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The Cephalic Insulin Response to Meal Ingestion in Humans Is Dependent on Both Cholinergic and Noncholinergic Mechanisms and Is Important for Postprandial Glycemia
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We studied the mechanisms and physiological relevance of the cephalic insulin response to meal ingestion in 12 healthy women (age 63 ± 0.4 years; BMI 27.7 ± 1.7 kg/m2). The ganglionic antagonist, trimethaphan, which impairs neurotransmission across parasympathetic and sympathetic autonomic ganglia, or atropine or saline was given intravenously during the first 15 min after ingestion of a standard meal (350 kcal). During saline infusion, insulin levels increased during the first 10 min after meal ingestion, whereas the first increase in glucose was evident at 15 min. The preabsorptive 10-min insulin response was reduced by 73 ± 11% by trimethaphan (P = 0.009), accompanied by impaired reduction of glucose levels from 25 to 60 min after meal ingestion (Δglucose = –1.27 ± 0.5 [with saline] vs. 0.1 ± 0.4 mmol/l [with trimethaphan]; P = 0.008). This reduction at 25–60 min in glucose levels correlated significantly to the 10-min insulin response (r = 0.65, P = 0.024). The 10-min insulin response to meal ingestion was also reduced by atropine, but only by 20 ± 9% (P = 0.045), which was lower than the reduction with trimethaphan (P = 0.004). The preabsorptive insulin response was not accompanied by any increase in circulating levels of gastric inhibitory polypeptide (GIP) or glucagon-like peptide 1 (GLP-1). In conclusion, 1) the early preabsorptive insulin response to meal ingestion in humans can be largely attributed to autonomic activation mediated by noncholinergic and cholinergic mechanisms, 2) this cephalic insulin response is required for a normal postprandial glucose tolerance, and 3) GIP and GLP-1 do not contribute to the preabsorptive cephalic phase insulin response to meal ingestion.
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“The neural mechanism underlying cephalic phase insulin response was found to include cholinergic and non-cholinergic processes136 as well as the dorsal vagal complex located in the medulla oblongata.137”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [136]
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“Moreover, cephalic phase insulin response is pivotal for ensuring normal postprandial glucose management.136”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [136]
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Cites
The Pharmacological Basis of Therapeutics
(1976) · American Journal of Health-System Pharmacy · doi:10.1093/ajhp/33.4.373a · Cited by 9,216
The pharmacological basis of therapeutics
Starr, I. (1941) · American Heart Journal · doi:10.1016/s0002-8703(41)90958-4 · Cited by 1,907
Kieffer, T. J., & Habener, J. F. (1999) · Endocrine Reviews · doi:10.1210/edrv.20.6.0385 · Cited by 1,062
Autonomic regulation of islet hormone secretion - Implications for health and disease
Åhrén, B. (2000) · Diabetologia · doi:10.1007/s001250051322 · Cited by 929
Tissue and Plasma Concentrations of Amidated and Glycine-Extended Glucagon-Like Peptide I in Humans
Ørskov, C., Rabenhøj, L., Wettergren, A., Kofod, H., & Holst, J. J. (1994) · Diabetes · doi:10.2337/diab.43.4.535 · Cited by 916
Self-citationScrocchi, L. A., Brown, T. J., Maclusky, N., Brubaker, P. L., Auerbach, A. B., Joyner, A. L., & Drucker, D. J. (1996) · Nature Medicine · doi:10.1038/nm1196-1254 · Cited by 793
Mitrakou, A., Kelley, D., Mokan, M., Veneman, T., Pangburn, T., Reilly, J., & Gerich, J. (1992) · New England Journal of Medicine · doi:10.1056/nejm199201023260104 · Cited by 595
Miyawaki, K., Yamada, Y., Yano, H., Niwa, H., Ban, N., Ihara, Y., Kubota, A., Fujimoto, S., Kajikawa, M., Kuroe, A., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.14843 · Cited by 454
Avignon, A., Radauceanu, A., & Monnier, L. (1997) · Diabetes Care · doi:10.2337/diacare.20.12.1822 · Cited by 363
Cephalic phase, reflex insulin secretion neuroanatomical and physiological characterization
Berthoud, H. R., Bereiter, D. A., Trimble, E. R., Siegel, E. G., & Jeanrenaud, B. (1981) · Diabetologia · doi:10.1007/bf00254508 · Cited by 231
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
“The response is noticeable after 10 min, but occurs later than the “cephalic phase” stimulation of insulin secretion (3), suggesting that the neuronal, possibly vagal, signals that cause insulin secretion do not influence GLP-1 (or GIP) secretion.”
