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Physiology of the Incretin Hormones, GIP and GLP‐1—Regulation of Release and Posttranslational Modifications

Jens J. Holst, Nicolai J. Wewer Albrechtsen, Mette M. Rosenkilde, Carolyn F. Deacon

10.1002/cphy.c180013

Source: Volume 9, Issue 4, October 2019

Published online: September 2019

Full Article on Wiley Online Library



Abstract

The focus of this article is on the analysis of the release and postrelease fate of the incretin hormones, glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide. Their actions are dealt with to the extent that they are linked to their secretion. For both hormones, their posttranslational processing is analyzed in detail, because of its importance for the understanding of the molecular heterogeneity of the hormones. Methods of analysis, in particular regarding measurements in plasma from in vivo experiments, are discussed in detail in relation to the molecular heterogeneity of the hormones, and the importance of the designations “total” versus “intact hormones” is explained. Both hormones are substrates for the ubiquitous enzyme, dipeptidyl peptidase‐4, which inactivates the peptides with dramatic consequences for their physiological spectrum of activities. The role of endogenous and exogenous antagonists of the receptors is discussed in detail because of their importance for the elucidation of the physiology and pathophysiology of the hormones. Regarding the actual secretion, the most important factors are discussed, including gastric emptying rate and the influence of the different macronutrients. Additional factors discussed are the role of bile, paracrine regulation, the role of the microbiota, pharmaceuticals, and exercise. Finally, the secretion during pathological conditions is discussed. © 2019 American Physiological Society. Compr Physiol 9:1339‐1381, 2019.

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Figure 1. Figure 1. The incretin effect and its impairment in type 2 diabetes. Patients with type 2 diabetes and matched healthy controls received 50 g of glucose orally (black circles). On a subsequent day, they received an intravenous infusion of glucose (white circles), which was adjusted so that the plasma glucose concentrations were similar to those obtained on the day with the oral glucose administration. Subsequently, insulin and C‐peptide concentrations were measured in peripheral blood. Asterisks indicate significant (p < 0.05) differences. The figure illustrates the classical method of investigating the incretin effect: isoglycemic oral and intravenous glucose administration. In the control subjects, much more insulin is secreted during the oral compared to the intravenous administration. The difference is the incretin effect. C‐peptide measurements show about the same difference between oral and intravenous glucose, but the changes are more accurately related to the actual insulin secretion rate, since C‐peptide is not extracted in the liver. In the people with type 2 diabetes, the differences between responses to oral and intravenous glucose are much smaller, and for C‐peptide, the difference is not significant. This indicates the lack of incretin effect. Reused, with permission, from Nauck M, et al., 1986 288.
Figure 2. Figure 2. A schematic representation of the differential processing of proglucagon in the pancreas and in the intestine. The numbers refer to the numbering of the amino acid residues of proglucagon, counting from the N‐terminus. GRPP, Glicentin‐related pancreatic polypeptide; IP‐1, intervening peptide‐1; IP‐2, intervening peptide‐2. GLP‐1 (glucagon‐like peptide‐1) thus corresponds to proglucagon 78‐107NH2 (meaning that its carboxyterminus is amidated). It is seen that in the (human) pancreas, proglucagon is cleaved (by the prohormone convertase PC‐2) to the pancreatic glicentin‐related peptide (GRPP) corresponding to proglucagon (PG) 1‐30; glucagon (PG 33‐61); a small intervening peptide; and the major proglucagon fragment (MPGF) consisting of amino acid residues PG 72‐158. In the gut, the processing products (PC1/3) are glicentin (PG1‐69), about 1/3 is processed further to GRPP and oxyntomodulin (PG 33‐69); GLP‐1 (PG 78‐107amide); and GLP‐2 (PG 126‐158) (the missing amino acids are cleaved off by the processing enzymes).
Figure 3. Figure 3. Healthy subjects were given glucose orally with or without a concomitant infusion of exendin 9‐39, and had insulin and glucagon concentrations measured in their peripheral blood. During exendin infusions, insulin and C‐peptide responses to glucose were clearly reduced, whereas glucagon responses increased. The interpretation is that GLP‐1 secreted from the gut in response to glucose normally acts to enhance insulin secretion but also to inhibit glucagon secretion, and that both responses are prevented or even reversed by exendin 9‐39. Reused, with permission, from Salehi M, et al., 2008 365.
Figure 4. Figure 4. Total GLP‐1 responses to a mixed meal (538 kcal) in 54 patients with type 2 diabetes (HbA1c 8.4%—black circles), 33 matched controls with normal glucose tolerance (white circles), and 15 subjects with impaired glucose tolerance (white squares). Asterisks indicate significant differences between patients and controls. The study shows that in these cohorts of patients and controls (which were carefully matched for body weight, age, and gender), there was a significantly impaired GLP‐1 response to the mixed meal in the patients with T2DM. Interestingly, the fasting concentrations in the patients were significantly higher than that of the other groups, and it is clear that the impaired response occurs rather late, with the curves separating around 1 h after meal intake. Note the tendency to a rise already after 10 min. A biphasic response has been mentioned in the literature, but clearly is not seen here. The figure shows “total GLP‐1” responses (see text for explanation). In younger and leaner populations, greater meal responses may be seen 320. Reused, with permission, from Toft‐Nielsen MB, et al., 2001 419.
Figure 5. Figure 5. Glucose absorption and GLP‐1 secretion from isolated perfused rat upper small intestine. (A) Effluent concentrations of glucose (blue) and GLP‐1 (black) during brief luminal administration of a 20% glucose solution in saline. Bombesin (BBS), a Gq‐activating ligand of the bombesin 2 receptor, was infused toward the end of the experiment as a positive control. (B) Correlation between GLP‐1 and glucose concentrations in the venous effluent. (C and D) Responses to repeated stimulations with 20% glucose. (D and F) Effect of the SGLT‐1 inhibitor, phloridzin, on GLP‐1 responses to glucose. The experiments illustrate the effect of luminal administration of glucose on the secretion of GLP‐1 from the gut. The gut preparation also absorbs the luminal glucose load, measured as increasing glucose concentrations in the venous effluent from the perfused segment. Not only are GLP‐1 secretion and glucose absorption highly correlated (panel B), but the powerful sodium‐glucose cotransporter (SGLT‐1) inhibitor, phloridzin, nearly completely blocked the GLP‐1 response. This indicates that the glucose absorption is required for GLP‐1 secretion, and suggests that it is the glucose entry into the L‐cell that is responsible for stimulation of secretion. Further details may be found in Kuhre et al. 228.
Figure 6. Figure 6. Diagrammatic representation of the gastrointestinal anatomy after a Roux‐en‐Y gastric bypass operation. Importantly, the gastric pouch is very small (∼30 mL), which means that there is no reservoir for retention of food, which therefore passes directly on to a more distal segment of the small intestine. The so‐called alimentary limb draining the pouch does not receive any of the digestive secretions (bile, gastric, and pancreatic secretion) and, therefore, depends entirely on its brush‐border enzymes for digestive capacity. Digestion requiring the digestive secretions can only begin distal to the entero‐entero‐anastomosis between the secretory limb and the alimentary limb, together forming the “common limb,” but this where the density of, for instance, the L‐cells is high.
Figure 7. Figure 7. A diagrammatic representation of the degradation of GLP‐1 by dipeptidyl peptidase‐4 (DPP‐4). The figure shows a (very enlarged) intestinal villus with a single yellow open‐type L‐cell. Newly secreted GLP‐1 is indicated by black dots. Upon stimulation, GLP‐1 is released by exocytosis and diffuses across the lamina propria of the mucosa until it finds and enters a capillary. Here, the GLP‐1 molecules meet DPP‐4 expressed on the luminal surface of the endothelial cells lining the capillary. As a result, only about 33%‐25% of what leaves the gut remains in the intact form. In the liver, there is also the DPP‐4 activity degrading about half of what the liver receives. This means that only about 10%‐15% of what was released makes it to the systemic circulation in the intact form. In plasma, there is soluble DPP‐4 causing further degradation, and it has been calculated that only about 8% of what was originally released reaches the target organs (e.g. the pancreas) in the intact form 169.
Figure 8. Figure 8. Degradation of GLP‐1 by DPP‐4. (A) DPP‐4 mediated degradation of the GLP‐1 molecule. The diagram shows that the enzyme cleaves off the two N‐terminal amino acids leaving the inactive metabolite, GLP‐1 9‐36/37, and that this occurs rapidly (resulting in a plasma half‐life in humans of about 2 min) and with a high plasma clearance. If DPP‐4 is blocked, it can be determined that the kidneys alone are responsible for a high plasma clearance, resulting in a plasma half‐life of 4‐5 min. (B) Concentrations in plasma of intact GLP‐1 and total GLP‐1 (intact GLP‐1 7‐36amide + the metabolite GLP‐1 9‐36amide) after i.v. injection of the maximally tolerated dose of GLP‐1 (1.5 nmol/kg) in patients with type 2 diabetes. In spite of the high dose injected, very little GLP‐1 survives in the intact form. Reused, with permission, from Deacon CF, et al., 1995 82.
Figure 9. Figure 9. An alternative signaling pathway for GLP‐1 via sensory afferent of the vagus nerve. Confer with Figure 7. During the diffusion across the lamina propria, newly secreted GLP‐1, which is still intact, has the chance of binding to GLP‐1 receptors expressed on nerve fibers of sensory afferents of the parasympathetic nervous system (f). Indeed, such receptors are synthesized in the cell bodies of these neurons in the nodose ganglion (c). The neurons project to the nucleus of the solitary tract (a) where they may interact with other neurons, projecting to the hypothalamus or to the dorsal vagal motor nuclei (b), eventually leading to stimulation of efferent nerve fibers reaching the peripheral organs (g, h) via the vagus. Reused, with permission, from Holst and Deacon, 2005 172.
Figure 10. Figure 10. Processing of proglucagon and antigenic determinants utilized for antibody generation allowing specific measurement of the various circulating components. The processing scheme is identical to the one shown in Figure 2, but also shows the various molecular forms of GLP‐1 resulting from the differential pancreatic and intestinal processing, the absence or presence of amidation, and DPP‐4‐mediated degradation products. Obviously, the black antibodies, directed against a mid‐region of GLP‐1 (the so‐called side‐viewing), will react with all of the molecular forms of GLP‐1 regardless of the origin (including the major proglucagon fragment), and therefore completely lack specificity. The C‐terminal antibodies (terminal wrapping) will react with GLP‐1 1‐36NH2, 7‐36NH2, and 9‐36NH2, and have therefore been used for measuring “total GLP‐1” (although the cross‐reaction with GLP‐1 1‐36NH2, which is derived from the pancreas, represents a problem). Similar results may be obtained with a sandwich ELISA combination of black and red antibodies, which currently is the combination used in commercial ELISAs for “total GLP‐1.” For specific measurement of the Gly‐extended molecular forms, a terminal‐wrapping antibody against the free acid in position 37 is required (yellow antibody). For specific measurement of the individual molecular forms, a combination of the C‐terminal‐wrapping antibodies and N‐terminal‐wrapping antibodies may be used. Thus, for intact GLP‐1 sandwich ELISAs, blue and red antibodies or blue and yellow antibodies may be used. It is clear that specific measurement of GLP‐1 in the circulation is challenging, and not many assays are sufficiently specific. Indeed, most antibodies claimed to be truly terminal are somewhat “side‐viewing” and, therefore, suffer from lack of specificity.
Figure 11. Figure 11. Secretion of GLP‐1 and GIP in patients with type 2 diabetes (blue curves) and in healthy control subjects (green curves) in response to increasing doses of glucose (25, 75, and 125 g) and in response to intravenous infusions of glucose resulting in similar glucose excursions (isoglycemia). Color tones indicate each set of OGTT and IGII [light, 25‐g OGTT (closed symbols) and corresponding IIGI (open symbols); medium, 75‐g OGTT (closed symbols) and corresponding IIGI (open symbols); and dark, 125‐g OGTT (closed symbols) and corresponding IIGI (open symbols)]. In these experiments, none of the intravenous infusions resulted in any changes in hormone secretion, as expected. The responses to oral administration were clearly dependent on the dose, with short‐lived increases in GIP secretion after the low glucose dose and more protracted responses to the larger doses, although reaching almost the same peak or plateau levels. For GLP‐1, a similar pattern was observed for the two larger doses, whereas the response to the low dose was clearly smaller. These responses are readily explained by the markedly different rates of gastric emptying associated with the three doses, as shown in the bottom panel. The nutrient regulation of gastric emptying ensures that a rather constant amount of nutrients (in kcal/min) is delivered to the small intestine as long as there is something left in the gastric reservoir. The hormone responses, which are generated by the presentation and absorption of the nutrients, therefore follow the gastric emptying rate. Reused, with permission, from Bagger JI, et al., 2011 19.
Figure 12. Figure 12. The relationship between the intestinal somatostatin cells and the L‐cells. The diagram shows three cells, an L‐cell, a somatostatin producing D‐cell, and an interspaced enterocyte. Both the D‐cell and the L‐cell are of the “open” type with a projection with microvilli reaching the gut lumen, but the D‐cell has the characteristic basal cytoplasmic process of the paracrine cells, which, in this case, contacts the L‐cells. The L‐cell expresses somatostatin receptors, and the D‐cell expresses GLP‐1 receptors, so that GLP‐1 reaching the D‐cells stimulates somatostatin secretion, which in turn restrains L‐cell secretion. If the feedback cycle is interrupted with receptor antagonists, GLP‐1 secretion increases markedly. Reused, with permission, from Hansen L, et al., 2000 145.
Figure 13. Figure 13. ProGIP and its intestinal processing. Once the signal peptide of Prepro‐GIP is cleaved off in the Golgi apparatus, the remaining proGIP is processed further in the granules by the prohormone convertase 1/3 to release full‐length GIP 1‐42 (proGIP 52‐93). In the circulation, about half of circulating GIP is degraded by dipeptidyl peptidase‐4 (DPP‐4) to generate GIP 3‐42 (whereas GIP, unlike GLP‐1, does not seem to be degraded locally in the gut). Small amounts of a C‐terminally truncated and amidated form, GIP 1‐30NH2, which is a full agonist on the GIP receptor, may also be formed and, upon DPP‐4 digestion, this form may be degraded to generate GIP 3‐30NH2, which is a potent GIP receptor antagonist. The figure also indicates how antibodies against specific regions of the molecules may be used to measure the various molecular forms identified in the circulation.


