Diabetes Volume 63, February 2014
407
Jenny Tong1 and David D’Alessio1,2
Give the Receptor a Brake: Slowing Gastric Emptying by GLP-1 Diabetes 2014;63:407–409 | DOI: 10.2337/db13-1764
the duration of exposure. For example, GLP-1R agonists with protracted plasma residence time and duration of action seem to have lesser effects on gastric motility and greater effects on islet hormone release compared with shorter-acting GLP-1–based drugs (11). Moreover, in studies with native GLP-1, a waning of the effect on GE has been noted. Nauck et al. (12) infused GLP-1 to healthy subjects over 8–9 h and measured GE and glycemia following sequential meals. They observed that the delay in GE and reduction in postprandial glucose seen with GLP-1 administration during the first meal were less pronounced after the second meal. While this result was established with an appropriate and conservative analysis, the effect size was small and the dye dilution method used to measure GE in this study is not considered to be as precise as other methodologies such as scintigraphy. Therefore, while raising the question that the GE effect of GLP-1 is subject to tachyphylaxis with prolonged elevation of plasma concentrations, confirmation of this finding is awaited. In this issue, Umapathysivam et al. (13) examined the effects of prolonged, intermittent, and acute GLP-1 administration on GE and glycemia in 10 healthy men. They found that acute infusions of GLP-1, either singly (acute) or separated by 20 h (intermittent), delayed GE to a greater extent than a 24-h continuous infusion. The dose of GLP-1 used in the study was pharmacological and GE was measured by scintigraphy, using detection of 99m Tc calcium-phytate colloid–labeled meal retention rate in the stomach. Both intermittent and prolonged GLP-1 delayed GE when compared with placebo, but the 20-h period of no infusion in the intermittent paradigm had a significantly greater delay in GE when compared with continuous administration. Moreover, there was no difference in the effect of acute administrations of GLP-1
1Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, OH 2Cincinnati Veterans Affairs Medical Center, Cincinnati, OH
© 2014 by the American Diabetes Association. See http://creativecommons .org/licenses/by-nc-nd/3.0/ for details.
Corresponding author: Jenny Tong, [email protected].
See accompanying article, p. 785.
COMMENTARY
The conventional view of endocrinologists is that glucose regulation after a meal depends on the interplay of insulin and glucagon secretion, hepatic glucose production, and glucose disposal. However, in recent years the role of gastric motility and its effect on glucose appearance from the gut have been revived as a determinant of glucose tolerance (1,2). This is due in great part to the availability of diabetes therapeutics that act, in part, by delaying gastric emptying (GE). Yet it is important to note that much of the variance in oral glucose tolerance is accounted for by differences in GE rate, an observation made over two decades ago (1). Even a minor perturbation in GE carries a substantial impact on postprandial glycemia in healthy individuals (1) and those with diabetes (3), such that more rapid GE results in a greater initial glycemic response and slower gastric delivery of meal contents to the intestine leads to smaller glucose excursion (4). Glucagon-like peptide 1 (GLP-1) normalizes glycemia by promoting glucose-dependent insulin secretion and inhibiting glucagon secretion in the fasting state (5). A deceleration of GE is also characteristic of GLP-1 action and occurs both in patients with type 2 diabetes (T2D) and healthy individuals (6–8). In fact, glucose lowering by GLP-1 was significantly attenuated when the actions on GE were overridden by treatment with erythromycin (9). This has led to questions as to whether islet or gastrointestinal effects of GLP-1 predominate in its effects on glycemia (10). Long-acting GLP-1 receptor (GLP-1R) agonists, recently developed and now commonly used in the treatment of T2D, stimulate insulin secretion and reduce GE (5), but the relative impact of these two physiologic actions on acute and chronic control of blood glucose is not clear. Recent studies have raised the possibility that the effects of GLP-1R stimulation to regulate GE vary with
408
Commentary
either at the beginning or the end of the intermittent protocol. Postprandial glucose and insulin tracked with GE and were lower during acute/intermittent GLP-1 infusion than during the extended administration. The clever study design used by the authors allowed for direct comparison of repeated short and prolonged GLP-1 infusion on GE in the same individual, increasing the statistical power of these observations. The other major strength of the study is the use of scintigraphy to measure GE, a method that has been well validated and produces reproducible results (14,15). While the findings by Umapathysivam et al. seem incontrovertible, there are several limitations worth considering. First, the study used doses of GLP-1 that achieved plasma levels well above those occurring in the postprandial state (16), and better reflect pharmacology than physiology; the realistic extension of this study is to short- and long-acting GLP-1R agonists. Second, the study was carried out in healthy individuals so it is unclear whether the findings can be extrapolated to the population of diabetic patients who use GLP-1–based therapeutics. Third, despite a waning effect of 24 h of GLP-1 on GE, it is unclear whether this effect would be abolished if exposure of the GLP-1R agonist continued for longer, as occurs with some of the newer drugs that are dosed weekly. Finally, the interval between the intermittent GLP-1 infusions, 20 h, is significantly longer than average meal intervals or the administration of short-acting GLP-1R agonists such as exenatide. In practice, lengthening the interval of GLP-1R agonist administration could preserve its effect on GE but may lead to worsening glycemic control in subjects who ingest multiple meals per day. Despite these remaining questions, this study is consistent with the previous findings of Nauck et al. (12) and supports tachyphylaxis of the GLP-1 effect on GE. These findings have implications
Diabetes Volume 63, February 2014
both for understanding the workings of the GLP-1R system and for clinical therapeutics. The mechanism by which GLP-1 affects gastrointestinal motility is not fully understood but seems to be neurally mediated (17). For example, GLP-1 has been shown to inhibit gastropancreatic function by inhibiting central parasympathetic outflow (18); the effect of GLP-1 on GE is lost in subjects who underwent truncal vagotomy (19). Furthermore, plasma concentrations of pancreatic polypeptide, a surrogate measure of vagal nervous activity (20), show a similar pattern to what has been described here for GE with levels markedly suppressed by GLP-1 during a first meal, but the suppression was significantly less after the second test meal (12), suggesting an adaption of the autonomic nervous system to continuous GLP-1 administration. In contrast to the data supporting neural mediation of GLP-1 effects on the gut, there is little evidence to support direct actions on gastric GLP-1R. Recent studies of GLP-1R distribution have noted expression in the gastric mucosa (21), compatible with regulation of secretion but not motility. Given a current consensus that delayed GE caused by GLP-1R activity is neurally mediated, the waning of this effect with continuous exposure requires a central nervous system mechanism. In this light, it is notable that other drugs with actions that have some component of vagal mediation (e.g., nitroglycerine, antidepressants, and b2adrenergic receptor agonists) are prone to tachyphylaxis (22,23), raising a precedent for the effects demonstrated in this article. In the context of the findings on GE, it is of worth considering that other effects of GLP-1 do not seem to be susceptible to attenuation by continuous exposure. Effects of GLP-1 on insulin secretion have not been compared in a variable dosing paradigm such as that applied by Umapathysivam et al. (13). However, in
Figure 1—The central and peripheral effects of GLP-1 have different susceptibility to tachyphylaxis.
diabetes.diabetesjournals.org
subjects with T2D a 3-h infusion of GLP-1 stimulated insulin secretion to a greater degree than a 30-min exposure (24). In a seminal study, Zander et al. (25) gave GLP-1 to diabetic subjects for 6 weeks through a continuous subcutaneous infusion and noted significant improvement in plasma glucose, HbA1c, insulin secretion, and insulin sensitivity that was persistent for 6 weeks. Moreover, experience with GLP-1R agonists that have extended durations of action (26) has demonstrated clinical efficacy that persists for months despite chronic elevations of plasma drug levels. These observations suggest that other key actions of GLP-1, presumably on islet hormone secretion, are not subject to tachyphylaxis. Thus, the current available data supports a model of centrally mediated effects of GLP-1, some of which, like GE, are blunted by continuous exposure and peripherally mediated actions, like insulin secretion, that are not (Fig. 1). Of course, this model requires considerable refinement. It is important to understand whether other actions of GLP-1 that are neurally mediated, such as satiety or nausea, also diminish with continuous exposure to GLP-1R agonists. It would also be useful to compare central and peripheral effects in the same subjects at the same time. In either case, the article by Umapathysivam et al. (13) provides a useful approach to these kinds of questions.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
References
Tong and D’Alessio
409
9. Meier JJ, Kemmeries G, Holst JJ, Nauck MA. Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects. Diabetes 2005;54: 2212–2218 10. Nauck MA. Is glucagon-like peptide 1 an incretin hormone? Diabetologia 1999;42:373–379 11. Drucker DJ, Buse JB, Taylor K, et al.; DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008;372:1240–1250 12. Nauck MA, Kemmeries G, Holst JJ, Meier JJ. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 2011;60:1561–1565 13. Umapathysivam MM, Lee MY, Jones KL, et al. Comparative effects of prolonged and intermittent stimulation of the glucagon-like peptide 1 receptor on gastric emptying and glycemia. Diabetes 2014;63:785–790 14. Camilleri M, Iturrino J, Bharucha AE, et al. Performance characteristics of scintigraphic measurement of gastric emptying of solids in healthy participants. Neurogastroenterol Motil 2012;24:1076–e562 15. Rao SS, Camilleri M, Hasler WL, et al. Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies. Neurogastroenterol Motil 2011;23:8–23 16. Nauck MA, Bartels E, Orskov C, Ebert R, Creutzfeldt W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 1993;76:912–917 17. Holmes GM, Browning KN, Tong M, Qualls-Creekmore E, Travagli RA. Vagally mediated effects of glucagon-like peptide 1: in vitro and in vivo gastric actions. J Physiol 2009;587:4749–4759 18. Wettergren A, Wøjdemann M, Holst JJ. Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol 1998;275:G984–G992
1. Horowitz M, Edelbroek MA, Wishart JM, Straathof JW. Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia 1993;36:857–862
19. Plamboeck A, Veedfald S, Deacon CF, et al. The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am J Physiol Gastrointest Liver Physiol 2013;304:G1117–G1127
2. Vella A, Camilleri M, Rizza RA. The gastrointestinal tract and glucose tolerance. Curr Opin Clin Nutr Metab Care 2004;7:479–484
20. Schwartz TW. Pancreatic polypeptide: a unique model for vagal control of endocrine systems. J Auton Nerv Syst 1983;9:99–111
3. Jones KL, Horowitz M, Wishart MJ, Maddox AF, Harding PE, Chatterton BE. Relationships between gastric emptying, intragastric meal distribution and blood glucose concentrations in diabetes mellitus. J Nucl Med 1995;36:2220–2228
21. Broide E, Bloch O, Ben-Yehudah G, Cantrell D, Shirin H, Rapoport MJ. GLP-1 receptor is expressed in human stomach mucosa: analysis of its cellular association and distribution within gastric glands. J Histochem Cytochem 2013;61:649–658
4. Gonlachanvit S, Hsu CW, Boden GH, et al. Effect of altering gastric emptying on postprandial plasma glucose concentrations following a physiologic meal in type-II diabetic patients. Dig Dis Sci 2003;48:488–497 5. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696–1705
22. Klemenska E, Beresewicz A. Bioactivation of organic nitrates and the mechanism of nitrate tolerance. Cardiol J 2009;16:11–19 23. Lieb J, Balter A. Antidepressant tachyphylaxis. Med Hypotheses 1984;15: 279–291
6. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 1993;38:665–673
24. Quddusi S, Vahl TP, Hanson K, Prigeon RL, D’Alessio DA. Differential effects of acute and extended infusions of glucagon-like peptide-1 on firstand second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care 2003;26:791–798
7. Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997;273:E981–E988
25. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002;359:824–830
8. Meier JJ, Gallwitz B, Salmen S, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab 2003;88:2719–2725
26. Henry RR, Rosenstock J, Logan DK, Alessi TR, Luskey K, Baron MA. Randomized trial of continuous subcutaneous delivery of exenatide by ITCA 650 versus twice-daily exenatide injections in metformin-treated type 2 diabetes. Diabetes Care 2013;36:2559–2565
407
Jenny Tong1 and David D’Alessio1,2
Give the Receptor a Brake: Slowing Gastric Emptying by GLP-1 Diabetes 2014;63:407–409 | DOI: 10.2337/db13-1764
the duration of exposure. For example, GLP-1R agonists with protracted plasma residence time and duration of action seem to have lesser effects on gastric motility and greater effects on islet hormone release compared with shorter-acting GLP-1–based drugs (11). Moreover, in studies with native GLP-1, a waning of the effect on GE has been noted. Nauck et al. (12) infused GLP-1 to healthy subjects over 8–9 h and measured GE and glycemia following sequential meals. They observed that the delay in GE and reduction in postprandial glucose seen with GLP-1 administration during the first meal were less pronounced after the second meal. While this result was established with an appropriate and conservative analysis, the effect size was small and the dye dilution method used to measure GE in this study is not considered to be as precise as other methodologies such as scintigraphy. Therefore, while raising the question that the GE effect of GLP-1 is subject to tachyphylaxis with prolonged elevation of plasma concentrations, confirmation of this finding is awaited. In this issue, Umapathysivam et al. (13) examined the effects of prolonged, intermittent, and acute GLP-1 administration on GE and glycemia in 10 healthy men. They found that acute infusions of GLP-1, either singly (acute) or separated by 20 h (intermittent), delayed GE to a greater extent than a 24-h continuous infusion. The dose of GLP-1 used in the study was pharmacological and GE was measured by scintigraphy, using detection of 99m Tc calcium-phytate colloid–labeled meal retention rate in the stomach. Both intermittent and prolonged GLP-1 delayed GE when compared with placebo, but the 20-h period of no infusion in the intermittent paradigm had a significantly greater delay in GE when compared with continuous administration. Moreover, there was no difference in the effect of acute administrations of GLP-1
1Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, OH 2Cincinnati Veterans Affairs Medical Center, Cincinnati, OH
© 2014 by the American Diabetes Association. See http://creativecommons .org/licenses/by-nc-nd/3.0/ for details.
Corresponding author: Jenny Tong, [email protected].
See accompanying article, p. 785.
COMMENTARY
The conventional view of endocrinologists is that glucose regulation after a meal depends on the interplay of insulin and glucagon secretion, hepatic glucose production, and glucose disposal. However, in recent years the role of gastric motility and its effect on glucose appearance from the gut have been revived as a determinant of glucose tolerance (1,2). This is due in great part to the availability of diabetes therapeutics that act, in part, by delaying gastric emptying (GE). Yet it is important to note that much of the variance in oral glucose tolerance is accounted for by differences in GE rate, an observation made over two decades ago (1). Even a minor perturbation in GE carries a substantial impact on postprandial glycemia in healthy individuals (1) and those with diabetes (3), such that more rapid GE results in a greater initial glycemic response and slower gastric delivery of meal contents to the intestine leads to smaller glucose excursion (4). Glucagon-like peptide 1 (GLP-1) normalizes glycemia by promoting glucose-dependent insulin secretion and inhibiting glucagon secretion in the fasting state (5). A deceleration of GE is also characteristic of GLP-1 action and occurs both in patients with type 2 diabetes (T2D) and healthy individuals (6–8). In fact, glucose lowering by GLP-1 was significantly attenuated when the actions on GE were overridden by treatment with erythromycin (9). This has led to questions as to whether islet or gastrointestinal effects of GLP-1 predominate in its effects on glycemia (10). Long-acting GLP-1 receptor (GLP-1R) agonists, recently developed and now commonly used in the treatment of T2D, stimulate insulin secretion and reduce GE (5), but the relative impact of these two physiologic actions on acute and chronic control of blood glucose is not clear. Recent studies have raised the possibility that the effects of GLP-1R stimulation to regulate GE vary with
408
Commentary
either at the beginning or the end of the intermittent protocol. Postprandial glucose and insulin tracked with GE and were lower during acute/intermittent GLP-1 infusion than during the extended administration. The clever study design used by the authors allowed for direct comparison of repeated short and prolonged GLP-1 infusion on GE in the same individual, increasing the statistical power of these observations. The other major strength of the study is the use of scintigraphy to measure GE, a method that has been well validated and produces reproducible results (14,15). While the findings by Umapathysivam et al. seem incontrovertible, there are several limitations worth considering. First, the study used doses of GLP-1 that achieved plasma levels well above those occurring in the postprandial state (16), and better reflect pharmacology than physiology; the realistic extension of this study is to short- and long-acting GLP-1R agonists. Second, the study was carried out in healthy individuals so it is unclear whether the findings can be extrapolated to the population of diabetic patients who use GLP-1–based therapeutics. Third, despite a waning effect of 24 h of GLP-1 on GE, it is unclear whether this effect would be abolished if exposure of the GLP-1R agonist continued for longer, as occurs with some of the newer drugs that are dosed weekly. Finally, the interval between the intermittent GLP-1 infusions, 20 h, is significantly longer than average meal intervals or the administration of short-acting GLP-1R agonists such as exenatide. In practice, lengthening the interval of GLP-1R agonist administration could preserve its effect on GE but may lead to worsening glycemic control in subjects who ingest multiple meals per day. Despite these remaining questions, this study is consistent with the previous findings of Nauck et al. (12) and supports tachyphylaxis of the GLP-1 effect on GE. These findings have implications
Diabetes Volume 63, February 2014
both for understanding the workings of the GLP-1R system and for clinical therapeutics. The mechanism by which GLP-1 affects gastrointestinal motility is not fully understood but seems to be neurally mediated (17). For example, GLP-1 has been shown to inhibit gastropancreatic function by inhibiting central parasympathetic outflow (18); the effect of GLP-1 on GE is lost in subjects who underwent truncal vagotomy (19). Furthermore, plasma concentrations of pancreatic polypeptide, a surrogate measure of vagal nervous activity (20), show a similar pattern to what has been described here for GE with levels markedly suppressed by GLP-1 during a first meal, but the suppression was significantly less after the second test meal (12), suggesting an adaption of the autonomic nervous system to continuous GLP-1 administration. In contrast to the data supporting neural mediation of GLP-1 effects on the gut, there is little evidence to support direct actions on gastric GLP-1R. Recent studies of GLP-1R distribution have noted expression in the gastric mucosa (21), compatible with regulation of secretion but not motility. Given a current consensus that delayed GE caused by GLP-1R activity is neurally mediated, the waning of this effect with continuous exposure requires a central nervous system mechanism. In this light, it is notable that other drugs with actions that have some component of vagal mediation (e.g., nitroglycerine, antidepressants, and b2adrenergic receptor agonists) are prone to tachyphylaxis (22,23), raising a precedent for the effects demonstrated in this article. In the context of the findings on GE, it is of worth considering that other effects of GLP-1 do not seem to be susceptible to attenuation by continuous exposure. Effects of GLP-1 on insulin secretion have not been compared in a variable dosing paradigm such as that applied by Umapathysivam et al. (13). However, in
Figure 1—The central and peripheral effects of GLP-1 have different susceptibility to tachyphylaxis.
diabetes.diabetesjournals.org
subjects with T2D a 3-h infusion of GLP-1 stimulated insulin secretion to a greater degree than a 30-min exposure (24). In a seminal study, Zander et al. (25) gave GLP-1 to diabetic subjects for 6 weeks through a continuous subcutaneous infusion and noted significant improvement in plasma glucose, HbA1c, insulin secretion, and insulin sensitivity that was persistent for 6 weeks. Moreover, experience with GLP-1R agonists that have extended durations of action (26) has demonstrated clinical efficacy that persists for months despite chronic elevations of plasma drug levels. These observations suggest that other key actions of GLP-1, presumably on islet hormone secretion, are not subject to tachyphylaxis. Thus, the current available data supports a model of centrally mediated effects of GLP-1, some of which, like GE, are blunted by continuous exposure and peripherally mediated actions, like insulin secretion, that are not (Fig. 1). Of course, this model requires considerable refinement. It is important to understand whether other actions of GLP-1 that are neurally mediated, such as satiety or nausea, also diminish with continuous exposure to GLP-1R agonists. It would also be useful to compare central and peripheral effects in the same subjects at the same time. In either case, the article by Umapathysivam et al. (13) provides a useful approach to these kinds of questions.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
References
Tong and D’Alessio
409
9. Meier JJ, Kemmeries G, Holst JJ, Nauck MA. Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects. Diabetes 2005;54: 2212–2218 10. Nauck MA. Is glucagon-like peptide 1 an incretin hormone? Diabetologia 1999;42:373–379 11. Drucker DJ, Buse JB, Taylor K, et al.; DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008;372:1240–1250 12. Nauck MA, Kemmeries G, Holst JJ, Meier JJ. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 2011;60:1561–1565 13. Umapathysivam MM, Lee MY, Jones KL, et al. Comparative effects of prolonged and intermittent stimulation of the glucagon-like peptide 1 receptor on gastric emptying and glycemia. Diabetes 2014;63:785–790 14. Camilleri M, Iturrino J, Bharucha AE, et al. Performance characteristics of scintigraphic measurement of gastric emptying of solids in healthy participants. Neurogastroenterol Motil 2012;24:1076–e562 15. Rao SS, Camilleri M, Hasler WL, et al. Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies. Neurogastroenterol Motil 2011;23:8–23 16. Nauck MA, Bartels E, Orskov C, Ebert R, Creutzfeldt W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 1993;76:912–917 17. Holmes GM, Browning KN, Tong M, Qualls-Creekmore E, Travagli RA. Vagally mediated effects of glucagon-like peptide 1: in vitro and in vivo gastric actions. J Physiol 2009;587:4749–4759 18. Wettergren A, Wøjdemann M, Holst JJ. Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol 1998;275:G984–G992
1. Horowitz M, Edelbroek MA, Wishart JM, Straathof JW. Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia 1993;36:857–862
19. Plamboeck A, Veedfald S, Deacon CF, et al. The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am J Physiol Gastrointest Liver Physiol 2013;304:G1117–G1127
2. Vella A, Camilleri M, Rizza RA. The gastrointestinal tract and glucose tolerance. Curr Opin Clin Nutr Metab Care 2004;7:479–484
20. Schwartz TW. Pancreatic polypeptide: a unique model for vagal control of endocrine systems. J Auton Nerv Syst 1983;9:99–111
3. Jones KL, Horowitz M, Wishart MJ, Maddox AF, Harding PE, Chatterton BE. Relationships between gastric emptying, intragastric meal distribution and blood glucose concentrations in diabetes mellitus. J Nucl Med 1995;36:2220–2228
21. Broide E, Bloch O, Ben-Yehudah G, Cantrell D, Shirin H, Rapoport MJ. GLP-1 receptor is expressed in human stomach mucosa: analysis of its cellular association and distribution within gastric glands. J Histochem Cytochem 2013;61:649–658
4. Gonlachanvit S, Hsu CW, Boden GH, et al. Effect of altering gastric emptying on postprandial plasma glucose concentrations following a physiologic meal in type-II diabetic patients. Dig Dis Sci 2003;48:488–497 5. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696–1705
22. Klemenska E, Beresewicz A. Bioactivation of organic nitrates and the mechanism of nitrate tolerance. Cardiol J 2009;16:11–19 23. Lieb J, Balter A. Antidepressant tachyphylaxis. Med Hypotheses 1984;15: 279–291
6. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 1993;38:665–673
24. Quddusi S, Vahl TP, Hanson K, Prigeon RL, D’Alessio DA. Differential effects of acute and extended infusions of glucagon-like peptide-1 on firstand second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care 2003;26:791–798
7. Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997;273:E981–E988
25. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002;359:824–830
8. Meier JJ, Gallwitz B, Salmen S, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab 2003;88:2719–2725
26. Henry RR, Rosenstock J, Logan DK, Alessi TR, Luskey K, Baron MA. Randomized trial of continuous subcutaneous delivery of exenatide by ITCA 650 versus twice-daily exenatide injections in metformin-treated type 2 diabetes. Diabetes Care 2013;36:2559–2565