BackgroundSelf-citationAcetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome
Perry, R. J., Peng, L., Barry, N. A., Cline, G. W., Zhang, D., Cardone, R. L., Petersen, K. F., Kibbey, R. G., Goodman, A. L., & Shulman, G. I. (2016) · Nature · doi:10.1038/nature18309 · Cited by 1,299
Pancreatic regulation of glucose homeostasis.
Röder, P. V., Wu, B., Liu, Y., & Han, W. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.6 · Cited by 985
Animal models of obesity and diabetes mellitus
Kleinert, M., Clemmensen, C., Hofmann, S. M., Moore, M. C., Renner, S., Woods, S. C., Huypens, P., Beckers, J., de Angelis, M. H., Schürmann, A., et al. (2018) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.161 · Cited by 893
Obstructive Sleep Apnea and Diabetes
Reutrakul, S., & Mokhlesi, B. (2017) · Chest · doi:10.1016/j.chest.2017.05.009 · Cited by 667
Havel, P. J. (2005) · Nutrition Reviews · doi:10.1111/j.1753-4887.2005.tb00132.x · Cited by 607
Steinert, 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
“Insulin secretion CCK PYY(3-36) Nutrients FIGURE 7.”
BackgroundInfluentialWEINZIMER, S. A., Steil, G. M., Swan, K. L., Dziura, J., Kurtz, N., & Tamborlane, W. V. (2008) · Diabetes Care · doi:10.2337/dc07-1967 · Cited by 567
Mechanisms and Physiological Significance of the Cholinergic Control of Pancreatic -Cell Function
Gilon, P., & Henquin, J. (2001) · Endocrine Reviews · doi:10.1210/edrv.22.5.0440 · Cited by 521
“It corresponds to a rise of approximately 20% (28, 216, 217) or more FIG.”
BackgroundPhysiology 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
“Parasympathetic cholinergic signaling mediates cephalic insulin secretion, a response most clearly apparent in rats, but also in humans (5, 394).”
BackgroundFeasibility of Automating Insulin Delivery for the Treatment of Type 1 Diabetes
Steil, G. M., Rebrin, K., Darwin, C. H., Hariri, F., & Saad, M. F. (2006) · Diabetes · doi:10.2337/db06-0419 · Cited by 473
Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down?
Nauck, M. A., Vardarli, I., Deacon, C. F., Holst, J. J., & Meier, J. J. (2011) · Diabetologia · doi:10.1007/s00125-010-1896-4 · Cited by 465
“The temporal pattern of nutrient intake-related increments in plasma GLP-1 begins with a rather early rise (starting approximately 10 to 15 min after eating [22]), peaks during the second hour and then slowly declines to baseline over several hours.”
BackgroundSelf-citationInnervation Patterns of Autonomic Axons in the Human Endocrine Pancreas
Rodriguez-Diaz, R., Abdulreda, M. H., Formoso, A. L., Gans, I., Ricordi, C., Berggren, P.-O., & Caicedo, A. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.05.008 · Cited by 356
“Thus, a direct neural influence on insulin secretion during feeding may be relatively small in humans (Ahrén and Holst, 2001; Teff et al., 1991).”
Pancreatic β-cell identity, glucose sensing and the control of insulin secretion
Rutter, G. A., Pullen, T. J., Hodson, D. J., & Martínez-Sánchez, A. (2015) · Biochemical Journal · doi:10.1042/bj20141384 · Cited by 355
Metabolic effects of non-nutritive sweeteners
Pepino, M. Y. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.06.024 · Cited by 285
“However, given that 1) classical or Pavlovian conditioning is one of the most basic forms of learning (demonstrated even in invertebrates such as the Aplysia (33), 2) cephalic responses are elicited when people taste and chew food (34) (reviewed in 35), and 3) studies in human subjects show that cephalic responses are…”
BackgroundSalivary Amylase: Digestion and Metabolic Syndrome
Gachons, C. P. D., & Breslin, P. A. S. (2016) · Current Diabetes Reports · doi:10.1007/s11892-016-0794-7 · Cited by 305
Anticipatory physiological regulation in feeding biology: Cephalic phase responses
Power, M. L., & Schulkin, J. (2008) · Appetite · doi:10.1016/j.appet.2007.10.006 · Cited by 258
“3; Ahren & Holst, 2001).”
Cephalic phase responses and appetite
Smeets, P. A. M., Erkner, A., & de Graaf, C. (2010) · Nutrition Reviews · doi:10.1111/j.1753-4887.2010.00334.x · Cited by 263
The somatostatin-secreting pancreatic δ-cell in health and disease
Rorsman, P., & Huising, M. O. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0020-6 · Cited by 259
Ma, J., Bellon, M., Wishart, J. M., Young, R. L., Blackshaw, L. A., Jones, K. L., Horowitz, M., & Rayner, C. K. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.90708.2008 · Cited by 256
The 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
“Nevertheless, secretion of the two hormones generally shows up at the same, very early time point [26], and experiments in rats have shown that the upper half of the small intestine can produce GLP-1 with the same kinetics and in similar amounts as the distal small intestine [27].”
BackgroundSelf-citationWhat do we know about the secretion and degradation of incretin hormones?
Deacon, C. F. (2005) · Regulatory Peptides · doi:10.1016/j.regpep.2004.06.007 · Cited by 244
Grimaldi, D., Beccuti, G., Touma, C., Cauter, E. V., & Mokhlesi, B. (2013) · Diabetes Care · doi:10.2337/dc13-0933 · Cited by 224
Mandel, A. L., & Breslin, P. A. S. (2012) · Journal of Nutrition · doi:10.3945/jn.111.156984 · Cited by 208
The endocrinology of food intake
Begg, D. P., & Woods, S. C. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.136 · Cited by 214
Ford, H. E., Peters, V., Martin, N. M., Sleeth, M., Ghatei, M. A., Frost, G. S., & Bloom, S. R. (2011) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2010.291 · Cited by 196
“This is in keeping with previous studies which have not demonstrated a cephalic phase GLP-1 response to either ingestion of a mixed meal (Ahren and Holst, 2001) or to a sham-fed meal (Luscombe-Marsh et al., 2009).”
ResultIncretin hormones and the satiation signal
Holst, J. J. (2013) · International Journal of Obesity · doi:10.1038/ijo.2012.208 · Cited by 191
Self-citationG-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes
Winzell, M. S., & Åhrén, B. (2007) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2007.08.002 · Cited by 188
“Activation of the parasympathetic nerves enhances insulin secretion and it is particularly important for the so-called cephalic phase, which occurs prior to the elevation of plasma glucose levels (Ahrén & Holst, 2001).”
BackgroundPostprandial metabolism of meal triglyceride in humans
Lambert, J. E., & Parks, E. J. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2012.01.006 · Cited by 182
Postprandial hypertriglyceridemia as a coronary risk factor
Borén, J., Matikainen, N., Adiels, M., & Taskinen, M.-R. (2014) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.01.015 · Cited by 182
Renard, É., Place, J., Cantwell, M., Chevassus, H., & Palerm, C. C. (2009) · Diabetes Care · doi:10.2337/dc09-1080 · Cited by 176
Functional magnetic resonance imaging of human hypothalamic responses to sweet taste and calories
Smeets, P. A. M., de Graaf, C., Stafleu, A., van Osch, M. J. P., & van der Grond, J. (2005) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/82.5.1011 · Cited by 171
Chapter 15 Glucose‐Dependent Insulinotropic Polypeptide (Gastric Inhibitory Polypeptide; GIP)
McIntosh, C. H. S., Widenmaier, S. B., & Kim, S. (2009) · Vitamins and hormones · doi:10.1016/s0083-6729(08)00615-8 · Cited by 173
Ingestion of Diet Soda Before a Glucose Load Augments Glucagon-Like Peptide-1 Secretion
Brown, R. J., Walter, M. F., & Rother, K. I. (2009) · Diabetes Care · doi:10.2337/dc09-1185 · Cited by 169
“This is unlikely, because cephalic-phase insulin release typically occurs 2–10 min after taste exposure and does not occur with pure oral glucose or artificial sweeteners (8), and cephalic-phase GLP-1 response has not been observed in humans (9).”
BackgroundFunctional MRI of human hypothalamic responses following glucose ingestion
Smeets, P. A. M., de Graaf, C., Stafleu, A., van Osch, M. J. P., & van der Grond, J. (2004) · NeuroImage · doi:10.1016/j.neuroimage.2004.07.073 · Cited by 160
“Although a relatively small amount of insulin is secreted, it is important in preventing post-prandial peaks in blood glucose ( Ahren and Holst, 2001; Harju and Nordback, 1987; Kraegen et al., 1981).”
BackgroundBremer, A. A., Stanhope, K. L., Graham, J. L., Cummings, B. P., Wang, W., Saville, B. R., & Havel, P. J. (2011) · Clinical and Translational Science · doi:10.1111/j.1752-8062.2011.00298.x · Cited by 148
Muscarinic Receptors Control Glucagon-Like Peptide 1 Secretion by Human Endocrine L Cells
Anini, Y., & Brubaker, P. L. (2003) · Endocrinology · doi:10.1210/en.2003-0143 · Cited by 135
The neural/cephalic phase reflexes in the physiology of nutrition
Zafra, M. A., Molina, F., & Puerto, A. (2006) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2006.03.005 · Cited by 132
“The insulin released during the cephalic phase depends on the functional integrity of the vagus nerve, especially of its hepatic and gastric branches (Berthoud and Powley, 1990; Herath et al., 1999; Ahrén and Holst, 2001).”
Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation
Brandt, C., Nolte, H., Henschke, S., Engström, L., Awazawa, M., Morgan, D. A., Gabel, P., Sprenger, H., Hess, M. E., Günther, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.10.015 · Cited by 133
Physiology 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
“Sham-feeding does not alter GLP-1 concentrations [53], while basal GLP-1 and GIP concentrations remain unchanged in the preabsorptive (cephalic) period [54], and are unaffected by the non-specific muscarinic blocker atropine.”
BackgroundHow neural mediation of anticipatory and compensatory insulin release helps us tolerate food
Teff, K. L. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.01.012 · Cited by 132
“Conversely, the infusion of somatostatin during the beginning of meal onset to inhibit early insulin release has been shown to impair glucose tolerance in normal healthy subjects [56] as has the infusion of trimethaphan, a ganglionic antagonist which also inhibits early insulin release [57].”
Functional neuroimaging of gastric distention
Stephan, E., Pardo, J. V., Faris, P. L., Hartman, B. K., Kim, S. W., Ivanov, E. H., Daughters, R. S., Costello, P. A., & Goodale, R. L. (2003) · Journal of Gastrointestinal Surgery · doi:10.1016/s1091-255x(03)00071-4 · Cited by 116
Parada, J., & Santos, J. L. (2015) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2013.840260 · Cited by 116
“It has been described that, although PIR is weak and probably represents only a minor proportion of secreted insulin, it may have an important influence on glycemic response (Ahr en and Holst, 2001).”
BackgroundLindgren, O., Mari, A., Deacon, C. F., Carr, R. D., Winzell, M. S., Vikman, J., & Ahrén, B. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0366 · Cited by 111
“One possibility could be neural factors; it is well known that the initial insulin secretion after meal ingestion is neurally mediated during the so-called cephalic phase (20).”
BackgroundEmerging 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
“A long-recognized example is the “cephalic phase” of insulin secretion (47,60).”
BackgroundRegulation of Chylomicron Secretion: Focus on Post-Assembly Mechanisms
Xiao, C., Stahel, P., & Lewis, G. F. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.10.015 · Cited by 114
“A cephalic phase response of insulin secretion may involve both cholinergic and noncholinergic autonomic activation.(90) Sham fat feeding is associated with cephalic phase responses, including release of pancreatic polypeptide, insulin, and CM TGs, which is believed to be related to vagal stimulation and increased par…”
BackgroundThe Incretin Approach for Diabetes Treatment
Holst, J. J., & Ørskov, C. (2004) · Diabetes · doi:10.2337/diabetes.53.suppl_3.s197 · Cited by 110
“Thus, dysfunction of the autonomic innervation of the islets could be responsible, perhaps particularly with respect to the early insulin response to meal (5,6).”
BackgroundSelf-citationGlucagon-related peptide 1 (GLP-1): hormone and neurotransmitter
Larsen, P. J., & Holst, J. J. (2004) · Regulatory Peptides · doi:10.1016/j.regpep.2004.08.026 · Cited by 108
Self-citationHuman pancreatic neuro-insular network in health and fatty infiltration
Tang, S.-C., Baeyens, L., Shen, C.-N., Peng, S.-J., Chien, H.-J., Scheel, D. W., Chamberlain, C. E., & German, M. (2017) · Diabetologia · doi:10.1007/s00125-017-4409-x · Cited by 85
Sensory nerves contribute to insulin secretion by glucagon-like peptide-1 in mice
Åhrén, B. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00423.2003 · Cited by 99
“The idea that GLP-1 activates autonomic nerves to the pancreas, which may contribute to the insulin response after meal ingestion, may also partially explain findings that neuronal ganglionic blockade reduces the insulin response to meal intake (4).”
BackgroundBurcelin, R., & Gourdy, P. (2016) · Obesity Reviews · doi:10.1111/obr.12465 · Cited by 99
Åhrén, B., & Pacini, G. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00199.2002 · Cited by 98
Törrönen, R., Sarkkinen, E. S., Niskanen, T. H., Tapola, N. S., Kilpi, K., & NISKANEN, L. K. (2011) · British Journal Of Nutrition · doi:10.1017/s0007114511004557 · Cited by 96
“Despite the magnitude of the CPIR being low, just detectable, it plays a significant physiological role preparing the body for the more efficient handling of the nutrients((29)).”
K-cells and Glucose-Dependent Insulinotropic Polypeptide in Health and Disease
Cho, Y. M., & Kieffer, T. J. (2010) · Vitamins and hormones · doi:10.1016/b978-0-12-381517-0.00004-7 · Cited by 98
Nutrition and taste and smell dysfunction
Kershaw, J. C., & Mattes, R. D. (2018) · World Journal of Otorhinolaryngology - Head and Neck Surgery · doi:10.1016/j.wjorl.2018.02.006 · Cited by 87
Role of VIP and PACAP in islet function
Winzell, M. S., & Åhrén, B. (2007) · Peptides · doi:10.1016/j.peptides.2007.04.024 · Cited by 91
Unravelling innervation of pancreatic islets
Hampton, R. F., Jiménez-González, M., & Stanley, S. A. (2022) · Diabetologia · doi:10.1007/s00125-022-05691-9 · Cited by 82
“Atropine also blunts postprandial insulin release in monkeys [84] and after nutrient infusion in rats [85].”
BackgroundCopy Number Polymorphism of the Salivary Amylase Gene: Implications in Human Nutrition Research
Santos, J. L., Saus, E., Smalley, S. V., Cataldo, L. R., Alberti, G., Parada, J., Gratacòs, M., & Estivill, X. (2012) · Lifestyle Genomics · doi:10.1159/000339951 · Cited by 85
Hypothalamic Obesity: The Sixth Cranial Endocrinopathy
Lustig, R. H. (2002) · The Endocrinologist · doi:10.1097/00019616-200205000-00008 · Cited by 81
The neuropeptide pituitary adenylate cyclase-activating polypeptide and islet function.
Filipsson, K., Kvist-Reimer, M., & Bo, A.-R. (2001) · Diabetes · doi:10.2337/diabetes.50.9.1959 · Cited by 88
Bedinger, D., & Adams, S. H. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.08.013 · Cited by 85
Use and importance of nonhuman Primates in metabolic disease research: current state of the field
Havel, P. J., Kievit, P., Comuzzie, A. G., & Bremer, A. A. (2017) · ILAR Journal · doi:10.1093/ilar/ilx031 · Cited by 75
Wice, B. M., Wang, S., Crimmins, D. L., Diggs‐Andrews, K. A., Althage, M. C., Ford, E. L., Tran, H. D., Ohlendorf, M. F., Griest, T. A., Wang, Q., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.129304 · Cited by 74
Wice, B. M., Reeds, D. N., Tran, H. D., Crimmins, D. L., Patterson, B. W., Dunai, J., Wallendorf, M., Ladenson, J. H., Villareal, D. T., & Polonsky, K. S. (2012) · Diabetes · doi:10.2337/db11-1451 · Cited by 75
“Moreover, the effects of GIP on ISRs remained elevated even after this initial transient response, suggesting that like the cephalic response (32), this early response to GIP may play an important role in amplifying subsequent insulin secretion.”
BackgroundSuzuki, H., Fukushima, M., Okamoto, S., Takahashi, O., Shimbo, T., Kurose, T., Yamada, Y., Inagaki, N., Seino, Y., & Fukui, T. (2005) · Metabolism · doi:10.1016/j.metabol.2005.06.006 · Cited by 84
“Preabsorptive or cephalic-phase insulin release, a vagally mediated response, occurs within the first few minutes of food ingestion [6] and is thought to be required for normal postprandial glucose tolerance [7].”
BackgroundNeuropeptides and the Regulation of Islet Function
Åhrén, B., Wierup, N., & Sundler, F. (2006) · Diabetes · doi:10.2337/db06-s013 · Cited by 72
“Reproduced with permission from the American Diabetes Association (7).”
BackgroundInfluentialSweet Taste Is Complex: Signaling Cascades and Circuits Involved in Sweet Sensation
von Molitor, E., Riedel, K., Krohn, M., Hafner, M., Rudolf, R., & Cesetti, T. (2021) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2021.667709 · Cited by 67
“CPIR is important to prepare the body for ingestion, digestion, and storage of carbohydrate (Ahrén and Holst, 2001; Smeets et al., 2010).”
BackgroundThe Cholinergic System Controls Ghrelin Release and Ghrelin-Induced Growth Hormone Release in Humans
Maier, C., Schaller, G., Buranyi, B., Nowotny, P., Geyer, G., Wolzt, M., & Luger, A. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0656 · Cited by 66
Pancreatic neuro-insular network in young mice revealed by 3D panoramic histology
Tang, S., Shen, C., Lin, P.-Y., Peng, S.-J., Chien, H., Chou, Y.-H., Chamberlain, C. E., & Pasricha, P. J. (2017) · Diabetologia · doi:10.1007/s00125-017-4408-y · Cited by 69
Ranawana, V., Henry, C. J., & Pratt, M. (2010) · Nutrition Research · doi:10.1016/j.nutres.2010.06.002 · Cited by 62
Dhillon, J., Lee, J. Y., & Mattes, R. D. (2017) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.09.009 · Cited by 62
Beta cell connectivity in pancreatic islets: a type 2 diabetes target?
Rutter, G. A., & Hodson, D. J. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1755-4 · Cited by 62
“Such activation underpins the cephalic phase of 11 insulin secretion in anticipation of food [77].”
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Ahmad, S. Y., Friel, J. K., & MacKay, D. (2019) · Nutrition Reviews · doi:10.1093/nutrit/nuz099 · Cited by 65
Chien, H.-J., Chiang, T.-C., Peng, S.-J., Chung, M.-H., Chou, Y.-H., Lee, C.-Y., Jeng, Y., Yu-Wen, T., & Tang, S.-C. (2019) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00116.2019 · Cited by 51
Autonomic Dysfunction of the β-Cell and the Pathogenesis of Obesity
Lustig, R. H. (2003) · Reviews in Endocrine and Metabolic Disorders · doi:10.1023/a:1021819318484 · Cited by 58
“This phenomenon is responsible for the vagally-mediated “cephalic” or preabsorptive phase of insulin secretion, which is glucose-independent and can be blocked by atropine [ 39 ].”
BackgroundRossi, J., Santamäki, P., Airaksinen, M. S., & Herzig, K.-H. (2005) · Diabetes · doi:10.2337/diabetes.54.5.1324 · Cited by 55
“Ahren and Holst (40) suggested that a failure of islet parasympathetic innervation may be involved in the development of glucose intolerance and that augmentation of neural-induced insulin secretion might be a target for treatment of islet dysfunction in diabetes.”
BackgroundThe elusive cephalic phase insulin response: triggers, mechanisms, and functions
Langhans, W., Watts, A. G., & Spector, A. C. (2022) · Physiological Reviews · doi:10.1152/physrev.00025.2022 · Cited by 57
Holst, J. J., Albrechtsen, N. J. W., ROSENKILDE, M. M., & Deacon, C. F. (2019) · Comprehensive physiology · doi:10.1002/cphy.c180013 · Cited by 72
Self-citationKokrashvili, Z., Yee, K. K., Ilegems, E., Iwatsuki, K., Li, Y., Mosinger, B. J., & Margolskee, R. F. (2014) · British Journal Of Nutrition · doi:10.1017/s0007114513002262 · Cited by 53
“Cephalic-phase responses are well established for insulin and ghrelin((7,8)), but controversial or thought not to occur with the incretin hormones GLP-1 and glucose-dependent insulinotropic peptide((15)).”
BackgroundCephalic phase secretion of insulin and other enteropancreatic hormones in humans.
Veedfald, S., Plamboeck, A., Deacon, C., Hartmann, B., Knop, F., Vilsbøll, T., & Holst, J. (2016) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00222.2015 · Cited by 43
“The absence of a cephalic phase of GLP-1 secretion is in accord with other human data (2, 21, 46).”
ResultSelf-citationSuarez, A. N., Noble, E. E., & Kanoski, S. E. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00101 · Cited by 55
“In addition to this endocrine metabolic pathway, a neural pathway via vagal inputs to the pancreas mediates a cephalic insulin response, which elevates insulin secretion within the first few minutes of initiating a meal (triggered, in part, by oral nutrient detection; Berthoud et al., 1981; Powley, 2000; Ahrén and Hol…”
BackgroundMechanisms and effects of “fat taste” in humans
Tucker, R. M., Mattes, R. D., & Running, C. A. (2014) · BioFactors · doi:10.1002/biof.1162 · Cited by 51
Incretin Hormone Secretion Over the Day
Åhrén, B., Carr, R. D., & Deacon, C. F. (2010) · Vitamins and hormones · doi:10.1016/b978-0-12-381517-0.00007-2 · Cited by 52
Fridlyand, L. E., & Philipson, L. H. (2016) · PLoS ONE · doi:10.1371/journal.pone.0152869 · Cited by 49
“This increase, termed "cephalic phase", is thought to be largely mediated by the release of acetylcholine from nerves innervating pancreatic islets or from the alpha cells [6, 62, 180].”
BackgroundSalehi, M., Woods, S. C., & D’Alessio, D. A. (2015) · Obesity · doi:10.1002/oby.21186 · Cited by 47
“However, beyond premeal insulin secretion, parasympathetic nervous system (PNS) activation has been found to make an important contribution to the b-cell response to food intake (26,27).”
BackgroundImaging of the islet neural network
Tang, S., Peng, S.-J., & Chien, H. (2014) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12342 · Cited by 47
“The physiological importance of islet parasympathetic innervation has been suggested by its potential roles in mediating the cephalic phase of insulin secretion [4,34,35] and synchronizing the pulsatile insulin secretion from individual”
BackgroundChaikomin, R., Wu, K.-L., Doran, S., Jones, K., Smout, A., Renooij, W., Holloway, R., Meyer, J. H., Horowitz, M., & Rayner, C. (2007) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00519.2006 · Cited by 40
“There is good evidence, on the other hand, that first-phase insulin secretion is under autonomic control (1) and therefore could be inhibited by hyoscine.”
BackgroundMármol, P., Pardo, B., Wiederkehr, A., del Arco, A., Wollheim, C. B., & Satrústegui, J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806729200 · Cited by 46
Food anticipatory hormonal responses: a systematic review of animal and human studies.
Skvortsova, A., Veldhuijzen, D., Kloosterman, I. E. M., Pacheco-López, G., & Evers, A. (2021) · Neuroscience and Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.03.030 · Cited by 29
Satiety and substrate mobilization after oral fat stimulation
Smeets, A. J. P. G., & Westerterp‐Plantenga, M. S. (2006) · British Journal Of Nutrition · doi:10.1079/bjn20051725 · Cited by 45
“…20051725 Published online by Cam bridge U niversity Press The duration of the effects we observed as increased glucose and insulin concentrations indicate that not just a cephalic response, but also vagal stimulation appeared to be achieved by MSF (Ahren & Holst, 2001).”
BackgroundEvidence for cephalic phase insulin release in humans: A systematic review and meta-analysis
Wiedemann, S. J., Rachid, L., Illigens, B. M. W., Böni‐Schnetzler, M., & Donath, M. Y. (2020) · Appetite · doi:10.1016/j.appet.2020.104792 · Cited by 44
“…responses to ingestive S.J. Wiedemann et al. Appetite 155 (2020) 104792 stimuli have reported a rise in blood glucose only 10 min after food intake (Ahrén & Holst, 2001; Teff, Levin, et al., 1993), we nonetheless assessed whether a more stringent analysis only including studies that report…”
BackgroundNatali, A., Ribeiro, R. T., Baldi, S., Tulipani, A., Rossi, M., Venturi, E., Mari, A., Macedo, M. P., & Ferrannini, E. (2013) · Diabetologia · doi:10.1007/s00125-013-2836-x · Cited by 43
“Therefore, neural control mechanisms, such as the parasympathetic cholinergic outflow to the pancreas (the cephalic phase of insulin secretion [28, 29]), may be involved.”
BackgroundTherapeutic potential of VIP vs PACAP in diabetes
Şanlioğlu, A. D., Karaçay, B., Balcı, M. K., Griffith, T. S., & Şanlıoğlu, S. (2012) · Journal of Molecular Endocrinology · doi:10.1530/jme-12-0156 · Cited by 44
Endocrine Cephalic Phase Responses to Food Cues: A Systematic Review
Lasschuijt, M. P., Mars, M., de Graaf, C., & Smeets, P. A. M. (2020) · Advances in Nutrition · doi:10.1093/advances/nmaa059 · Cited by 43
“A cephalic insulin response of this size would correspond to only 1% of the total postprandial insulin response (AUC) after a mixed nutrient meal (26).”
BackgroundXie, H., Yepuri, N., Meng, Q., Dhawan, R. K., Leech, C. A., Chepurny, O. G., Holz, G. G., & Cooney, R. N. (2020) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-020-09584-3 · Cited by 48
Brain Control of Insulin and Glucagon Secretion
Osundiji, M. A., & Evans, M. L. (2012) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2012.11.006 · Cited by 42
Nicotine’ actions on energy balance: Friend or foe?
Seoane‐Collazo, P., Diéguez, C., Nogueiras, R., Rahmouni, K., Fernández‐Real, J. M., & López, M. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107693 · Cited by 42
“Thus, ACh release from α -cells in human islets and parasympathetic nerves in both mouse and human appears tostimulate the pre-absorptive phase of insulin secretion (Ahren & Holst, 2001; Rodriguez-Diaz et al., 2011; Rodriguez-Diaz et al., 2011).”
Ganic, E., Singh, T., Luan, C., Fadista, J., Johansson, J. K., Cyphert, H. A., Bennet, H., Storm, P., Prost, G., Ahlenius, H., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.02.002 · Cited by 41
“This is in contrast to previous findings that pre-absorptive insulin secretion is inhibited by the nicotinic ganglionic blocker trimethaphan but only partially impaired by muscarinic antagonists (Ahrén and Holst, 2001), which argues for a function of nicotinic receptor activity in human islet cells.”
BackgroundResultNeuroendocrine mechanisms in insulin resistance
Sjöstrand, M., & Eriksson, J. G. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.05.010 · Cited by 37
“This vagus mediated insulin secretion can be blocked by atropine and is called the cephalic insulin response (43).”
BackgroundHuman amylase gene copy number variation as a determinant of metabolic state
Elder, P., Ramsden, D. B., Burnett, D. A., Weickert, M. O., & Barber, T. M. (2018) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2018.1499466 · Cited by 37
“CPIR is required for normal postprandial glucose tolerance [14,69] and mediated primarily by autonomic mechanisms triggered by oral sensory stimulation [69].”
Background
Metadata
- Authors
- Ahrén, B., & Holst, J. J.
- Affiliations
- Department of Medicine, Lund University, Lund, Sweden, and
- University of Copenhagen (DK)
- ORCID
- Holst, Jens J.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2001-05-01
- Volume
- 50
- Issue
- 5
- Pages
- 1030-1038
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2168149788
- Cited by
- 292
- References
- 52
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 11 · 2023: 9 · 2022: 9 · 2021: 15 · 2020: 12 · 2019: 14 · 2018: 17 · 2017: 13 · 2016: 16 · 2015: 22 · 2014: 14 · 2013: 9 · 2012: 11
- FWCI
- 8.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- meal ingestion, postprandial blood glucose, cholinergic mechanisms, trimethaphan, atropine, autonomic nervous system, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucose tolerance
- MeSH terms
- Insulin Secretion, Blood Glucose, Blood Pressure, Eating, Female, Ganglionic Blockers, Gastric Inhibitory Polypeptide, Glucagon, Humans, Insulin, Middle Aged, Peptide Fragments, Protein Precursors, Reference Values, Time Factors, Trimethaphan, Body Mass Index, Postmenopause, Postprandial Period, Area Under Curve, Glucagon-Like Peptide 1
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