Figure 1. The incretin effect and its impairment in type 2 diabetes. Patients with type 2 diabetes and matched healthy controls received 50 g of glucose orally (black circles). On a subsequent day, they received an intravenous infusion of glucose (white circles), which was adjusted so that the plasma glucose concentrations were similar to those obtained on the day with the oral glucose administration. Subsequently, insulin and C‐peptide concentrations were measured in peripheral blood. Asterisks indicate significant (p < 0.05) differences. The figure illustrates the classical method of investigating the incretin effect: isoglycemic oral and intravenous glucose administration. In the control subjects, much more insulin is secreted during the oral compared to the intravenous administration. The difference is the incretin effect. C‐peptide measurements show about the same difference between oral and intravenous glucose, but the changes are more accurately related to the actual insulin secretion rate, since C‐peptide is not extracted in the liver. In the people with type 2 diabetes, the differences between responses to oral and intravenous glucose are much smaller, and for C‐peptide, the difference is not significant. This indicates the lack of incretin effect. Reused, with permission, from Nauck M, et al., 1986 288.


Figure 2. A schematic representation of the differential processing of proglucagon in the pancreas and in the intestine. The numbers refer to the numbering of the amino acid residues of proglucagon, counting from the N‐terminus. GRPP, Glicentin‐related pancreatic polypeptide; IP‐1, intervening peptide‐1; IP‐2, intervening peptide‐2. GLP‐1 (glucagon‐like peptide‐1) thus corresponds to proglucagon 78‐107NH2 (meaning that its carboxyterminus is amidated). It is seen that in the (human) pancreas, proglucagon is cleaved (by the prohormone convertase PC‐2) to the pancreatic glicentin‐related peptide (GRPP) corresponding to proglucagon (PG) 1‐30; glucagon (PG 33‐61); a small intervening peptide; and the major proglucagon fragment (MPGF) consisting of amino acid residues PG 72‐158. In the gut, the processing products (PC1/3) are glicentin (PG1‐69), about 1/3 is processed further to GRPP and oxyntomodulin (PG 33‐69); GLP‐1 (PG 78‐107amide); and GLP‐2 (PG 126‐158) (the missing amino acids are cleaved off by the processing enzymes).


Figure 3. Healthy subjects were given glucose orally with or without a concomitant infusion of exendin 9‐39, and had insulin and glucagon concentrations measured in their peripheral blood. During exendin infusions, insulin and C‐peptide responses to glucose were clearly reduced, whereas glucagon responses increased. The interpretation is that GLP‐1 secreted from the gut in response to glucose normally acts to enhance insulin secretion but also to inhibit glucagon secretion, and that both responses are prevented or even reversed by exendin 9‐39. Reused, with permission, from Salehi M, et al., 2008 365.


Figure 4. Total GLP‐1 responses to a mixed meal (538 kcal) in 54 patients with type 2 diabetes (HbA1c 8.4%—black circles), 33 matched controls with normal glucose tolerance (white circles), and 15 subjects with impaired glucose tolerance (white squares). Asterisks indicate significant differences between patients and controls. The study shows that in these cohorts of patients and controls (which were carefully matched for body weight, age, and gender), there was a significantly impaired GLP‐1 response to the mixed meal in the patients with T2DM. Interestingly, the fasting concentrations in the patients were significantly higher than that of the other groups, and it is clear that the impaired response occurs rather late, with the curves separating around 1 h after meal intake. Note the tendency to a rise already after 10 min. A biphasic response has been mentioned in the literature, but clearly is not seen here. The figure shows “total GLP‐1” responses (see text for explanation). In younger and leaner populations, greater meal responses may be seen 320. Reused, with permission, from Toft‐Nielsen MB, et al., 2001 419.


Figure 5. Glucose absorption and GLP‐1 secretion from isolated perfused rat upper small intestine. (A) Effluent concentrations of glucose (blue) and GLP‐1 (black) during brief luminal administration of a 20% glucose solution in saline. Bombesin (BBS), a Gq‐activating ligand of the bombesin 2 receptor, was infused toward the end of the experiment as a positive control. (B) Correlation between GLP‐1 and glucose concentrations in the venous effluent. (C and D) Responses to repeated stimulations with 20% glucose. (D and F) Effect of the SGLT‐1 inhibitor, phloridzin, on GLP‐1 responses to glucose. The experiments illustrate the effect of luminal administration of glucose on the secretion of GLP‐1 from the gut. The gut preparation also absorbs the luminal glucose load, measured as increasing glucose concentrations in the venous effluent from the perfused segment. Not only are GLP‐1 secretion and glucose absorption highly correlated (panel B), but the powerful sodium‐glucose cotransporter (SGLT‐1) inhibitor, phloridzin, nearly completely blocked the GLP‐1 response. This indicates that the glucose absorption is required for GLP‐1 secretion, and suggests that it is the glucose entry into the L‐cell that is responsible for stimulation of secretion. Further details may be found in Kuhre et al. 228.


Figure 6. Diagrammatic representation of the gastrointestinal anatomy after a Roux‐en‐Y gastric bypass operation. Importantly, the gastric pouch is very small (∼30 mL), which means that there is no reservoir for retention of food, which therefore passes directly on to a more distal segment of the small intestine. The so‐called alimentary limb draining the pouch does not receive any of the digestive secretions (bile, gastric, and pancreatic secretion) and, therefore, depends entirely on its brush‐border enzymes for digestive capacity. Digestion requiring the digestive secretions can only begin distal to the entero‐entero‐anastomosis between the secretory limb and the alimentary limb, together forming the “common limb,” but this where the density of, for instance, the L‐cells is high.


Figure 7. A diagrammatic representation of the degradation of GLP‐1 by dipeptidyl peptidase‐4 (DPP‐4). The figure shows a (very enlarged) intestinal villus with a single yellow open‐type L‐cell. Newly secreted GLP‐1 is indicated by black dots. Upon stimulation, GLP‐1 is released by exocytosis and diffuses across the lamina propria of the mucosa until it finds and enters a capillary. Here, the GLP‐1 molecules meet DPP‐4 expressed on the luminal surface of the endothelial cells lining the capillary. As a result, only about 33%‐25% of what leaves the gut remains in the intact form. In the liver, there is also the DPP‐4 activity degrading about half of what the liver receives. This means that only about 10%‐15% of what was released makes it to the systemic circulation in the intact form. In plasma, there is soluble DPP‐4 causing further degradation, and it has been calculated that only about 8% of what was originally released reaches the target organs (e.g. the pancreas) in the intact form 169.


Figure 8. Degradation of GLP‐1 by DPP‐4. (A) DPP‐4 mediated degradation of the GLP‐1 molecule. The diagram shows that the enzyme cleaves off the two N‐terminal amino acids leaving the inactive metabolite, GLP‐1 9‐36/37, and that this occurs rapidly (resulting in a plasma half‐life in humans of about 2 min) and with a high plasma clearance. If DPP‐4 is blocked, it can be determined that the kidneys alone are responsible for a high plasma clearance, resulting in a plasma half‐life of 4‐5 min. (B) Concentrations in plasma of intact GLP‐1 and total GLP‐1 (intact GLP‐1 7‐36amide + the metabolite GLP‐1 9‐36amide) after i.v. injection of the maximally tolerated dose of GLP‐1 (1.5 nmol/kg) in patients with type 2 diabetes. In spite of the high dose injected, very little GLP‐1 survives in the intact form. Reused, with permission, from Deacon CF, et al., 1995 82.


Figure 9. An alternative signaling pathway for GLP‐1 via sensory afferent of the vagus nerve. Confer with Figure 7. During the diffusion across the lamina propria, newly secreted GLP‐1, which is still intact, has the chance of binding to GLP‐1 receptors expressed on nerve fibers of sensory afferents of the parasympathetic nervous system (f). Indeed, such receptors are synthesized in the cell bodies of these neurons in the nodose ganglion (c). The neurons project to the nucleus of the solitary tract (a) where they may interact with other neurons, projecting to the hypothalamus or to the dorsal vagal motor nuclei (b), eventually leading to stimulation of efferent nerve fibers reaching the peripheral organs (g, h) via the vagus. Reused, with permission, from Holst and Deacon, 2005 172.


Figure 10. Processing of proglucagon and antigenic determinants utilized for antibody generation allowing specific measurement of the various circulating components. The processing scheme is identical to the one shown in Figure 2, but also shows the various molecular forms of GLP‐1 resulting from the differential pancreatic and intestinal processing, the absence or presence of amidation, and DPP‐4‐mediated degradation products. Obviously, the black antibodies, directed against a mid‐region of GLP‐1 (the so‐called side‐viewing), will react with all of the molecular forms of GLP‐1 regardless of the origin (including the major proglucagon fragment), and therefore completely lack specificity. The C‐terminal antibodies (terminal wrapping) will react with GLP‐1 1‐36NH2, 7‐36NH2, and 9‐36NH2, and have therefore been used for measuring “total GLP‐1” (although the cross‐reaction with GLP‐1 1‐36NH2, which is derived from the pancreas, represents a problem). Similar results may be obtained with a sandwich ELISA combination of black and red antibodies, which currently is the combination used in commercial ELISAs for “total GLP‐1.” For specific measurement of the Gly‐extended molecular forms, a terminal‐wrapping antibody against the free acid in position 37 is required (yellow antibody). For specific measurement of the individual molecular forms, a combination of the C‐terminal‐wrapping antibodies and N‐terminal‐wrapping antibodies may be used. Thus, for intact GLP‐1 sandwich ELISAs, blue and red antibodies or blue and yellow antibodies may be used. It is clear that specific measurement of GLP‐1 in the circulation is challenging, and not many assays are sufficiently specific. Indeed, most antibodies claimed to be truly terminal are somewhat “side‐viewing” and, therefore, suffer from lack of specificity.


Figure 11. Secretion of GLP‐1 and GIP in patients with type 2 diabetes (blue curves) and in healthy control subjects (green curves) in response to increasing doses of glucose (25, 75, and 125 g) and in response to intravenous infusions of glucose resulting in similar glucose excursions (isoglycemia). Color tones indicate each set of OGTT and IGII [light, 25‐g OGTT (closed symbols) and corresponding IIGI (open symbols); medium, 75‐g OGTT (closed symbols) and corresponding IIGI (open symbols); and dark, 125‐g OGTT (closed symbols) and corresponding IIGI (open symbols)]. In these experiments, none of the intravenous infusions resulted in any changes in hormone secretion, as expected. The responses to oral administration were clearly dependent on the dose, with short‐lived increases in GIP secretion after the low glucose dose and more protracted responses to the larger doses, although reaching almost the same peak or plateau levels. For GLP‐1, a similar pattern was observed for the two larger doses, whereas the response to the low dose was clearly smaller. These responses are readily explained by the markedly different rates of gastric emptying associated with the three doses, as shown in the bottom panel. The nutrient regulation of gastric emptying ensures that a rather constant amount of nutrients (in kcal/min) is delivered to the small intestine as long as there is something left in the gastric reservoir. The hormone responses, which are generated by the presentation and absorption of the nutrients, therefore follow the gastric emptying rate. Reused, with permission, from Bagger JI, et al., 2011 19.


Figure 12. The relationship between the intestinal somatostatin cells and the L‐cells. The diagram shows three cells, an L‐cell, a somatostatin producing D‐cell, and an interspaced enterocyte. Both the D‐cell and the L‐cell are of the “open” type with a projection with microvilli reaching the gut lumen, but the D‐cell has the characteristic basal cytoplasmic process of the paracrine cells, which, in this case, contacts the L‐cells. The L‐cell expresses somatostatin receptors, and the D‐cell expresses GLP‐1 receptors, so that GLP‐1 reaching the D‐cells stimulates somatostatin secretion, which in turn restrains L‐cell secretion. If the feedback cycle is interrupted with receptor antagonists, GLP‐1 secretion increases markedly. Reused, with permission, from Hansen L, et al., 2000 145.


Figure 13. ProGIP and its intestinal processing. Once the signal peptide of Prepro‐GIP is cleaved off in the Golgi apparatus, the remaining proGIP is processed further in the granules by the prohormone convertase 1/3 to release full‐length GIP 1‐42 (proGIP 52‐93). In the circulation, about half of circulating GIP is degraded by dipeptidyl peptidase‐4 (DPP‐4) to generate GIP 3‐42 (whereas GIP, unlike GLP‐1, does not seem to be degraded locally in the gut). Small amounts of a C‐terminally truncated and amidated form, GIP 1‐30NH2, which is a full agonist on the GIP receptor, may also be formed and, upon DPP‐4 digestion, this form may be degraded to generate GIP 3‐30NH2, which is a potent GIP receptor antagonist. The figure also indicates how antibodies against specific regions of the molecules may be used to measure the various molecular forms identified in the circulation.
References
 1. Aaboe K , Akram S , Deacon CF , Holst JJ , Madsbad S , Krarup T . Restoration of the insulinotropic effect of glucose‐dependent insulinotropic polypeptide contributes to the antidiabetic effect of dipeptidyl peptidase‐4 inhibitors. Diabetes Obes Metab 17: 74‐81, 2015.
 2. Adriaenssens AE , Reimann F , Gribble FM . Distribution and stimulus secretion coupling of enteroendocrine cells along the intestinal tract. Compr Physiol 8: 1603‐1638, 2018.
 3. Adrian TE , Ballantyne GH , Longo WE , Bilchik AJ , Graham S , Basson MD , Tierney RP , Modlin IM . Deoxycholate is an important releaser of peptide YY and enteroglucagon from the human colon. Gut 34: 1219‐1224, 1993.
 4. Adrian TE , Gariballa S , Parekh KA , Thomas SA , Saadi H , Al KJ , Nagelkerke N , Gedulin B , Young AA . Rectal taurocholate increases L cell and insulin secretion, and decreases blood glucose and food intake in obese type 2 diabetic volunteers. Diabetologia 55: 2343‐2347, 2012.
 5. Ahren B , Gomis R , Standl E , Mills D , Schweizer A . Twelve‐ and 52‐week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin‐treated patients with type 2 diabetes. Diabetes Care 27: 2874‐2880, 2004.
 6. Ahren B , Holst JJ . The cephalic insulin response to meal ingestion in humans is dependent on both cholinergic and noncholinergic mechanisms and is important for postprandial glycemia. Diabetes 50: 1030‐1038, 2001.
 7. Ahren B , Holst JJ , Efendic S . Antidiabetogenic action of cholecystokinin‐8 in type 2 diabetes. J Clin Endocrinol Metab 85: 1043‐1048, 2000.
 8. Ahren B , Larsson H . Peptide YY does not inhibit glucose‐stimulated insulin secretion in humans. Eur J Endocrinol 134: 362‐365, 1996.
 9. Andersen DK , Elahi D , Brown JC , Tobin JD , Andres R . Oral glucose augmentation of insulin secretion: interactions of gastric inhibitory polypeptide with ambient glucose and insuln levels. J Clin Invest 49: 152‐161, 1978.
 10. Andreasen JJ , Orskov C , Holst JJ . Secretion of glucagon‐like peptide‐1 and reactive hypoglycemia after partial gastrectomy. Digestion 55: 221‐228, 1994.
 11. Anini Y , Brubaker PL . Muscarinic receptors control glucagon‐like peptide 1 secretion by human endocrine L cells. Endocrinology 144: 3244‐3250, 2003.
 12. Arora T , Akrami R , Pais R , Bergqvist L , Johansson BR , Schwartz TW , Reimann F , Gribble FM , Backhed F . Microbial regulation of the L cell transcriptome. Sci Rep 8: 1207, 2018.
 13. Asmar A , Simonsen L , Asmar M , Madsbad S , Holst JJ , Frandsen E , Moro C , Jonassen T , Bulow J . Renal extraction and acute effects of glucagon‐like peptide‐1 on central and renal hemodynamics in healthy men. Am J Physiol Endocrinol Metab 308: E641‐E649, 2015.
 14. Asmar M , Asmar A , Simonsen L , Gasbjerg LS , Sparre‐Ulrich AH , Rosenkilde MM , Hartmann B , Dela F , Holst JJ , Bulow J . The gluco‐ and liporegulatory and vasodilatory effects of glucose‐dependent insulinotropic polypeptide (GIP) are abolished by an antagonist of the human GIP receptor. Diabetes 66: 2363‐2371, 2017.
 15. Asmar M , Simonsen L , Madsbad S , Stallknecht B , Holst JJ , Bulow J . Glucose‐dependent insulinotropic polypeptide may enhance fatty acid re‐esterification in subcutaneous abdominal adipose tissue in lean humans. Diabetes 59: 2160‐2163, 2010.
 16. Asmar M , Tangaa W , Madsbad S , Hare K , Astrup A , Flint A , Bulow J , Holst JJ . On the role of glucose‐dependent insulintropic polypeptide in postprandial metabolism in humans. Am J Physiol Endocrinol Metab 298: E614‐E621, 2010.
 17. Azaryan AV , Krieger TJ , Hook VY . Purification and characteristics of the candidate prohormone processing proteases PC2 and PC1/3 from bovine adrenal medulla chromaffin granules. J Biol Chem 270: 8201‐8208, 1995.
 18. Bagger JI , Knop FK , Lund A , Holst JJ , Vilsboll T . Glucagon responses to increasing oral loads of glucose and corresponding isoglycaemic intravenous glucose infusions in patients with type 2 diabetes and healthy individuals. Diabetologia 57: 1720‐1725, 2014.
 19. Bagger JI , Knop FK , Lund A , Vestergaard H , Holst JJ , Vilsboll T . Impaired regulation of the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab 96: 737‐745, 2011.
 20. Baggio LL , Yusta B , Mulvihill EE , Cao X , Streutker CJ , Butany J , Cappola TP , Margulies KB , Drucker DJ . GLP‐1 receptor expression within the human heart. Endocrinology 159: 1570‐1584, 2018.
 21. Bailey CJ . Metformin: historical overview. Diabetologia 60: 1566‐1576, 2017.
 22. Bak MJ , Wewer Albrechtsen NJ , Pedersen J , Knop FK , Vilsboll T , Jorgensen NB , Hartmann B , Deacon CF , Dragsted LO , Holst JJ . Specificity and sensitivity of commercially available assays for glucagon‐like peptide‐1 (GLP‐1): implications for GLP‐1 measurements in clinical studies. Diabetes Obes Metab 16: 1155‐1164, 2014.
 23. Baldissera FG , Holst JJ , Jensen SL , Krarup T . Distribution and molecular forms of peptides containing somatostatin immunodeterminants in extracts from the entire gastrointestinal tract of man and pig. Biochim Biophys Acta 838: 132‐143, 1985.
 24. Baldissera FG , Holst JJ , Knuhtsen S , Hilsted L , Nielsen OV . Oxyntomodulin (glicentin‐(33‐69)): pharmacokinetics, binding to liver cell membranes, effects on isolated perfused pig pancreas, and secretion from isolated perfused lower small intestine of pigs. Regul Pept 21: 151‐166, 1988.
 25. Baldissera FG , Nielsen OV , Holst JJ . The intestinal mucosa preferentially releases somatostatin‐28 in pigs. Regul Pept 11: 251‐262, 1985.
 26. Balkan B , Li X . Portal GLP‐1 administration in rats augments the insulin response to glucose via neuronal mechanisms. Am J Physiol Regul Integr Comp Physiol 279: R1449‐R1454, 2000.
 27. Ban K , Noyan‐Ashraf MH , Hoefer J , Bolz SS , Drucker DJ , Husain M . Cardioprotective and vasodilatory actions of glucagon‐like peptide 1 receptor are mediated through both glucagon‐like peptide 1 receptor‐dependent and ‐independent pathways. Circulation 117: 2340‐2350, 2008.
 28. Baranov O , Kahle M , Deacon CF , Holst JJ , Nauck MA . Feedback suppression of meal‐induced glucagon‐like peptide‐1 (GLP‐1) secretion mediated through elevations in intact GLP‐1 caused by dipeptidyl peptidase‐4 inhibition: a randomized, prospective comparison of sitagliptin and vildagliptin treatment. Diabetes Obes Metab 18: 1100‐1109, 2016.
 29. Baum F , Nauck MA , Ebert R , Cantor P , Hoffmann G , Choudhury AR , Schmidt WE , Creutzfeldt W . Role of endogenously released cholecystokinin in determining postprandial insuln levels in man: effects of loxiglumide, a specific cholecystokinin receptor antagonist. Digestion 53: 189‐199, 2001.
 30. Baumgartner I , Pacheco‐Lopez G , Ruttimann EB , Arnold M , Asarian L , Langhans W , Geary N , Hillebrand JJ . Hepatic‐portal vein infusions of glucagon‐like peptide‐1 reduce meal size and increase c‐Fos expression in the nucleus tractus solitarii, area postrema and central nucleus of the amygdala in rats. J Neuroendocrinol 22: 557‐563, 2010.
 31. Bell GI , Sanchez‐Pescador R , Laybourn PJ , Najarian RC . Exon duplication and divergence in the human preproglucagon gene. Nature 304: 368‐371, 1983.
 32. Bell GI , Santerre RF , Mullenbach GT . Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature 302: 716‐718, 1983.
 33. Belza A , Ritz C , Sorensen MQ , Holst JJ , Rehfeld JF , Astrup A . Contribution of gastroenteropancreatic appetite hormones to protein‐induced satiety. Am J Clin Nutr 97: 980‐989, 2013.
 34. Berthoud HR , Trimble ER , Moody AJ . Lack of gastric inhibitory polypeptide (GIP) response to vagal stimulation in the rat. Peptides 3: 907‐912, 1982.
 35. Besterman HS , Mallinson CN , Modigliani R , Christofides ND , Pera A , Ponti V , Sarson DL , Bloom SR . Gut hormones in inflammatory bowel disease. Scand J Gastroenterol 18: 845‐852, 1983.
 36. Bjarnason NH , Henriksen EE , Alexandersen P , Christgau S , Henriksen DB , Christiansen C . Mechanism of circadian variation in bone resorption. Bone 30: 307‐313, 2002.
 37. Bojsen‐Moller KN , Jacobsen SH , Dirksen C , Jorgensen NB , Reitelseder S , Jensen JE , Kristiansen VB , Holst JJ , van HG and Madsbad S. Accelerated protein digestion and amino acid absorption after Roux‐en‐Y gastric bypass. Am J Clin Nutr 102: 600‐607, 2015.
 38. Bollag RJ , Zhong Q , Phillips P , Min L , Zhong L , Cameron R , Mulloy AL , Rasmussen H , Qin F , Ding KH , Isales CM . Osteoblast‐derived cells express functional glucose‐dependent insulinotropic peptide receptors. Endocrinology 141: 1228‐1235, 2000.
 39. Bonde L , Vilsboll T , Nielsen T , Bagger JI , Svare JA , Holst JJ , Larsen S , Knop FK . Reduced postprandial GLP‐1 responses in women with gestational diabetes mellitus. Diabetes Obes Metab 15: 713‐720, 2013.
 40. Bottcher G , Alumets J , Hakanson R , Sundler F . Co‐existence of glicentin and peptide YY in colorectal L‐cells in cat and man: an electron microscopic study. Regul Pept 13: 283‐291, 1986.
 41. Bouillon R , Drucker DJ , Ferrannini E , Grinspoon S , Rosen CJ , Zimmet P . The past 10 years‐new hormones, new functions, new endocrine organs. Nat Rev Endocrinol 11: 681‐686, 2015.
 42. Brener W , Hendrix TR , McHugh PR . Regulation of the gastric emptying of glucose. Gastroenterology 85: 76‐82, 1983.
 43. Brighton CA , Rievaj J , Kuhre RE , Glass LL , Schoonjans K , Holst JJ , Gribble FM , Reimann F . Bile acids trigger GLP‐1 release predominantly by accessing basolaterally located G protein‐coupled bile acid beceptors. Endocrinology 156: 3961‐3970, 2015.
 44. Bronden A , Alber A , Rohde U , Gasbjerg LS , Rehfeld JF , Holst JJ , Vilsboll T , Knop FK . The bile acid‐sequestering resin sevelamer eliminates the acute GLP‐1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes. Diabetes Obes Metab 20: 362‐369, 2018.
 45. Bronden A , Alber A , Rohde U , Rehfeld JF , Holst JJ , Vilsboll T , Knop FK . Single‐dose metformin enhances bile acid‐induced glucagon‐like peptide‐1 secretion in patients with type 2 diabetes. J Clin Endocrinol Metab 102: 4153‐4162, 2017.
 46. Brown JC . Gastric inhibitory polypeptide. Monogr Endocrinol 24:III–XI, 1–88: III–88, 1982.
 47. Brubaker PL . Glucagon‐like peptide‐2 and the regulation of intestinal growth and function. Compr Physiol 8: 1185‐1210, 2018.
 48. Brubaker PL , Schloos J , Drucker DJ . Regulation of glucagon‐like peptide‐1 synthesis and secretion in the GLUTag enteroendocrine cell line. Endocrinology 139: 4108‐4114, 1998.
 49. Bucinskaite V , Tolessa T , Pedersen J , Rydqvist B , Zerihun L , Holst JJ , Hellstrom PM . Receptor‐mediated activation of gastric vagal afferents by glucagon‐like peptide‐1 in the rat. Neurogastroenterol Motil 21: 978‐e78, 2009.
 50. Buhl T , Thim L , Kofod H , Orskov C , Harling H , Holst JJ . Naturally occurring products of proglucagon 111–160 in the porcine and human small intestine. J Biol Chem 263: 8621‐8624, 1988.
 51. Buse JB , Defronzo RA , Rosenstock J , Kim T , Burns C , Skare S , Baron A , Fineman M . The primary glucose‐lowering effect of metformin resides in the Gut, not the circulation: results from short‐term pharmacokinetic and 12‐week dose‐ranging studies. Diabetes Care 39: 198‐205, 2016.
 52. Calanna S , Christensen M , Holst JJ , Laferrere B , Gluud LL , Vilsboll T , Knop FK . Secretion of glucagon‐like peptide‐1 in patients with type 2 diabetes mellitus: systematic review and meta‐analyses of clinical studies. Diabetologia 56: 965‐972, 2013.
 53. Calbet JA , Holst JJ . Gastric emptying, gastric secretion and enterogastrone response after administration of milk proteins or their peptide hydrolysates in humans. Eur J Nutr 43: 127‐139, 2004.
 54. Campbell JE , Drucker DJ . Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 17: 819‐837, 2013.
 55. Campbell JE , Drucker DJ . Islet alpha cells and glucagon – critical regulators of energy homeostasis. Nat Rev Endocrinol 11: 329‐338, 2015.
 56. Canfora EE , van der Beek CM , Jocken JWE , Goossens GH , Holst JJ , Olde Damink SWM , Lenaerts K , Dejong CHC , Blaak EE . Colonic infusions of short‐chain fatty acid mixtures promote energy metabolism in overweight/obese men: a randomized crossover trial. Sci Rep 7: 2360, 2017.
 57. Cao Y , Cao X , Liu XM . Expression of cholecystokinin2‐receptor in rat and human L cells and the stimulation of glucagon‐like peptide‐1 secretion by gastrin treatment. Acta Histochem 117: 205‐210, 2015.
 58. Carr RD , Larsen MO , Winzell MS , Jelic K , Lindgren O , Deacon CF , Ahren B . Incretin and islet hormonal responses to fat and protein ingestion in healthy men. Am J Physiol Endocrinol Metab 295: E779‐E784, 2008.
 59. Chambers AP , Sorrell JE , Haller A , Roelofs K , Hutch CR , Kim KS , Gutierrez‐Aguilar R , Li B , Drucker DJ , D'Alessio DA , Seeley RJ , Sandoval DA . The role of pancreatic preproglucagon in glucose homeostasis in mice. Cell Metab 25: 927‐934, 2017.
 60. Chappell DL , Lee AY , Castro‐Perez J , Zhou H , Roddy TP , Lassman ME , Shankar SS , Yates NA , Wang W , Laterza OF . An ultrasensitive method for the quantitation of active and inactive GLP‐1 in human plasma via immunoaffinity LC‐MS/MS. Bioanalysis 6: 33‐42, 2014.
 61. Chen YE , Drucker DJ . Tissue‐specific expression of unique mRNAs that encode proglucagon‐derived peptides or exendin 4 in the lizard. J Biol Chem 272: 4108‐4115, 1997.
 62. Chia CW , Carlson OD , Kim W , Shin YK , Charles CP , Kim HS , Melvin DL , Egan JM . Exogenous glucose‐dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. Diabetes 58: 1342‐1349, 2009.
 63. Chisholm C , Greenberg GR . Somatostatin‐28 regulates GLP‐1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures. Am J Physiol Endocrinol Metab 283: E311‐E317, 2002.
 64. Christensen LW , Kuhre RE , Janus C , Svendsen B , Holst JJ . Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP‐1 secretion from isolated perfused rat small intestine. Physiol Rep 3: 2015.
 65. Christensen MB , Lund A , Calanna S , Jorgensen NR , Holst JJ , Vilsboll T , Knop FK . Glucose‐dependent insulinotropic polypeptide (GIP) inhibits bone resorption independently of insulin and glycemia. J Clin Endocrinol Metab 103: 288‐294, 2018.
 66. Christgau S , Bitsch‐Jensen O , Hanover BN , Gamwell HE , Qvist P , Alexandersen P , Bang HD . Serum CrossLaps for monitoring the response in individuals undergoing antiresorptive therapy. Bone 26: 505‐511, 2000.
 67. Christiansen CB , Gabe MBN , Svendsen B , Dragsted LO , Rosenkilde MM , Holst JJ . The impact of short chain fatty acids on GLP‐1 and PYY secretion from the isolated perfused rat colon. Am J Physiol Gastrointest Liver Physiol, 2018.
 68. Christiansen CB , Lind SJ , Svendsen B , Balk‐Moller E , Dahlby T , Kuhre RE , Hartmann B , Mandrup‐Poulsen T , Deacon CF , Wewer Albrechtsen NJ , Holst JJ . Acute administration of interleukin‐6 does not increase secretion of glucagon‐like peptide‐1 in mice. Physiol Rep 6: e13788, 2018.
 69. Craig CM , Liu LF , Deacon CF , Holst JJ , McLaughlin TL . Critical role for GLP‐1 in symptomatic post‐bariatric hypoglycaemia. Diabetologia 60: 531‐540, 2017.
 70. Creutzfeldt W , Talaulicar M , Ebert R , Willms B . Inhibition of gastric inhibitory polypeptide (GIP) release by insulin and glucose in juvenile diabetes. Diabetes 29: 140‐145, 1980.
 71. Dawson JM , Greathead HM , Sessions VA , Tye FM , Buttery PJ . Effect of gastric inhibitory polypeptide on bovine fat metabolism. Comp Biochem Physiol B Biochem Mol Biol 123: 79‐88, 1999.
 72. Day JW , Ottaway N , Patterson JT , Gelfanov V , Smiley D , Gidda J , Findeisen H , Bruemmer D , Drucker DJ , Chaudhary N , Holland J , Hembree J , Abplanalp W , Grant E , Ruehl J , Wilson H , Kirchner H , Lockie SH , Hofmann S , Woods SC , Nogueiras R , Pfluger PT , Perez‐Tilve D , DiMarchi R , Tschop MH . A new glucagon and GLP‐1 co‐agonist eliminates obesity in rodents. Nat Chem Biol 5: 749‐757, 2009.
 73. Deacon CF , Danielsen P , Klarskov L , Olesen M , Holst JJ . Dipeptidyl peptidase IV inhibition reduces the degradation and clearance of GIP and potentiates its insulinotropic and antihyperglycemic effects in anesthetized pigs. Diabetes 50: 1588‐1597, 2001.
 74. Deacon CF , Holst JJ . Immunoassays for the incretin hormones GIP and GLP‐1. Best Pract Res Clin Endocrinol Metab 23: 425‐432, 2009.
 75. Deacon CF , Holst JJ . Dipeptidyl peptidase‐4 inhibitors for the treatment of type 2 diabetes: comparison, efficacy and safety. Expert Opin Pharmacother 14: 2047‐2058, 2013.
 76. Deacon CF , Hughes TE , Holst JJ . Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon‐like peptide 1 in the anesthetized pig. Diabetes 47: 764‐769, 1998.
 77. Deacon CF , Johnsen AH , Holst JJ . Degradation of glucagon‐like peptide‐1 by human plasma in vitro yields an N‐terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 80: 952‐957, 1995.
 78. Deacon CF , Johnsen AH , Holst JJ . Human colon produces fully processed glucagon‐like peptide‐1 (7‐36) amide. FEBS Lett 372: 269‐272, 1995.
 79. Deacon CF , Kelstrup M , Trebbien R , Klarskov L , Olesen M , Holst JJ . Differential regional metabolism of glucagon in anesthetized pigs. Am J Physiol Endocrinol Metab 285: E552‐E560, 2003.
 80. Deacon CF , Knudsen LB , Madsen K , Wiberg FC , Jacobsen O , Holst JJ . Dipeptidyl peptidase IV resistant analogues of glucagon‐like peptide‐1 which have extended metabolic stability and improved biological activity. Diabetologia 41: 271‐278, 1998.
 81. Deacon CF , Nauck MA , Meier J , Hucking K , Holst JJ . Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide. J Clin Endocrinol Metab 85: 3575‐3581, 2000.
 82. Deacon CF , Nauck MA , Toft‐Nielsen M , Pridal L , Willms B , Holst JJ . Both subcutaneously and intravenously administered glucagon‐like peptide I are rapidly degraded from the NH2‐terminus in type II diabetic patients and in healthy subjects. Diabetes 44: 1126‐1131, 1995.
 83. Deacon CF , Plamboeck A , Moller S , Holst JJ . GLP‐1‐(9‐36)amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion. Am J Physiol Endocrinol Metab 282: E873‐E879, 2002.
 84. Deacon CF , Plamboeck A , Rosenkilde MM , de Heer J , Holst JJ . GIP‐(3‐42) does not antagonize insulinotropic effects of GIP at physiological concentrations. Am J Physiol Endocrinol Metab 291: E468‐E475, 2006.
 85. Deacon CF , Pridal L , Klarskov L , Olesen M , Holst JJ . Glucagon‐like peptide 1 undergoes differential tissue‐specific metabolism in the anesthetized pig. Am J Physiol 271: E458‐E464, 1996.
 86. Deacon CF , Wamberg S , Bie P , Hughes TE , Holst JJ . Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal‐induced incretin secretion in dogs. J Endocrinol 172: 355‐362, 2002.
 87. Deane AM , Nguyen NQ , Stevens JE , Fraser RJ , Holloway RH , Besanko LK , Burgstad C , Jones KL , Chapman MJ , Rayner CK , Horowitz M . Endogenous glucagon‐like peptide‐1 slows gastric emptying in healthy subjects, attenuating postprandial glycemia. J Clin Endocrinol Metab 95: 215‐221, 2010.
 88. DePaula AL , Stival AR , DePaula CC , Halpern A , Vencio S . Surgical treatment of type 2 diabetes in patients with BMI below 35: mid‐term outcomes of the laparoscopic ileal interposition associated with a sleeve gastrectomy in 202 consecutive cases. J Gastrointest Surg 16: 967‐976, 2012.
 89. Diakogiannaki E , Pais R , Tolhurst G , Parker HE , Horscroft J , Rauscher B , Zietek T , Daniel H , Gribble FM , Reimann F . Oligopeptides stimulate glucagon‐like peptide‐1 secretion in mice through proton‐coupled uptake and the calcium‐sensing receptor. Diabetologia 56: 2688‐2696, 2013.
 90. Dickinson CJ , Sawada M , Guo YJ , Finniss S , Yamada T . Specificity of prohormone convertase endoproteolysis of progastrin in AtT‐20 cells. J Clin Invest 96: 1425‐1431, 1995.
 91. Dirksen C , Jorgensen NB , Bojsen‐Moller KN , Kielgast U , Jacobsen SH , Clausen TR , Worm D , Hartmann B , Rehfeld JF , Damgaard M , Madsen JL , Madsbad S , Holst JJ , Hansen DL . Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux‐en‐Y gastric bypass. Int J Obes (Lond) 37: 1452‐1459, 2013.
 92. Drucker DJ , Erlich P , Asa SL , Brubaker PL . Induction of intestinal epithelial proliferation by glucagon‐like peptide 2. Proc Natl Acad Sci USA 93: 7911‐7916, 1996.
 93. Drucker DJ , Habener JF , Holst JJ . Discovery, characterization, and clinical development of the glucagon‐like peptides. J Clin Invest 127: 4217‐4227, 2017.
 94. Drucker DJ , Yusta B . Physiology and pharmacology of the enteroendocrine hormone glucagon‐like peptide‐2. Annu Rev Physiol 76: 561‐583, 2014.
 95. Dupre J , Ross SA , Watson D , Brown JC . Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab 37: 826‐828, 1973.
 96. Dyer J , Salmon KS , Zibrik L , Shirazi‐Beechey SP . Expression of sweet taste receptors of the T1R family in the intestinal tract and enteroendocrine cells. Biochem Soc Trans 33: 302‐305, 2005.
 97. Ebert R , Creutzfeldt W . Influence of gastric inhibitory polypeptide antiserum on glucose‐induced insulin secretion in rats. Endocrinology 111: 1601‐1606, 1982.
 98. Eckel RH , Kahn SE , Ferrannini E , Goldfine AB , Nathan DM , Schwartz MW , Smith RJ , Smith SR . Obesity and type 2 diabetes: what can be unified and what needs to be individualized? Diabetes Care 34: 1424‐1430, 2011.
 99. Edwards CM , Todd JF , Mahmoudi M , Wang Z , Wang RM , Ghatei MA , Bloom SR . Glucagon‐like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9‐39. Diabetes 48: 86‐93, 1999.
 100. Egerod KL , Petersen N , Timshel PN , Rekling JC , Wang Y , Liu Q , Schwartz TW , Gautron L . Profiling of G protein‐coupled receptors in vagal afferents reveals novel gut‐to‐brain sensing mechanisms. Mol Metab 12: 62‐75, 2018.
 101. Eissele R , Goke R , Willemer S , Harthus HP , Vermeer H , Arnold R , Goke B . Glucagon‐like peptide‐1 cells in the gastrointestinal tract and pancreas of rat, pig and man. Eur J Clin Invest 22: 283‐291, 1992.
 102. Elahi D , McAloon Dyke M , Fukagawa NK , Meneilly GS , Sclater AL , Minaker KL , Habener JF , Andersen DK . The insulinotropic actions of glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (7–37) in normal and diabetic subjects. Regul Pept 51: 63‐74, 1994.
 103. Ellingsgaard H , Hauselmann I , Schuler B , Habib AM , Baggio LL , Meier DT , Eppler E , Bouzakri K , Wueest S , Muller YD , Hansen AM , Reinecke M , Konrad D , Gassmann M , Reimann F , Halban PA , Gromada J , Drucker DJ , Gribble FM , Ehses JA , Donath MY . Interleukin‐6 enhances insulin secretion by increasing glucagon‐like peptide‐1 secretion from L cells and alpha cells. Nat Med 17: 1481‐1489, 2011.
 104. Elliott RM , Morgan LM , Tredger JA , Deacon S , Wright J , Marks V . Glucagon‐like peptide‐1 (7–36)amide and glucose‐dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post‐prandial and 24‐h secretion patterns. J Endocrinol 138: 159‐166, 1993.
 105. Eriksen M , Jensen DH , Tribler S , Holst JJ , Madsbad S , Krarup T . Reduction of insulinotropic properties of GLP‐1 and GIP after glucocorticoid‐induced insulin resistance. Diabetologia 58: 920‐928, 2015.
 106. Estall JL , Drucker DJ . Glucagon‐like peptide‐2. Annu Rev Nutr 26: 391‐411, 2006.
 107. Faerch K , Torekov SS , Vistisen D , Johansen NB , Witte DR , Jonsson A , Pedersen O , Hansen T , Lauritzen T , Sandbaek A , Holst JJ , Jorgensen ME . GLP‐1 response to oral glucose is reduced in prediabetes, screen‐detected Type 2 diabetes, and obesity and influenced by sex: the ADDITION‐PRO study. Diabetes 64: 2513‐2525, 2015.
 108. Falken Y , Hellstrom PM , Holst JJ , Naslund E . Changes in glucose homeostasis after Roux‐en‐Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides. J Clin Endocrinol Metab 96: 2227‐2235, 2011.
 109. Fehmann HC , Goke B . Characterization of GIP(1‐30) and GIP(1‐42) as stimulators of proinsulin gene transcription. Peptides 16: 1149‐1152, 1995.
 110. Fieseler P , Bridenbaugh S , Nustede R , Martell J , Orskov C , Holst JJ , Nauck MA . Physiological augmentation of amino acid‐induced insulin secretion by GIP and GLP‐I but not by CCK‐8. Am J Physiol 268: E949‐E955, 1995.
 111. Finan B , Ma T , Ottaway N , Muller TD , Habegger KM , Heppner KM , Kirchner H , Holland J , Hembree J , Raver C , Lockie SH , Smiley DL , Gelfanov V , Yang B , Hofmann S , Bruemmer D , Drucker DJ , Pfluger PT , Perez‐Tilve D , Gidda J , Vignati L , Zhang L , Hauptman JB , Lau M , Brecheisen M , Uhles S , Riboulet W , Hainaut E , Sebokova E , Conde‐Knape K , Konkar A , Dimarchi RD , Tschop MH . Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med 5: 209ra151, 2013.
 112. Fineman MS , Bicsak TA , Shen LZ , Taylor K , Gaines E , Varns A , Kim D , Baron AD . Effect on glycemic control of exenatide (synthetic exendin‐4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care 26: 2370‐2377, 2003.
 113. Ford HE , Peters V , Martin NM , Sleeth ML , Ghatei MA , Frost GS , Bloom SR . Effects of oral ingestion of sucralose on gut hormone response and appetite in healthy normal‐weight subjects. Eur J Clin Nutr 65: 508‐513, 2011.
 114. Freeland KR , Wolever TM . Acute effects of intravenous and rectal acetate on glucagon‐like peptide‐1, peptide YY, ghrelin, adiponectin and tumour necrosis factor‐alpha. Br J Nutr 103: 460‐466, 2010.
 115. Frias JP , Nauck MA , Van J , Kutner ME , Cui X , Benson C , Urva S , Gimeno RE , Milicevic Z , Robins D , Haupt A . Efficacy and safety of LY3298176, a novel dual GIP and GLP‐1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo‐controlled and active comparator‐controlled phase 2 trial. Lancet, 2018.
 116. Frid AH , Nilsson M , Holst JJ , Bjorck IM . Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects. Am J Clin Nutr 82: 69‐75, 2005.
 117. Fujita Y , Asadi A , Yang GK , Kwok YN , Kieffer TJ . Differential processing of pro‐glucose‐dependent insulinotropic polypeptide in gut. Am J Physiol Gastrointest Liver Physiol 298: G608‐G614, 2010.
 118. Fujita Y , Wideman RD , Asadi A , Yang GK , Baker R , Webber T , Zhang T , Wang R , Ao Z , Warnock GL , Kwok YN , Kieffer TJ . Glucose‐dependent insulinotropic polypeptide is expressed in pancreatic islet alpha‐cells and promotes insulin secretion. Gastroenterology 138: 1966‐1975, 2010.
 119. Fulurija A , Lutz TA , Sladko K , Osto M , Wielinga PY , Bachmann MF , Saudan P . Vaccination against GIP for the treatment of obesity. PLoS One 3: e3163, 2008.
 120. Gabe MBN , Sparre‐Ulrich AH , Pedersen MF , Gasbjerg LS , Inoue A , Brauner‐Osborne H , Hartmann B , Rosenkilde MM . Human GIP(3‐30)NH2 inhibits G protein‐dependent as well as G protein‐independent signaling and is selective for the GIP receptor with high‐affinity binding to primate but not rodent GIP receptors. Biochem Pharmacol 150: 97‐107, 2018.
 121. Galsgaard KD , Winther‐Sorensen M , Orskov C , Kissow H , Poulsen SS , Vilstrup H , Prehn C , Adamski J , Jepsen SL , Hartmann B , Hunt J , Charron MJ , Pedersen J , Wewer Albrechtsen NJ , Holst JJ . Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver‐alpha‐cell axis. Am J Physiol Endocrinol Metab 314: E93‐E103, 2018.
 122. Gasbjerg LS , Christensen MB , Hartmann B , Lanng AR , Sparre‐Ulrich AH , Gabe MBN , Dela F , Vilsboll T , Holst JJ , Rosenkilde MM , Knop FK . GIP(3‐30)NH2 is an efficacious GIP receptor antagonist in humans: a randomised, double‐blinded, placebo‐controlled, crossover study. Diabetologia 61: 413‐423, 2018.
 123. Gasbjerg LS , Gabe MBN , Hartmann B , Christensen MB , Knop FK , Holst JJ , Rosenkilde MM . Glucose‐dependent insulinotropic polypeptide (GIP) receptor antagonists as anti‐diabetic agents. Peptides 100: 173‐181, 2018.
 124. Gasbjerg LS , Helsted MM , Hartmann B , Jensen MH , Gabe MBN , Sparre‐Ulrich AH , Veedfald S , Stensen S , Lanng AR , Bergmann NC , Christensen MB , Vilsbøll T , Holst JJ , Rosenkilde MM , Knop FK . Separate and combined glucometabolic effects of endogenous glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide 1 in healthy individuals. Diabetes 68 (5): 906‐917, 2019.
 125. Gault VA , Parker JC , Harriott P , Flatt PR , O'Harte FP . Evidence that the major degradation product of glucose‐dependent insulinotropic polypeptide, GIP(3‐42), is a GIP receptor antagonist in vivo. J Endocrinol 175: 525‐533, 2002.
 126. Gelling RW , Du XQ , Dichmann DS , Romer J , Huang H , Cui L , Obici S , Tang B , Holst JJ , Fledelius C , Johansen PB , Rossetti L , Jelicks LA , Serup P , Nishimura E , Charron MJ . Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA 100: 1438‐1443, 2003.
 127. Ghatei MA , Uttenthal LO , Christofides ND , Bryant MG , Bloom SR . Molecular forms of human enteroglucagon in tissue and plasma: plasma responses to nutrient stimuli in health and in disorders of the upper gastrointestinal tract. J Clin Endocrinol Metab 57: 488‐495, 1983.
 128. Goke B , Fuder H , Wieckhorst G , Theiss U , Stridde E , Littke T , Kleist P , Arnold R , Lucker PW . Voglibose (AO‐128) is an efficient alpha‐glucosidase inhibitor and mobilizes the endogenous GLP‐1 reserve. Digestion 56: 493‐501, 1995.
 129. Goke B , Herrmann C , Goke R , Fehmann HC , Berghofer P , Richter G , Arnold R . Intestinal effects of alpha‐glucosidase inhibitors: absorption of nutrients and enterohormonal changes. Eur J Clin Invest 24 (Suppl 2): 25‐30, 1994.
 130. Goke R , Fehmann HC , Linn T , Schmidt H , Krause M , Eng J , Goke B . Exendin‐4 is a high potency agonist and truncated exendin‐(9‐39)‐ amide an antagonist at the glucagon‐like peptide 1‐(7‐36)‐amide receptor of insulin‐secreting beta‐cells. J Biol Chem 268: 19650‐19655, 1993.
 131. Greenberg GR , Pokol‐Daniel S . Neural modulation of glucose‐dependent insulinotropic peptide (GIP) and insulin secretion in conscious dogs. Pancreas 9: 531‐535, 1994.
 132. Greenfield JR , Farooqi IS , Keogh JM , Henning E , Habib AM , Blackwood A , Reimann F , Holst JJ , Gribble FM . Oral glutamine increases circulating glucagon‐like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects. Am J Clin Nutr 89: 106‐113, 2009.
 133. Gribble FM , Diakogiannaki E , Reimann F . Gut hormone regulation and secretion via FFA1 and FFA4. Handb Exp Pharmacol 236: 181‐203, 2017.
 134. Gribble FM , Reimann F . Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu Rev Physiol 78: 277‐299, 2016.
 135. Grimelius L , Hultquist GT , Stenkvist B . Cytological differentiation of asymptomatic pancreatic islet cell tumours in autopsy material. Virchows Arch A Pathol Anat Histol 365: 275‐288, 1975.
 136. Gromada J , Franklin I , Wollheim CB . Alpha‐cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 28: 84‐116, 2007.
 137. Guedes TP , Martins S , Costa M , Pereira SS , Morais T , Santos A , Nora M , Monteiro MP . Detailed characterization of incretin cell distribution along the human small intestine. Surg Obes Relat Dis 11: 1323‐1331, 2015.
 138. Han VK , Hynes MA , Jin C , Towle AC , Lauder JM , Lund PK . Cellular localization of proglucagon/glucagon‐like peptide I messenger RNAs in rat brain. J Neurosci Res 16: 97‐107, 1986.
 139. Hansen AM , Bodvarsdottir TB , Nordestgaard DN , Heller RS , Gotfredsen CF , Maedler K , Fels JJ , Holst JJ , Karlsen AE . Upregulation of alpha cell glucagon‐like peptide 1 (GLP‐1) in Psammomys obesus – an adaptive response to hyperglycaemia? Diabetologia 54: 1379‐1387, 2011.
 140. Hansen CF , Vrang N , Sangild PT , Jelsing J . Novel insight into the distribution of L‐cells in the rat intestinal tract. Am J Transl Res 5: 347‐358, 2013.
 141. Hansen HS , Rosenkilde MM , Holst JJ , Schwartz TW . GPR119 as a fat sensor. Trends Pharmacol Sci 33: 374‐381, 2012.
 142. Hansen KB , Rosenkilde MM , Knop FK , Wellner N , Diep TA , Rehfeld JF , Andersen UB , Holst JJ , Hansen HS . 2‐Oleoyl glycerol is a GPR119 agonist and signals GLP‐1 release in humans. J Clin Endocrinol Metab 96: E1409‐E1417, 2011.
 143. Hansen KB , Vilsboll T , Bagger JI , Holst JJ , Knop FK . Reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high‐calorie diet impairs the incretin effect in healthy subjects. J Clin Endocrinol Metab 95: 3309‐3317, 2010.
 144. Hansen L , Deacon CF , Orskov C , Holst JJ . Glucagon‐like peptide‐1‐(7‐36)amide is transformed to glucagon‐like peptide‐1‐(9‐36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine [In Process Citation]. Endocrinology 140: 5356‐5363, 1999.
 145. Hansen L , Hartmann B , Bisgaard T , Mineo H , Jørgensen PN , Holst JJ . Somatostatin restrains the secretion of glucagon‐like peptide‐1 and 2 from isolated perfused porcine ileum. Am J Physiol 278: E1010‐E1018, 2000.
 146. Hansen L , Hartmann B , Mineo H , Holst JJ . Glucagon‐like peptide‐1 secretion is influenced by perfusate glucose concentration and by a feedback mechanism involving somatostatin in isolated perfused porcine ileum. Regul Pept 118: 11‐18, 2004.
 147. Hansen L , Holst JJ . The effects of duodenal peptides on glucagon‐like peptide‐1 secretion from the ileum. A duodeno–ileal loop? Regul Pept 110: 39‐45, 2002.
 148. Hansen L , Lampert S , Mineo H , Holst JJ . Neural regulation of glucagon‐like peptide‐1 secretion in pigs. Am J Physiol Endocrinol Metab 287: E939‐E947, 2004.
 149. Hansen LS , Sparre‐Ulrich AH , Christensen M , Knop FK , Hartmann B , Holst JJ , Rosenkilde MM . N‐terminally and C‐terminally truncated forms of glucose‐dependent insulinotropic polypeptide are high‐affinity competitive antagonists of the human GIP receptor. Br J Pharmacol 173: 826‐838, 2016.
 150. Hansen M , Hjollund KR , Hartmann B , Plamboeck A , Deacon CF , Wewer Albrechtsen NJ , Holst JJ . Important species differences regarding lymph contribution to gut hormone responses. Peptides 71: 28‐31, 2015.
 151. Hansen M , Scheltema MJ , Sonne DP , Hansen JS , Sperling M , Rehfeld JF , Holst JJ , Vilsboll T , Knop FK . Effect of chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucagon‐like peptide‐1 secretion. Diabetes Obes Metab 18: 571‐580, 2016.
 152. Hansotia T , Baggio LL , Delmeire D , Hinke SA , Yamada Y , Tsukiyama K , Seino Y , Holst JJ , Schuit F , Drucker DJ . Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP‐IV inhibitors. Diabetes 53: 1326‐1335, 2004.
 153. Harder‐Lauridsen NM , Krogh‐Madsen R , Holst JJ , Plomgaard P , Leick L , Pedersen BK , Fischer CP . Effect of IL‐6 on the insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol Metab 306: E769‐E778, 2014.
 154. Hayes MR , Kanoski SE , De Jonghe BC , Leichner TM , Alhadeff AL , Fortin SM , Arnold M , Langhans W , Grill HJ . The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon‐like‐peptide‐1. Am J Physiol Regul Integr Comp Physiol 301: R1479‐R1485, 2011.
 155. Henriksen DB , Alexandersen P , Bjarnason NH , Vilsboll T , Hartmann B , Henriksen EE , Byrjalsen I , Krarup T , Holst JJ , Christiansen C . Role of gastrointestinal hormones in postprandial reduction of bone resorption. J Bone Miner Res 18: 2180‐2189, 2003.
 156. Henriksen DB , Alexandersen P , Byrjalsen I , Hartmann B , Bone HG , Christiansen C , Holst JJ . Reduction of nocturnal rise in bone resorption by subcutaneous GLP‐2. Bone 34: 140‐147, 2004.
 157. Henriksen DB , Alexandersen P , Hartmann B , Adrian CL , Byrjalsen I , Bone HG , Holst JJ , Christiansen C . Four‐month treatment with GLP‐2 significantly increases hip BMD: a randomized, placebo‐controlled, dose‐ranging study in postmenopausal women with low BMD. Bone 45: 833‐842, 2009.
 158. Herman GA , Bergman A , Stevens C , Kotey P , Yi B , Zhao P , Dietrich B , Golor G , Schrodter A , Keymeulen B , Lasseter KC , Kipnes MS , Snyder K , Hilliard D , Tanen M , Cilissen C , De Smet M , de Lepeleire I , Van DK , Wang AQ , Zeng W , Davies MJ , Tanaka W , Holst JJ , Deacon CF , Gottesdiener KM , Wagner JA . Effect of single oral doses of sitagliptin, a dipeptidyl peptidase‐4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 91: 4612‐4619, 2006.
 159. Hickson JC . The secretion of pancreatic juice in response to stimulation of the vagus nerves in the pig. J Physiol 206: 275‐297, 1970.
 160. Hirasawa A , Tsumaya K , Awaji T , Katsuma S , Adachi T , Yamada M , Sugimoto Y , Miyazaki S , Tsujimoto G . Free fatty acids regulate gut incretin glucagon‐like peptide‐1 secretion through GPR120. Nat Med 11: 90‐94, 2005.
 161. Hjollund KR , Deacon CF , Holst JJ . Dipeptidyl peptidase‐4 inhibition increases portal concentrations of intact glucagon‐like peptide‐1 (GLP‐1) to a greater extent than peripheral concentrations in anaesthetised pigs. Diabetologia 54: 2206‐2208, 2011.
 162. Hojberg PV , Vilsboll T , Rabol R , Knop FK , Bache M , Krarup T , Holst JJ , Madsbad S . Four weeks of near‐normalisation of blood glucose improves the insulin response to glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 52: 199‐207, 2009.
 163. Hojberg PV , Vilsboll T , Zander M , Knop FK , Krarup T , Volund A , Holst JJ , Madsbad S . Four weeks of near‐normalization of blood glucose has no effect on postprandial GLP‐1 and GIP secretion, but augments pancreatic B‐cell responsiveness to a meal in patients with Type 2 diabetes. Diabet Med 25: 1268‐1275, 2008.
 164. Holman RR , Bethel MA , Mentz RJ , Thompson VP , Lokhnygina Y , Buse JB , Chan JC , Choi J , Gustavson SM , Iqbal N , Maggioni AP , Marso SP , Ohman P , Pagidipati NJ , Poulter N , Ramachandran A , Zinman B , Hernandez AF . Effects of once‐weekly exenatide on cardiovascular outcomes in Type 2 diabetes. N Engl J Med 377: 1228‐1239, 2017.
 165. Holst JJ . Gut glucagon, enteroglucagon, gut glucagonlike immunoreactivity, glicentin‐current status. Gastroenterology 84: 1602‐1613, 1983.
 166. Holst JJ . Molecular heterogeneity of glucagon in normal subjects and in patients with glucagon‐producing tumours. Diabetologia 24: 359‐365, 1983.
 167. Holst JJ . Glucagon‐like Peptide 1(GLP‐1): an intestinal hormone signalling nutritional abundance, with an unusual therapeutic potential. Trends Endocrinol Metab 10: 229‐234, 1999.
 168. Holst JJ . Glucagon‐like peptide‐1: from extract to agent. The Claude Bernard Lecture, 2005. Diabetologia 49: 253‐260, 2006.
 169. Holst JJ . The physiology of glucagon‐like Peptide 1. Physiol Rev 87: 1409‐1439, 2007.
 170. Holst JJ , Albrechtsen NJW , Gabe MBN , Rosenkilde MM . Oxyntomodulin: actions and role in diabetes. Peptides 100: 48‐53, 2018.
 171. Holst JJ , Bersani M , Johnsen AH , Kofod H , Hartmann B , Orskov C . Proglucagon processing in porcine and human pancreas. J Biol Chem 269: 18827‐18833, 1994.
 172. Holst JJ , Deacon CF . Glucagon‐like peptide‐1 mediates the therapeutic actions of DPP‐IV inhibitors. Diabetologia 48: 612‐615, 2005.
 173. Holst JJ , Deacon CF , Toft‐Nielsen M‐B , Bjerre‐Knudsen L . On the treatment of diabetes mellitus with glucagon‐like peptide‐1. Ann N Y Acad Sci 865: 336‐343, 1998.
 174. Holst JJ , Gribble F , Horowitz M , Rayner CK . Roles of the gut in glucose homeostasis. Diabetes Care 39: 884‐892, 2016.
 175. Holst JJ , Knop FK , Vilsboll T , Krarup T , Madsbad S . Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care 34 (Suppl 2): S251‐S257, 2011.
 176. Holst JJ , Knuhtsen S , Orskov C , Skak‐Nielsen T , Poulsen SS , Jensen SL , Nielsen OV . GRP nerves in pig antrum: role of GRP in vagal control of gastrin secretion. Am J Physiol 253: G643‐G649, 1987.
 177. Holst JJ , Madsbad S . Mechanisms of surgical control of type 2 diabetes: GLP‐1 is key factor. Surg Obes Relat Dis 12: 1236‐1242, 2016.
 178. Holst JJ , Orskov C , Nielsen OV , Schwartz TW . Truncated glucagon‐like peptide I, an insulin‐releasing hormone from the distal gut. FEBS Lett 211: 169‐174, 1987.
 179. Holst JJ , Orskov C , Schwartz TW , Buhl T , Baldissera F . Proglucagon 78‐107, a potent insulinotropic hormone from the lower small intestine. Diabetologia 29: 549A, 1986 (Ref Type: Abstract).
 180. Holst JJ , Pedersen JH , Baldissera F , Stadil F . Circulating glucagon after total pancreatectomy in man. Diabetologia 25: 396‐399, 1983.
 181. Holst JJ , Schaffalitzky De Muckadell OB , Fahrenkrug J . Nervous control of pancreatic exocrine secretion in pigs. Acta Physiol Scand 105: 33‐51, 1979.
 182. Holst JJ , Schwartz TW , Lovgreen NA , Pedersen O , Beck‐Nielsen H . Diurnal profile of pancreatic polypeptide, pancreatic glucagon, gut glucagon and insulin in human morbid obesity. Int J Obes 7: 529‐538, 1983.
 183. Holst JJ , Sorensen TI , Andersen AN , Stadil F , Andersen B , Lauritsen KB , Klein HC . Plasma enteroglucagon after jejunoileal bypass with 3:1 or 1:3 jejunoileal ratio. Scand J Gastroenterol 14: 205‐207, 1979.
 184. Horowitz M , Dent J , Fraser R , Sun W , Hebbard G . Role and integration of mechanisms controlling gastric emptying. Dig Dis Sci 39: 7S‐13S, 1994.
 185. Horowitz M , Edelbroek MA , Wishart JM , Straathof JW . Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia 36: 857‐862, 1993.
 186. Hupe‐Sodmann K , McGregor GP , Bridenbaugh R , Goke R , Goke B , Thole H , Zimmermann B , Voigt K . Characterisation of the processing by human neutral endopeptidase 24.11 of GLP‐1(7‐36) amide and comparison of the substrate specificity of the enzyme for other glucagon‐like peptides. Regul Pept 58: 149‐156, 1995.
 187. Iepsen EW , Lundgren J , Holst JJ , Madsbad S , Torekov SS . Successful weight loss maintenance includes long‐term increased meal responses of GLP‐1 and PYY3‐36. Eur J Endocrinol 174: 775‐784, 2016.
 188. Irwin N , McClean PL , Patterson S , Hunter K , Flatt PR . Active immunisation against gastric inhibitory polypeptide (GIP) improves blood glucose control in an animal model of obesity‐diabetes. Biol Chem 390: 75‐80, 2009.
 189. Jacobsen SH , Bojsen‐Moller KN , Dirksen C , Jorgensen NB , Clausen TR , Wulff BS , Kristiansen VB , Worm D , Hansen DL , Holst JJ , van HG and Madsbad S. Effects of gastric bypass surgery on glucose absorption and metabolism during a mixed meal in glucose‐tolerant individuals. Diabetologia 56: 2250‐2254, 2013.
 190. Jacobsen SH , Olesen SC , Dirksen C , Jorgensen NB , Bojsen‐Moller KN , Kielgast U , Worm D , Almdal T , Naver LS , Hvolris LE , Rehfeld JF , Wulff BS , Clausen TR , Hansen DL , Holst JJ , Madsbad S . Changes in gastrointestinal hormone responses, insulin sensitivity, and beta‐cell function within 2 weeks after gastric bypass in non‐diabetic subjects. Obes Surg 22: 1084‐1096, 2012.
 191. Jang HJ , Kokrashvili Z , Theodorakis MJ , Carlson OD , Kim BJ , Zhou J , Kim HH , Xu X , Chan SL , Juhaszova M , Bernier M , Mosinger B , Margolskee RF , Egan JM . Gut‐expressed gustducin and taste receptors regulate secretion of glucagon‐like peptide‐1. Proc Natl Acad Sci U S A 104: 15069‐15074, 2007.
 192. Jejelava N , Kaufman S , Krieger JP , Terra MM , Langhans W , Arnold M . Intestinal lymph as a readout of meal‐induced GLP‐1 release in an unrestrained rat model. Am J Physiol Regul Integr Comp Physiol, 2018.
 193. Jensen CB , Pyke C , Rasch MG , Dahl AB , Knudsen LB , Secher A . Characterization of the glucagonlike peptide‐1 receptor in male mouse brain using a novel antibody and in situ hybridization. Endocrinology 159: 665‐675, 2018.
 194. Jensen CZ , Bojsen‐Moller KN , Svane M , Holst LM , Hermansen K , Holst JJ , Madsbad S . Exaggerated postprandial GLP‐1 secretion after Roux‐en‐Y gastric bypass is highest after glucose compared with fat and protein ingestion. Diabetologia 59 (Suppl 1): S254, 2016 (Ref Type: Abstract).
 195. Jensen EP , Poulsen SS , Kissow H , Holstein‐Rathlou NH , Deacon CF , Jensen BL , Holst JJ , Sorensen CM . Activation of GLP‐1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow. Am J Physiol Renal Physiol 308: F867‐F877, 2015.
 196. Ji C , Xue GF , Li G , Li D , Holscher C . Neuroprotective effects of glucose‐dependent insulinotropic polypeptide in Alzheimer's disease. Rev Neurosci 27: 61‐70, 2016.
 197. Jones KL , Horowitz M , Carney BI , Wishart JM , Guha S , Green L . Gastric emptying in early noninsulin‐dependent diabetes mellitus. J Nucl Med 37: 1643‐1648, 1996.
 198. Jones KL , O'Donovan D , Russo A , Meyer JH , Stevens JE , Lei Y , Keogh J , Tonkin A , Horowitz M . Effects of drink volume and glucose load on gastric emptying and postprandial blood pressure in healthy older subjects. Am J Physiol Gastrointest Liver Physiol 289: G240‐G248, 2005.
 199. Jorgensen MB , Idorn T , Knop FK , Holst JJ , Hornum M , Feldt‐Rasmussen B . Clearance of glucoregulatory peptide hormones during haemodialysis and haemodiafiltration in non‐diabetic end‐stage renal disease patients. Nephrol Dial Transplant 30: 513‐520, 2015.
 200. Jorgensen NB , Dirksen C , Bojsen‐Moller KN , Jacobsen SH , Worm D , Hansen DL , Kristiansen VB , Naver L , Madsbad S , Holst JJ . Exaggerated glucagon‐like peptide 1 response is important for improved beta‐cell function and glucose tolerance after Roux‐en‐Y gastric bypass in patients with type 2 diabetes. Diabetes 62: 3044‐3052, 2013.
 201. Jorgensen NB , Jacobsen SH , Dirksen C , Bojsen‐Moller KN , Naver L , Hvolris L , Clausen TR , Wulff BS , Worm D , Lindqvist HD , Madsbad S , Holst JJ . Acute and long‐term effects of Roux‐en‐Y gastric bypass on glucose metabolism in subjects with Type 2 diabetes and normal glucose tolerance. Am J Physiol Endocrinol Metab 303: E122‐E131, 2012.
 202. Jorsal T , Rhee NA , Pedersen J , Wahlgren CD , Mortensen B , Jepsen SL , Jelsing J , Dalboge LS , Vilmann P , Hassan H , Hendel JW , Poulsen SS , Holst JJ , Vilsboll T , Knop FK . Enteroendocrine K and L cells in healthy and type 2 diabetic individuals. Diabetologia 61: 284‐294, 2018.
 203. Kahles F , Meyer C , Mollmann J , Diebold S , Findeisen HM , Lebherz C , Trautwein C , Koch A , Tacke F , Marx N , Lehrke M . GLP‐1 secretion is increased by inflammatory stimuli in an IL‐6‐dependent manner, leading to hyperinsulinemia and blood glucose lowering. Diabetes 63: 3221‐3229, 2014.
 204. Keller J , Beglinger C , Holst JJ , Andresen V , Layer P . Mechanisms of gastric emptying disturbances in chronic and acute inflammation of the distal gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 297: G861‐G868, 2009.
 205. Keller J , Binnewies U , Rosch M , Juul HJ , Beglinger C , Andresen V , Layer P . Gastric emptying and disease activity in inflammatory bowel disease. Eur J Clin Invest 45: 1234‐1242, 2015.
 206. Kieffer TJ , McIntosh CH , Pederson RA . Degradation of glucose‐dependent insulinotropic polypeptide and truncated glucagon‐like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136: 3585‐3596, 1995.
 207. Kilimnik G , Kim A , Steiner DF , Friedman TC , Hara M . Intraislet production of GLP‐1 by activation of prohormone convertase 1/3 in pancreatic alpha‐cells in mouse models of ss‐cell regeneration. Islets 2: 149‐155, 2010.
 208. Kirkegaard P , Moody AJ , Holst JJ , Loud FB , Olsen PS , Christiansen J . Glicentin inhibits gastric acid secretion in the rat. Nature 297: 156‐157, 1982.
 209. Kissow H . Glucagon‐like peptides 1 and 2: intestinal hormones implicated in the pathophysiology of mucositis. Curr Opin Support Palliat Care 9: 196‐202, 2015.
 210. Knop FK , Aaboe K , Vilsboll T , Volund A , Holst JJ , Krarup T , Madsbad S . Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabetes Obes Metab 14: 500‐510, 2012.
 211. Knop FK , Vilsboll T , Larsen S , Hojberg PV , Volund A , Madsbad S , Holst JJ , Krarup T . Increased postprandial responses of GLP‐1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution. Am J Physiol Endocrinol Metab 292: E324‐E330, 2007.
 212. Knop FK , Vilsboll T , Madsbad S , Holst JJ , Krarup T . Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus. Diabetologia 50: 797‐805, 2007.
 213. Knudsen JB , Holst JJ , Asnaes S , Johansen A . Identification of cells with pancreatic‐type and gut‐type glucagon immunoreactivity in the human colon. Acta Pathol Microbiol Scand 83: 741‐743, 1975.
 214. Knudsen LB , Kiel D , Teng M , Behrens C , Bhumralkar D , Kodra JT , Holst JJ , Jeppesen CB , Johnson MD , de Jong JC , Jorgensen AS , Kercher T , Kostrowicki J , Madsen P , Olesen PH , Petersen JS , Poulsen F , Sidelmann UG , Sturis J , Truesdale L , May J , Lau J . Small‐molecule agonists for the glucagon‐like peptide 1 receptor. Proc Natl Acad Sci USA 104: 937‐942, 2007.
 215. Knudsen LB , Pridal L . Glucagon‐like peptide‐1‐(9‐36)amide is a major metabolite of glucagon‐like peptide‐1‐(7‐36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor. Eur J Pharmacol 318: 429‐435, 1996.
 216. Kohli R , Myronovych A , Tan BK , Salazar‐Gonzalez RM , Miles L , Zhang W , Oehrle M , Sandoval DA , Ryan KK , Seeley RJ , Setchell KD . Bile acid signaling: mechanism for bariatric surgery, cure for NASH? Dig Dis 33: 440‐446, 2015.
 217. Koopman ADM , Rutters F , Rauh SP , Nijpels G , Holst JJ , Beulens JW , Alssema M , Dekker JM . Incretin responses to oral glucose and mixed meal tests and changes in fasting glucose levels during 7 years of follow‐up: The Hoorn Meal Study. PLoS One 13: e0191114, 2018.
 218. Korner J , Bessler M , Inabnet W , Taveras C , Holst JJ . Exaggerated glucagon‐like peptide‐1 and blunted glucose‐dependent insulinotropic peptide secretion are associated with Roux‐en‐Y gastric bypass but not adjustable gastric banding. Surg Obes Relat Dis 3: 597‐601, 2007.
 219. Krarup T . Immunoreactive gastric inhibitory polypeptide. Endocr Rev 9: 122‐134, 1988.
 220. Krarup T , Holst JJ , Larsen KL . Responses and molecular heterogeneity of IR‐GIP after intraduodenal glucose and fat. Am J Physiol 249: E195‐E200, 1985.
 221. Krarup T , Holst JJ , Lindorff Larsen K , Madsbad S . Heterogeneity of IR‐GIP in normal subjects and insulin‐dependent diabetics. In: Blázquez E , editor. Gut Regulatory Peptides: Their Role in Health and Disease. Basel: Karger, 1987, p. 167‐174.
 222. Krarup T , Saurbrey N , Moody AJ , Kuhl C , Madsbad S . Effect of porcine gastric inhibitory polypeptide on beta‐cell function in type I and type II diabetes mellitus. Metabolism 36: 677‐682, 1987.
 223. Kreymann B , Williams G , Ghatei MA , Bloom SR . Glucagon‐like peptide‐1 7‐36: a physiological incretin in man. Lancet 2: 1300‐1304, 1987.
 224. Krieger JP , Arnold M , Pettersen KG , Lossel P , Langhans W , Lee SJ . Knockdown of GLP‐1 receptors in vagal afferents affects normal food intake and glycemia. Diabetes 65: 34‐43, 2016.
 225. Krieger JP , Langhans W , Lee SJ . Vagal mediation of GLP‐1's effects on food intake and glycemia. Physiol Behav 152: 372‐380, 2015.
 226. Kuhre RE , Albrechtsen NW , Windelov JA , Svendsen B , Hartmann B , Holst JJ . GLP‐1 amidation efficiency along the length of the intestine in mice, rats and pigs and in GLP‐1 secreting cell lines. Peptides 55: 52‐57, 2014.
 227. Kuhre RE , Christiansen CB , Saltiel MY , Wewer Albrechtsen NJ , Holst JJ . On the relationship between glucose absorption and glucose‐stimulated secretion of GLP‐1, neurotensin, and PYY from different intestinal segments in the rat. Physiol Rep 5, 2017. DOI: 10.14814/phy2.13507.
 228. Kuhre RE , Frost CR , Svendsen B , Holst JJ . Molecular mechanisms of glucose‐stimulated GLP‐1 secretion from perfused rat small intestine. Diabetes 64: 370‐382, 2015.
 229. Kuhre RE , Gribble FM , Hartmann B , Reimann F , Windelov JA , Rehfeld JF , Holst JJ . Fructose stimulates GLP‐1 but not GIP secretion in mice, rats, and humans. Am J Physiol Gastrointest Liver Physiol 306: G622‐G630, 2014.
 230. Kuhre RE , Wewer Albrechtsen NJ , Hartmann B , Deacon CF , Holst JJ . Measurement of the incretin hormones: glucagon‐like peptide‐1 and glucose‐dependent insulinotropic peptide. J Diabetes Complications 29: 445‐450, 2015.
 231. Kuhre RE , Wewer Albrechtsen NJ , Larsen O , Jepsen SL , Balk‐Moller E , Andersen DB , Deacon CF , Schoonjans K , Reimann F , Gribble FM , Albrechtsen R , Hartmann B , Rosenkilde MM , Holst JJ . Bile acids are important direct and indirect regulators of the secretion of appetite‐ and metabolism‐regulating hormones from the gut and pancreas. Mol Metab 11: 84‐95, 2018.
 232. Kumar D , Mains RE , Eipper BA . 60 YEARS OF POMC: From POMC and alpha‐MSH to PAM, molecular oxygen, copper, and vitamin C. J Mol Endocrinol 56: T63‐T76, 2016.
 233. Lambeir AM , Durinx C , Scharpe S , De M . I. Dipeptidyl‐peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci 40: 209‐294, 2003.
 234. Lang LL , Lyngbaek MP , Soederlund L , Legaard GE , Ehses JA , Heywood SE , Wewer Albrechtsen NJ , Holst JJ , Karstoft K , Pedersen BK , Ellingsgaard H . Interleukin‐6 delays gastric emptying in humans with direct effects on glycemic control. Cell Metab 27: 1201‐1211, 2018.
 235. Langhans W , Holst JJ . Afferent endocrine control of eating. In: Dixon S , Mercer JG , editors. Neuroendocrinology of Appetite. Wiley‐Blackwell, 2016, p. 24‐54.
 236. Larsen PJ , Holst JJ . Glucagon‐related peptide 1 (GLP‐1): hormone and neurotransmitter. Regul Pept 128: 97‐107, 2005.
 237. Larsen PJ , Tang‐Christensen M , Holst JJ , Orskov C . Distribution of glucagon‐like peptide‐1 and other preproglucagon‐derived peptides in the rat hypothalamus and brainstem. Neuroscience 77: 257‐270, 1997.
 238. Le Roux CW , Aylwin SJ , Batterham RL , Borg CM , Coyle F , Prasad V , Shurey S , Ghatei MA , Patel AG , Bloom SR . Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg 243: 108‐114, 2006.
 239. Le Roux CW , Welbourn R , Werling M , Osborne A , Kokkinos A , Laurenius A , Lonroth H , Fandriks L , Ghatei MA , Bloom SR , Olbers T . Gut hormones as mediators of appetite and weight loss after Roux‐en‐Y gastric bypass. Ann Surg 246: 780‐785, 2007.
 240. Lebrun LJ , Lenaerts K , Kiers D . Pais de Barros JP, Le GN, Plesnik J, Thomas C, Bourgeois T, Dejong CHC, Kox M, Hundscheid IHR, Khan NA, Mandard S, Deckert V, Pickkers P, Drucker DJ, Lagrost L and Grober J. Enteroendocrine L Cells Sense LPS after Gut Barrier Injury to Enhance GLP‐1 Secretion. Cell Rep 21: 1160‐1168, 2017.
 241. Lee A , Patrick P , Wishart J , Horowitz M , Morley JE . The effects of miglitol on glucagon‐like peptide‐1 secretion and appetite sensations in obese type 2 diabetics. Diabetes Obes Metab 4: 329‐335, 2002.
 242. Lee AY , Chappell DL , Bak MJ , Judo M , Liang L , Churakova T , Ayanoglu G , Castro‐Perez J , Zhou H , Previs S , Souza SC , Lassman ME , Laterza OF . Multiplexed quantification of proglucagon‐derived peptides by immunoaffinity enrichment and tandem mass spectrometry after a meal tolerance test. Clin Chem 62: 227‐235, 2016.
 243. Lehrskov‐Schmidt L , Lehrskov‐Schmidt L , Nielsen ST , Holst JJ , Moller K , Solomon TP . The effects of TNF‐alpha on GLP‐1‐stimulated plasma glucose kinetics. J Clin Endocrinol Metab 100: E616‐E622, 2015.
 244. LeRoith D , Spitz IM , Ebert R , Liel Y , Odes S , Creutzfeldt W . Acid‐induced gastric inhibitory polypeptide secretion in man. J Clin Endocrinol Metab 51: 1385‐1389, 1980.
 245. Lindgren O , Carr RD , Deacon CF , Holst JJ , Pacini G , Mari A , Ahren B . Incretin hormone and insulin responses to oral versus intravenous lipid administration in humans. J Clin Endocrinol Metab 96: 2519‐2524, 2011.
 246. Lindgren O , Pacini G , Tura A , Holst JJ , Deacon CF , Ahren B . Incretin effect after oral amino acid ingestion in humans. J Clin Endocrinol Metab 100: 1172‐1176, 2015.
 247. Lu WJ , Yang Q , Yang L , Lee D , D'Alessio D , Tso P . Chylomicron formation and secretion is required for lipid‐stimulated release of incretins GLP‐1 and GIP. Lipids 47: 571‐580, 2012.
 248. Lund A , Bagger JI , Wewer Albrechtsen NJ , Christensen M , Grondahl M , Hartmann B , Mathiesen ER , Hansen CP , Storkholm JH , van Hall G , Rehfeld JF , Hornburg D , Meissner F , Mann M , Larsen S , Holst JJ , Vilsboll T , Knop FK . Evidence of extrapancreatic glucagon secretion in man. Diabetes 65: 585‐597, 2016.
 249. Lundberg JM , Tatemoto K , Terenius L , Hellstrom PM , Mutt V , Hokfelt T , Hamberger B . Localization of peptide YY (PYY) in gastrointestinal endocrine cells and effects on intestinal blood flow and motility. Proc Natl Acad Sci U S A 79: 4471‐4475, 1982.
 250. Ma J , Pilichiewicz AN , Feinle‐Bisset C , Wishart JM , Jones KL , Horowitz M , Rayner CK . Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes. Diabet Med 29: 604‐608, 2012.
 251. Madsbad S , Dirksen C , Holst JJ . Mechanisms of changes in glucose metabolism and bodyweight after bariatric surgery. Lancet Diabetes Endocrinol 2: 152‐164, 2014.
 252. Maersk M , Belza A , Holst JJ , Fenger‐Gron M , Pedersen SB , Astrup A , Richelsen B . Satiety scores and satiety hormone response after sucrose‐sweetened soft drink compared with isocaloric semi‐skimmed milk and with non‐caloric soft drink: a controlled trial. Eur J Clin Nutr 66: 523‐529, 2012.
 253. Mandoe MJ , Hansen KB , Hartmann B , Rehfeld JF , Holst JJ , Hansen HS . The 2‐monoacylglycerol moiety of dietary fat appears to be responsible for the fat‐induced release of GLP‐1 in humans. Am J Clin Nutr 102: 548‐555, 2015.
 254. Marchetti P , Lupi R , Bugliani M , Kirkpatrick CL , Sebastiani G , Grieco FA , Del GS , D'Aleo V , Piro S , Marselli L , Boggi U , Filipponi F , Tinti L , Salvini L , Wollheim CB , Purrello F , Dotta F . A local glucagon‐like peptide 1 (GLP‐1) system in human pancreatic islets. Diabetologia 55: 3262‐3272, 2012.
 255. Margolskee RF , Dyer J , Kokrashvili Z , Salmon KS , Ilegems E , Daly K , Maillet EL , Ninomiya Y , Mosinger B , Shirazi‐Beechey SP . T1R3 and gustducin in gut sense sugars to regulate expression of Na+‐glucose cotransporter 1. Proc Natl Acad Sci USA 104: 15075‐15080, 2007.
 256. Marks V . GIP – the obesity hormone. In: James WPT , Parker SW , editors. Current Approaches: Obesity. Southampton: Duphar Medical Relations, 1988, p. 13‐19.
 257. Marso SP , Bain SC , Consoli A , Eliaschewitz FG , Jodar E , Leiter LA , Lingvay I , Rosenstock J , Seufert J , Warren ML , Woo V , Hansen O , Holst AG , Pettersson J , Vilsboll T . Semaglutide and cardiovascular outcomes in patients with Type 2 diabetes. N Engl J Med 375: 1834‐1844, 2016.
 258. Marso SP , Daniels GH , Brown‐Frandsen K , Kristensen P , Mann JF , Nauck MA , Nissen SE , Pocock S , Poulter NR , Ravn LS , Steinberg WM , Stockner M , Zinman B , Bergenstal RM , Buse JB . Liraglutide and cardiovascular outcomes in Type 2 diabetes. N Engl J Med 375: 311‐322, 2016.
 259. Martins C , Kulseng B , King NA , Holst JJ , Blundell JE . The effects of exercise‐induced weight loss on appetite‐related peptides and motivation to eat. J Clin Endocrinol Metab 95: 1609‐1616, 2010.
 260. Masur K , Tibaduiza EC , Chen C , Ligon B , Beinborn M . Basal receptor activation by locally produced glucagon‐like peptide‐1 contributes to maintaining beta‐cell function. Mol Endocrinol 19: 1373‐1382, 2005.
 261. Matikainen N , Bogl LH , Hakkarainen A , Lundbom J , Lundbom N , Kaprio J , Rissanen A , Holst JJ , Pietilainen KH . GLP‐1 responses are heritable and blunted in acquired obesity with high liver fat and insulin resistance. Diabetes Care 37: 242‐251, 2014.
 262. Maxwell V , Shulkes A , Brown JC , Solomon TE , Walsh JH , Grossman MI . Effect of gastric inhibitory polypeptide on pentagastrin‐stimulated acid secretion in man. Dig Dis Sci 25: 113‐116, 1980.
 263. Mayo KE , Miller LJ , Bataille D , Dalle S , Goke B , Thorens B , Drucker DJ . International union of pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev 55: 167‐194, 2003.
 264. McIntyre N , Holdsworth CD , Turner DS . New interpretation of oral glucose tolerance. Lancet II 20‐21, 1964.
 265. Meier JJ , Gallwitz B , Kask B , Deacon CF , Holst JJ , Schmidt WE , Nauck MA . Stimulation of insulin secretion by intravenous bolus injection and continuous infusion of gastric inhibitory polypeptide in patients with type 2 diabetes and healthy control subjects. Diabetes 53 (Suppl 3): S220‐S224, 2004.
 266. Meier JJ , Gethmann A , Nauck MA , Gotze O , Schmitz F , Deacon CF , Gallwitz B , Schmidt WE , Holst JJ . The glucagon‐like peptide‐1 metabolite GLP‐1‐(9‐36)amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans. Am J Physiol Endocrinol Metab 290: E1118‐E1123, 2006.
 267. Meier JJ , Nauck MA , Kranz D , Holst JJ , Deacon CF , Gaeckler D , Schmidt WE , Gallwitz B . Secretion, degradation, and elimination of glucagon‐like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes 53: 654‐662, 2004.
 268. Mentlein R . Dipeptidyl‐peptidase IV (CD26)–role in the inactivation of regulatory peptides. Regul Pept 85: 9‐24, 1999.
 269. Mentlein R , Gallwitz B , Schmidt WE . Dipeptidyl‐peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon‐like peptide‐1(7‐36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 214: 829‐835, 1993.
 270. Migoya EM , Bergeron R , Miller JL , Snyder RN , Tanen M , Hilliard D , Weiss B , Larson P , Gutierrez M , Jiang G , Liu F , Pryor KA , Yao J , Zhu L , Holst JJ , Deacon C , Herman G , Thornberry N , Amatruda J , Williams‐Herman D , Wagner JA , Sinharoy R . Dipeptidyl peptidase‐4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP‐1. Clin Pharmacol Ther 88: 801‐808, 2010.
 271. Miholic J , Orskov C , Holst JJ , Kotzerke J , Meyer HJ . Emptying of the gastric substitute, glucagon‐like peptide‐1 (GLP‐1), and reactive hypoglycemia after total gastrectomy. Dig Dis Sci 36: 1361‐1370, 1991.
 272. Miholic J , Orskov C , Holst JJ , Kotzerke J , Pichlmayr R . Postprandial release of glucagon‐like peptide‐1, pancreatic glucagon, and insulin after esophageal resection. Digestion 54: 73‐78, 1993.
 273. Miyawaki K , Yamada Y , Ban N , Ihara Y , Tsukiyama K , Zhou H , Fujimoto S , Oku A , Tsuda K , Toyokuni S , Hiai H , Mizunoya W , Fushiki T , Holst JJ , Makino M , Tashita A , Kobara Y , Tsubamoto Y , Jinnouchi T , Jomori T , Seino Y . Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 8: 738‐742, 2002.
 274. Miyawaki K , Yamada Y , Yano H , Niwa H , Ban N , Ihara Y , Kubota A , Fujimoto S , Kajikawa M , Kuroe A , Tsuda K , Hashimoto H , Yamashita T , Jomori T , Tashiro F , Miyazaki J , Seino Y . Glucose intolerance caused by a defect in the entero‐insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci USA 96: 14843‐14847, 1999.
 275. Mojsov S , Kopczynski MG , Habener JF . Both amidated and nonamidated forms of glucagon‐like peptide I are synthesized in the rat intestine and the pancreas. J Biol Chem 265: 8001‐8008, 1990.
 276. Mojsov S , Weir GC , Habener JF . Insulinotropin: glucagon‐like peptide I (7‐37) co‐encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest 79: 616‐619, 1987.
 277. Moody AJ , Holst JJ , Thim L , Jensen SL . Relationship of glicentin to proglucagon and glucagon in the porcine pancreas. Nature 289: 514‐516, 1981.
 278. Morinigo R , Moize V , Musri M , Lacy AM , Navarro S , Marin JL , Delgado S , Casamitjana R , Vidal J . Glucagon‐like peptide‐1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab 91: 1735‐1740, 2006.
 279. Mortensen K , christensen LL , Holst JJ , Orskov C . GLP‐1 and GIP are colocalized in a subset of endocrine cells in the small intestine. Regul Pept 114: 189‐196, 2003.
 280. Mortensen LS , Hartvigsen ML , Brader LJ , Astrup A , Schrezenmeir J , Holst JJ , Thomsen C , Hermansen K . Differential effects of protein quality on postprandial lipemia in response to a fat‐rich meal in type 2 diabetes: comparison of whey, casein, gluten, and cod protein. Am J Clin Nutr 90: 41‐48, 2009.
 281. Mulvihill EE , Varin EM , Gladanac B , Campbell JE , Ussher JR , Baggio LL , Yusta B , Ayala J , Burmeister MA , Matthews D , Bang KWA , Ayala JE , Drucker DJ . Cellular sites and mechanisms linking reduction of dipeptidyl peptidase‐4 activity to control of incretin hormone action and glucose homeostasis. Cell Metab 25: 152‐165, 2017.
 282. Muscelli E , Mari A , Casolaro A , Camastra S , Seghieri G , Gastaldelli A , Holst JJ , Ferrannini E . Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes 57: 1340‐1348, 2008.
 283. Nakabayashi H , Nishizawa M , Nakagawa A , Takeda R , Niijima A . Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP‐1. Am J Physiol 271: E808‐E813, 1996.
 284. Nakagawa A , Satake H , Nakabayashi H , Nishizawa M , Furuya K , Nakano S , Kigoshi T , Nakayama K , Uchida K . Receptor gene expression of glucagon‐like peptide‐1, but not glucose‐dependent insulinotropic polypeptide, in rat nodose ganglion cells. Auton Neurosci 110: 36‐43, 2004.
 285. Nakamura T , Tanimoto H , Mizuno Y , Tsubamoto Y , Noda H . Biological and functional characteristics of a novel low‐molecular weight antagonist of glucose‐dependent insulinotropic polypeptide receptor, SKL‐14959, in vitro and in vivo. Diabetes Obes Metab 14: 511‐517, 2012.
 286. Naslund E , Backman L , Holst JJ , Theodorsson E , Hellstrom PM . Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity. Obes Surg 8: 253‐260, 1998.
 287. Nauck M , Schmidt WE , Ebert R , Strietzel J , Cantor P , Hoffmann G , Creutzfeldt W . Insulinotropic properties of synthetic human gastric inhibitory polypeptide in man: interactions with glucose, phenylalanine, and cholecystokinin‐8. J Clin Endocrinol Metab 69: 654‐662, 1989.
 288. Nauck M , Stockmann F , Ebert R , Creutzfeldt W . Reduced incretin effect in type 2 (non‐insulin‐dependent) diabetes. Diabetologia 29: 46‐52, 1986.
 289. Nauck MA . A critical analysis of the clinical use of incretin‐based therapies: The benefits by far outweigh the potential risks. Diabetes Care 36: 2126‐2132, 2013.
 290. Nauck MA , Busing M , Orskov C , Siegel EG , Talartschik J , Baartz A , Baartz T , Hopt UT , Becker HD , Creutzfeldt W . Preserved incretin effect in type 1 diabetic patients with end‐stage nephropathy treated by combined heterotopic pancreas and kidney transplantation. Acta Diabetol 30: 39‐45, 1993.
 291. Nauck MA , Heimesaat MM , Orskov C , Holst JJ , Ebert R , Creutzfeldt W . Preserved incretin activity of glucagon‐like peptide 1 [7‐36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type‐2 diabetes mellitus. J Clin Invest 91: 301‐307, 1993.
 292. Nauck MA , Homberger E , Siegel EG , Allen RC , Eaton RP , Ebert R , Creutzfeldt W . Incretin effects of increasing glucose loads in man calculated from venous insulin and C‐peptide responses. J Clin Endocrinol Metab 63: 492‐498, 1986.
 293. Nauck MA , Kind J , Kothe LD , Holst JJ , Deacon CF , Broschag M , He YL , Kjems L , Foley J . Quantification of the contribution of GLP‐1 to mediating insulinotropic effects of DPP‐4 inhibition with vildagliptin in healthy subjects and patients with type 2 diabetes using exendin [9‐39] as a GLP‐1 receptor antagonist. Diabetes 65: 2440‐2447, 2016.
 294. Nauck MA , Meier JJ . Incretin hormones: Their role in health and disease. Diabetes Obes Metab 20 (Suppl 1): 5‐21, 2018.
 295. Nauck MA , Meier JJ , Cavender MA , Abd El AM , Drucker DJ . Cardiovascular actions and clinical outcomes with glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors. Circulation 136: 849‐870, 2017.
 296. Nauck MA , Siemsgluss J , Orskov C , Holst JJ . Release of glucagon‐like peptide 1 (GLP‐1 [7‐36 amide]), gastric inhibitory polypeptide (GIP) and insulin in response to oral glucose after upper and lower intestinal resections. Z Gastroenterol 34: 159‐166, 1996.
 297. Nauck MA , Vardarli I , Deacon CF , Holst JJ , Meier JJ . Secretion of glucagon‐like peptide‐1 (GLP‐1) in type 2 diabetes: what is up, what is down? Diabetologia 54: 10‐18, 2011.
 298. Nguyen AT , Mandard S , Dray C , Deckert V , Valet P , Besnard P , Drucker DJ , Lagrost L , Grober J . Lipopolysaccharides‐mediated increase in glucose‐stimulated insulin secretion: involvement of the GLP‐1 pathway. Diabetes 63: 471‐482, 2014.
 299. Nguyen NQ , Debreceni TL , Bambrick JE , Bellon M , Wishart J , Standfield S , Rayner CK , Horowitz M . Rapid gastric and intestinal transit is a major determinant of changes in blood glucose, intestinal hormones, glucose absorption and postprandial symptoms after gastric bypass. Obesity (Silver Spring) 22: 2003‐2009, 2014.
 300. Nie Y , Nakashima M , Brubaker PL , Li QL , Perfetti R , Jansen E , Zambre Y , Pipeleers D , Friedman TC . Regulation of pancreatic PC1 and PC2 associated with increased glucagon‐like peptide 1 in diabetic rats. J Clin Invest 105: 955‐965, 2000.
 301. Nielsen S , Svane MS , Kuhre RE , Clausen TR , Kristiansen VB , Rehfeld JF , Holst JJ , Madsbad S , Bojsen‐Moller KN . Chenodeoxycholic acid stimulates glucagon‐like peptide‐1 secretion in patients after Roux‐en‐Y gastric bypass. Physiol Rep 5, 2017.
 302. Nielsen ST , Janum S , Krogh‐Madsen R , Solomon TP , Moller K . The incretin effect in critically ill patients: a case‐control study. Crit Care 19 (402): 2015.
 303. Nikolaidis LA , Elahi D , Shen YT , Shannon RP . Active metabolite of GLP‐1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 289: H2401‐H2408, 2005.
 304. Nilsson M , Stenberg M , Frid AH , Holst JJ , Bjorck IM . Glycemia and insulinemia in healthy subjects after lactose‐equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins. Am J Clin Nutr 80: 1246‐1253, 2004.
 305. Nissen A , Christensen M , Knop FK , Vilsboll T , Holst JJ , Hartmann B . Glucose‐dependent insulinotropic polypeptide inhibits bone resorption in humans. J Clin Endocrinol Metab 99: E2325‐E2329, 2014.
 306. Novak U , Wilks A , Buell G , McEwen S . Identical mRNA for preproglucagon in pancreas and gut. Eur J Biochem 164: 553‐558, 1987.
 307. Okawa M , Fujii K , Ohbuchi K , Okumoto M , Aragane K , Sato H , Tamai Y , Seo T , Itoh Y , Yoshimoto R . Role of MGAT2 and DGAT1 in the release of gut peptides after triglyceride ingestion. Biochem Biophys Res Commun 390: 377‐381, 2009.
 308. O'Neil PM , Birkenfeld AL , McGowan B , Mosenzon O , Pedersen SD , Wharton S , Carson CG , Jepsen CH , Kabisch M , Wilding JPH . Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double‐blind, placebo and active controlled, dose‐ranging, phase 2 trial. Lancet 392: 637‐649, 2018.
 309. Ong WK , Gribble FM , Reimann F , Lynch MJ , Houslay MD , Baillie GS , Furman BL , Pyne NJ . The role of the PDE4D cAMP phosphodiesterase in the regulation of glucagon‐like peptide‐1 release. Br J Pharmacol 157: 633‐644, 2009.
 310. Orci L , Pictet R , Forssmann WG , Renold AE , Rouiller C . Structural evidence for glucagon producing cells in the intestinal mucosa of the rat. Diabetologia 4: 56‐67, 1968.
 311. Orgaard A , Holst JJ . The role of somatostatin in GLP‐1‐induced inhibition of glucagon secretion in mice. Diabetologia 60: 1731‐1739, 2017.
 312. Orskov C , Bersani M , Johnsen AH , Hojrup P , Holst JJ . Complete sequences of glucagon‐like peptide‐1 from human and pig small intestine. J Biol Chem 264: 12826‐12829, 1989.
 313. Orskov C , Holst JJ , Knuhtsen S , Baldissera FG , Poulsen SS , Nielsen OV . Glucagon‐like peptides GLP‐1 and GLP‐2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas. Endocrinology 119: 1467‐1475, 1986.
 314. Orskov C , Holst JJ , Nielsen OV . Effect of truncated glucagon‐like peptide‐1 [proglucagon‐(78‐107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology 123: 2009‐2013, 1988.
 315. Orskov C , Holst JJ , Poulsen SS , Kirkegaard P . Pancreatic and intestinal processing of proglucagon in man. Diabetologia 30: 874‐881, 1987.
 316. Orskov C , Jeppesen J , Madsbad S , Holst JJ . Proglucagon products in plasma of noninsulin‐dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine. J Clin Invest 87: 415‐423, 1991.
 317. Orskov C , Poulsen SS , Moller M , Holst JJ . Glucagon‐like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon‐like peptide I. Diabetes 45: 832‐835, 1996.
 318. Orskov C , Rabenhoj L , Wettergren A , Kofod H , Holst JJ . Tissue and plasma concentrations of amidated and glycine‐extended glucagon‐like peptide I in humans. Diabetes 43: 535‐539, 1994.
 319. Orskov C , Wettergren A , Holst JJ . Biological effects and metabolic rates of glucagonlike peptide‐1 7‐36 amide and glucagonlike peptide‐1 7‐37 in healthy subjects are indistinguishable. Diabetes 42: 658‐661, 1993.
 320. Orskov C , Wettergren A , Holst JJ . Secretion of the incretin hormones glucagon‐like peptide‐1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day. Scand J Gastroenterol 31: 665‐670, 1996.
 321. Overton HA , Fyfe MC , Reynet C . GPR119, a novel G protein‐coupled receptor target for the treatment of type 2 diabetes and obesity. Br J Pharmacol 153 (Suppl 1): S76‐S81, 2008.
 322. Packer M . Does Neprilysin Inhibition Potentiate or Minimize the Adverse Effects of Glucagon‐Like Peptide‐1 Receptor Agonists in Chronic Heart Failure? J Card Fail 24: 109‐111, 2018.
 323. Pais R , Gribble FM , Reimann F . Signalling pathways involved in the detection of peptones by murine small intestinal enteroendocrine L‐cells. Peptides 2015.
 324. Palnaes HC , Andreasen JJ , Holst JJ . The release of gastric inhibitory peptide, glucagon‐like peptide‐I, and insulin after oral glucose test in colectomized subjects. Scand J Gastroenterol 32: 473‐477, 1997.
 325. Pedersen J , Ugleholdt RK , