocrine functions, such as the secretion of gut hormones such as GLP-1, whose origin is yet unknown [67].”
BackgroundThe incretin system in healthy humans: The role of GIP and GLP-1
Holst, J. J. (2019) · Metabolism · doi:10.1016/j.metabol.2019.04.014 · Cited by 248
Gut Peptides in the Regulation of Food Intake and Energy Homeostasis
Murphy, K. G., Dhillo, W. S., & Bloom, S. R. (2006) · Endocrine Reviews · doi:10.1210/er.2006-0028 · Cited by 248
“We discovered that GLP-1 acts as a physiological incretin (109, 110) and suppressor of gastric acid secretion (111) in man.”
BackgroundSelf-citationInsulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro
Parkes, D. G., Pittner, R. A., Jodka, C. M., Smith, P., & Young, A. J. (2001) · Metabolism · doi:10.1053/meta.2001.22519 · Cited by 241
The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice
Chambers, A. P., Sorrell, J. E., Haller, A. M., Roelofs, K. J., Hutch, C. R., Kim, K., Gutiérrez‐Aguilar, R., Li, B., Drucker, D. J., D’Alessio, D. A., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.02.008 · Cited by 248
“Critical evidence for the endocrine model of GLP-1 comes from using pharmacological tools in humans (Edwards et al., 1999; Salehi et al., 2012; Schirra et al., 2006).”
Deane, A. M., Nguyen, N. Q., Stevens, J. E., Fraser, R. J., Holloway, R. H., Besanko, L. K., Burgstad, C. M., Jones, K. L., Chapman, M. J., Rayner, C. K., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1503 · Cited by 240
“At 60 min, ex(9-39)NH2 increased the rise in glycemia [ex(9-39)NH2, 9.”
BackgroundInfluentialGlucagon-Like Peptide 1 Secretion by the L-Cell
Lim, G. E., & Brubaker, P. L. (2006) · Diabetes · doi:10.2337/db06-s020 · Cited by 220
“Studies using GLP-1 receptor antagonists as well as GLP-1 receptor null mice have demonstrated that GLP-1 makes an essential contribution to the “incretin” effect after a meal (3,4).”
MethodGlucagon receptors on human islet cells contribute to glucose competence of insulin release
Huypens, P., Ling, Z., PIPELEERS, D. G., & Schuit, F. C. (2000) · Diabetologia · doi:10.1007/s001250051484 · Cited by 226
Little, T. J., Pilichiewicz, A. N., Russo, A., Phillips, L. K., Jones, K. L., Nauck, M. A., Wishart, J. M., Horowitz, M., & Feinle‐Bisset, C. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-2220 · Cited by 214
“In studies using the specific GLP-1 receptor antagonist, exendin (9–39), to examine the role of endogenous GLP-1 in postprandial glycemia in healthy humans (1, 37 ), GE was not quantified.”
BackgroundGastric Inhibitory Polypeptide and Glucagon-Like Peptide-1 in the Pathogenesis of Type 2 Diabetes
Nauck, M. A., Baller, B., & Meier, J. J. (2004) · Diabetes · doi:10.2337/diabetes.53.suppl_3.s190 · Cited by 163
Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes
Drucker, D. (2003) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.12.1.87 · Cited by 237
“Acute administration of the GLP-1R antagonist exendin(9-39) increases fasting glycaemia and impairs glucose clearance following glucose loading, in association with decreased levels of circulating insulin, in both rodents and human subjects [5,52-55].”
BackgroundGIP as a Therapeutic Target in Diabetes and Obesity: Insight From Incretin Co-agonists
Holst, J. J., & Rosenkilde, M. M. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa327 · Cited by 207
“With this tool, which was administered to humans in 1998-1999 (21), it was possible to characterize the actions of endogenous GLP1, and in several studies (22,23), the insulinotropic actions of endogenous GLP-1 were confirmed using exendin 9-39, which typically reduced insulin responses to oral/intestinal glucose admi…”
BackgroundMethodHyperglycaemia increases dipeptidyl peptidase IV activity in diabetes mellitus
Mannucci, E., Pala, L., Ciani, S., Bardini, G., Pezzatini, A., Sposato, I., Cremasco, F., Ognibene, A., & Rotella, C. M. (2005) · Diabetologia · doi:10.1007/s00125-005-1749-8 · Cited by 206
“The impairment of the GLP-1 response to meals could contribute to the reduction in early postprandial insulin secretion in patients with type 2 diabetes; in fact, the administration of GLP-1 receptor antagonists to healthy volunteers elicits an impairment of meal-induced insulin secretion and an increase in postprandi…”
ResultInsulin Regulates Glucagon-Like Peptide-1 Secretion from the Enteroendocrine L Cell
Lim, G. E., Huang, G. J., Flora, N., LeRoith, D., Rhodes, C. J., & Brubaker, P. L. (2009) · Endocrinology · doi:10.1210/en.2008-0726 · Cited by 200
“Given the demonstrated importance of endogenous GLP-1 release to the maintenance of normal insulin secretion and glucose homeostasis (47, 48), it is therefore somewhat paradoxical that postprandial GLP-1 release is decreased in subjects with type 2 diabetes and insulin resistance, independent of obesity (18–24).”
BackgroundInhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes
Pratley, R. E., & Salsali, A. (2007) · Current Medical Research and Opinion · doi:10.1185/030079906x162746 · Cited by 197
Reimer, M. K., Holst, J. J., & Åhrén, B. (2002) · European Journal of Endocrinology · doi:10.1530/eje.0.1460717 · Cited by 196
“The gut incretin hormones, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are both released in response to ingested nutrients and they both augment insulin secretion (1 ‐ 3). They are of main importance for a normal glucose tolerance after meal intake, as is illustrated by studies showing tha…”
BackgroundGasbjerg, L. S., Helsted, M. M., Hartmann, B., Jensen, M. H., Gabe, M. B. N., Sparre-Ulrich, A. H., Veedfald, S., Stensen, S., Lanng, A. R., Bergmann, N. C., et al. (2019) · Diabetes · doi:10.2337/db18-1123 · Cited by 193
“Study Design Each participant served as his own control and attended four 75-g OGTTs on four separate study days in a randomized order with infusion of GIP(3-30)NH2 (260 min at a rate of 800 pmol/kg/min), exendin(9-39)NH2 (20 min at 1,000 pmol/kg/min followed by 240 min at 450 pmol/ kg/min), GIP(3-30)NH2 and exendin(9…”
BackgroundMethodInfluentialAmelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy
Hong, Y., Lee, J. H., Jeong, K. W., Choi, C. S., & Jun, H. (2019) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12434 · Cited by 188
The Gut-Brain Axis, the Human Gut Microbiota and Their Integration in the Development of Obesity
Bliss, E., & Whiteside, E. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00900 · Cited by 196
“Finally, GLP1 decreases the rate of gastric emptying into the duodenum and hinders gastric acid secretion, which in turn increases gastric distension, limits excessive food consumption, enhances satiety and positively contributes to energy homeostasis (Edwards et al., 1999).”
BackgroundSvane, M. S., Jørgensen, N. B., Bojsen-Møller, K. N., Dirksen, C., Nielsen, S., Kristiansen, V. B., Toräng, S., Wewer Albrechtsen, N. J., Rehfeld, J. F., Hartmann, B., et al. (2016) · International Journal of Obesity · doi:10.1038/ijo.2016.121 · Cited by 185
Intestinal Cholecystokinin Controls Glucose Production through a Neuronal Network
Cheung, G. W. C., Kokorovic, A., Lam, C., Chari, M., & Lam, T. K. T. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.07.005 · Cited by 188
“In addition to GIP, GLP-1 is also known for its function as an incretin to regulate postprandial glucose levels [148] through its potentiating effects on GSIS.”
BackgroundNutrient–secretion coupling in the pancreatic islet β-cell: recent advances
Rutter, G. A. (2001) · Molecular Aspects of Medicine · doi:10.1016/s0098-2997(01)00013-9 · Cited by 180
Boushey, R. P., Yusta, B., & Drucker, D. J. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.5.e937 · Cited by 180
“GLP-1 plays an essential role in the regulation of glucose homeostasis in both rodents and human subjects (12, 18, 31, 38).”
BackgroundWhalley, N., Pritchard, L. E., Smith, D. M., & White, A. E. (2011) · Journal of Endocrinology · doi:10.1530/joe-11-0094 · Cited by 188
“GLP-1 is well known as an incretin hormone and its role in potentiating glucose-stimulated insulin secretion (GSIS) in response to a meal has been clearly elucidated (Edwards et al. 1999).”
BackgroundMinireview: Gut Peptides Regulating Satiety
Druce, M. R., Small, C. J., & Bloom, S. R. (2004) · Endocrinology · doi:10.1210/en.2004-0089 · Cited by 177
Self-citationLamont, B. J., Li, Y., Kwan, E. P., Brown, T. J., Gaisano, H. Y., & Drucker, D. J. (2011) · Journal of Clinical Investigation · doi:10.1172/jci42497 · Cited by 180
Role of Endogenous Glucagon-Like Peptide-1 in Islet Regeneration After Partial Pancreatectomy
León, D. D. D., Deng, S., Madani, R., Ahima, R. S., Drucker, D. J., & Stoffers, D. A. (2003) · Diabetes · doi:10.2337/diabetes.52.2.365 · Cited by 173
High-fructose corn syrup: is this what's for dinner?
Duffey, K. J., & Popkin, B. M. (2008) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.25825c · Cited by 163
Congenital Hyperinsulinism: Diagnosis and Treatment Update
Demirbilek, H., & Hussain, K. (2018) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.2017.s007 · Cited by 173
“Exendin-(9-39) is a specific GLP-1 receptor antagonist in mice and humans (161,162).”
BackgroundHellström, P. M., Näslund, E., Edholm, T., Schmidt, P. T., Kristensen, J., Theodorsson, E., Holst, J. J., & Efendic, S. (2008) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2007.01079.x · Cited by 160
Therapy of type 2 diabetes mellitus based on the actions of glucagon‐like peptide‐1
Holst, J. J. (2002) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.328 · Cited by 156
Green, B. D., Hand, K. V., Dougan, J. E., McDonnell, B. M., Cassidy, R. S., & Grieve, D. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.08.001 · Cited by 152
From the Incretin Concept and the Discovery of GLP-1 to Today's Diabetes Therapy
Holst, J. J. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00260 · Cited by 153
The physiological role of GLP-1 in human: incretin, ileal brake or more?
Schirra, J. R. J., & Göke, B. (2004) · Regulatory Peptides · doi:10.1016/j.regpep.2004.06.018 · Cited by 151
Meier, J. J., Kemmeries, G., Holst, J. J., & Nauck, M. A. (2005) · Diabetes · doi:10.2337/diabetes.54.7.2212 · Cited by 146
“(8) demonstrated a marked deterioration of oral glucose tolerance in healthy subjects during the administration of exendin [9–39].”
BackgroundRegulation of glucagon secretion by incretins
Holst, J. J., Christensen, M., Lund, A., de Heer, J., Svendsen, B., Kielgast, U. L., & Knop, F. K. (2011) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01452.x · Cited by 143
“That regulation of glucagon secretion by GLP-1 is a physiological phenomenon is evident from studies involving administration of the GLP-1 receptor antagonist exendin 9–39, which is associated with elevations of plasma glucagon concentrations, showing that endogenous GLP-1 inhibits glucagon secretion [38].”
BackgroundInterleukin-6 Delays Gastric Emptying in Humans with Direct Effects on Glycemic Control
Lang Lehrskov, L., Lyngbaek, M. P., Soederlund, L., Legaard, G. E., Ehses, J. A., Heywood, S. E., Wewer Albrechtsen, N. J., Holst, J. J., Karstoft, K., Pedersen, B. K., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.04.008 · Cited by 135
Kielgast, U., Holst, J. J., & Madsbad, S. (2011) · Diabetes · doi:10.2337/db10-1790 · Cited by 137
“This could theoretically be the result of 1) increases in GE (with more nutrients reaching the intestine and the L-cells [40]), 2) blockade of a negative feedback system between the GLP-1 and the L-cell (41), 3) changes in plasma clearance of GLP-1 (because the GLP-1 receptor [GLP-1R] is expressed in tubular cells of…”
BackgroundResultNutritional modulation of endogenous glucagon-like peptide-1 secretion: a review
Bodnaruc, A. M., Prud’homme, D., Blanchet, R., & Giroux, I. (2016) · Nutrition & Metabolism · doi:10.1186/s12986-016-0153-3 · Cited by 139
“cretion, as well as in impaired glucose tolerance [26, 27].”
BackgroundShah, M., Law, J. H., Micheletto, F., Sathananthan, M., Man, C. D., Cobelli, C., Rizza, R. A., Camilleri, M., Zinsmeister, A. R., & Vella, A. V. (2013) · Diabetes · doi:10.2337/db13-0954 · Cited by 134
“Assuming this is the case, the infusion rate of exendin-9,39 should be sufficient to inhibit GLP-1 actions at its receptor (33).”
BackgroundReceptor‐mediated activation of gastric vagal afferents by glucagon‐like peptide‐1 in the rat
Bucinskaite, V., Tolessa, T., Pedersen, J., Rydqvist, B., Zerihun, L., Holst, J. J., & Hellström, P. M. (2009) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2009.01317.x · Cited by 139
Gault, V. A., O'Harte, F. P. M., Harriott, P., Mooney, M., Green, B., & Flatt, P. R. (2003) · Diabetologia · doi:10.1007/s00125-002-1028-x · Cited by 134
“Therefore, exendin(9–39)amide has been used to assess the specific role of GLP-1 in the regulation of meal-induced insulin release and blood glucose homeostasis both in animals and humans [18, 19, 20, 21].”
BackgroundMethodHolst, J. J. (1999) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(99)00157-5 · Cited by 129
Gut peptides and type 2 diabetes mellitus treatment
Åhrén, B. (2003) · Current Diabetes Reports · doi:10.1007/s11892-003-0079-9 · Cited by 130
“Thus, GIP receptor antagonism by GIP7-30amide in rats and GLP-1 receptor antagonism by exendin9-39amide in humans reduce insulin secretion after meal ingestion [2, 3 ].”
BackgroundCircadian Secretion of the Intestinal Hormone GLP-1 by the Rodent L Cell
Gil‐Lozano, M., Mingomataj, E., Wu, W. K., Ridout, S. A., & Brubaker, P. L. (2014) · Diabetes · doi:10.2337/db13-1501 · Cited by 139
“insulin response to nutrient ingestion (16,17).”
Is GLP‐1 a hormone: Whether and When?
D'Alessio, D. (2016) · Journal of Diabetes Investigation · doi:10.1111/jdi.12466 · Cited by 130
“GLP-1 is cleaved from proglucagon in specific intestinal enterocytes called L cells, and secreted primarily as an amidated 30amino acid peptide GLP-1(7-36)NH2 (1,17).”
BackgroundInfluentialPhysiology of Incretins in Health and Disease
Deacon, C. F., & Åhrén, B. (2011) · The Review of Diabetic Studies · doi:10.1900/rds.2011.8.293 · Cited by 135
“Thus, when infused into healthy humans, exendin 9-39 was associated with increased postprandial glucose excursions [68].”
BackgroundGlucagon and Type 2 Diabetes: the Return of the Alpha Cell
Lund, A., Bagger, J. I., Christensen, M., Knop, F. K., & Vilsbøll, T. (2014) · Current Diabetes Reports · doi:10.1007/s11892-014-0555-4 · Cited by 127
New Drugs for Type 2 Diabetes Mellitus
Krentz, A. J., Patel, M., & Bailey, C. J. (2008) · Drugs · doi:10.2165/00003495-200868150-00005 · Cited by 122
“All of these actions are potentially favoupeptide hormones that are secreted in response to rable properties for a new putative anti-diabetic ingestion of a meal augment postprandial insulin drug.[93-96] secretion; this is known as the incretin effect and can account for up to ≈70% of postprandial insulin se- There is…”
Effect of endogenous GLP-1 on insulin secretion in type 2 diabetes
Salehi, M., Aulinger, B., Prigeon, R. L., & D'Alessio, D. A. (2010) · Diabetes · doi:10.2337/db09-1253 · Cited by 124
“IV glucose infusion at variable rates Exendin-(9-39) or saline infusion Saline Ex-9”
InfluentialJiménez, A., Casamitjana, R., Viaplana-Masclans, J., Lacy, A. M., & Vidal, J. (2013) · Diabetes Care · doi:10.2337/dc12-1535 · Cited by 119
The Role of Incretins on Insulin Function and Glucose Homeostasis
Holst, J. J., Gasbjerg, L. S., & ROSENKILDE, M. M. (2021) · Endocrinology · doi:10.1210/endocr/bqab065 · Cited by 141
“The infusions invariably elevate glucose concentrations and increase glucagon concentrations (44), but insulin responses are more variable, and decreases as well as increases have been found.”
BackgroundMinireview: Update on Incretin Biology: Focus on Glucagon-Like Peptide-1
Brubaker, P. L. (2010) · Endocrinology · doi:10.1210/en.2010-0115 · Cited by 122
“Finally, whether a small decrement in GLP-1 levels has a physiological impact remains to be demonstrated, although it is clear that complete blockade of GLP-1 action is associated with impaired glucose tolerance in rodents, as well as in humans (48).”
Incretins: their physiology and application in the treatment of diabetes mellitus
Tasyurek, H. M., Altunbas, H. A., Balci, M. K., & Sanlioglu, S. (2014) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2501 · Cited by 121
Evaluation of the incretin effect in humans using GIP and GLP-1 receptor antagonists
Gasbjerg, L. S., Bergmann, N. C., Stensen, S., Christensen, M. B., Rosenkilde, M. M., Holst, J. J., Nauck, M., & Knop, F. K. (2020) · Peptides · doi:10.1016/j.peptides.2019.170183 · Cited by 121
Phillips, L. K., & Prins, J. B. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06491.x · Cited by 122
Gil‐Lozano, M., Hunter, P. M., Behan, L., Gladanac, B., Casper, R. F., & Brubaker, P. L. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00298.2015 · Cited by 114
Nishizawa, M., Nakabayashi, H., Kawai, K., Ito, T., Kawakami, S., Nakagawa, A., Niijima, A., & Uchida, K. (2000) · Journal of the Autonomic Nervous System · doi:10.1016/s0165-1838(99)00086-7 · Cited by 110
Salehi, M., Vahl, T. P., & D'Alessio, D. A. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0605 · Cited by 108
“(7) demonstrated that blocking the GLP-1r increased the postprandial glucose AUC by 35% after a liquid glucose meal.”
BackgroundInfluentialCalabria, A. C., Li, C., Gallagher, P. R., Stanley, C. A., & León, D. D. D. (2012) · Diabetes · doi:10.2337/db12-0166 · Cited by 108
“Exendin-(9-39), a truncated form of the GLP-1 agonist exendin-4, is a specific GLP-1 receptor antagonist in mice and humans (5,11,12).”
Emerging Therapies Mimicking the Effects of Amylin and Glucagon-Like Peptide 1
Riddle, M. C., & Drucker, D. J. (2006) · Diabetes Care · doi:10.2337/diacare.29.02.06.dc05-1267 · Cited by 108
“These experiments have determined that GLP-1 is essential for control of both fasting and postprandial glucose in rodents (122) and human subjects (123,124).”
BackgroundMannucci, E., Ognibene, A., Cremasco, F., Bardini, G., Mencucci, A., Pierazzuoli, E., Ciani, S., Fanelli, A., Messeri, G., & Rotella, C. M. (2000) · Diabetic Medicine · doi:10.1046/j.1464-5491.2000.00367.x · Cited by 106
Gasbjerg, L. S., Christensen, M., Hartmann, B., Lanng, A. R., Sparre‐Ulrich, A. H., Gabe, M. B. N., Dela, F., Vilsbøll, T., Holst, J. J., ROSENKILDE, M. M., et al. (2017) · Diabetologia · doi:10.1007/s00125-017-4447-4 · Cited by 98
“One of the important tools in the elaboration of GLP-1 physiology and the development of GLP-1-based therapies is the GLP-1 receptor antagonist exendin(9-39), which was first described in 1991 [5], and has been applied in multiple human studies since 1998 [6, 7].”
MethodDeacon, C. F., Plamboeck, A., Møller, S., & Holst, J. J. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00452.2001 · Cited by 103
“Thus the GLP-1 receptor antagonist exendin-(9–39) (15) blocks GLP-1’s insulinotropic effect in vivo (11, 23, 35) but does not antagonize the peptide’s gastrointestinal effects in dogs (13) or its stimulatory effect on hepatic vagal afferent activity in rats (28).”
BackgroundIs glucagon-like peptide 1 an incretin hormone?
Nauck, M. A. (1999) · Diabetologia · doi:10.1007/s001250051165 · Cited by 102
“oral glucose load has recently been examined using exendin [9-39] in vivo in human volunteers [67].”
BackgroundMethodMeal-Anticipatory Glucagon-Like Peptide-1 Secretion in Rats
Vahl, T. P., Drazen, D. L., Seeley, R. J., D’Alessio, D. A., & Woods, S. C. (2009) · Endocrinology · doi:10.1210/en.2009-1002 · Cited by 100
“This antibody recognizes both the intact hormone GLP-1-(7-36)NH2 and the metabolite GLP-1-(9-36)-NH2 and is a reliable index of secreted hormone.”
BackgroundMarty, V. N., Farokhnia, M., Munier, J. J., Mulpuri, Y., Leggio, L., & Spigelman, I. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.599646 · Cited by 108
GLP1 Receptor Agonists—Effects beyond Obesity and Diabetes
Wilbon, S. S., & Kolonin, M. G. (2023) · Cells · doi:10.3390/cells13010065 · Cited by 101
“Postprandially, the levels of GLP1 increase dramatically to stimulate insulin biosynthesis and release, suppress glucagon release, delay gastric emptying, improve glucose metabolism, and increase satiety [3].”
BackgroundGlucagon-like peptides 1 and 2 in health and disease: A review
Marathe, C. S., Rayner, C. K., Jones, K. L., & Horowitz, M. (2013) · Peptides · doi:10.1016/j.peptides.2013.01.014 · Cited by 100
Metadata
- Authors
- Edwards, C. M., Todd, J. F., Mahmoudi, M., Wang, Z., Wang, R. M., Ghatei, M. A., & Bloom, S. R.
- Affiliations
- Hammersmith Hospital (GB)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1999-01-01
- Volume
- 48
- Issue
- 1
- Pages
- 86-93
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2146581079
- Cited by
- 344
- References
- 0
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 7 · 2021: 8 · 2020: 9 · 2019: 17 · 2018: 12 · 2017: 12 · 2016: 16 · 2015: 16 · 2014: 13 · 2013: 19 · 2012: 8
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- glucagon-like peptide-1, exendin-9-39, incretins, postprandial blood glucose, glucose-stimulated insulin secretion, pancreatic islets, glucagon suppression, gastric emptying, glucose tolerance, insulinotropic effect
- MeSH terms
- Insulin Secretion, Eating, Glucagon, Glucose, Glucose Tolerance Test, Humans, Insulin, Islets of Langerhans, Peptide Fragments, Protein Precursors, Cytokines, Glucagon-Like Peptide 1, In Vitro Techniques
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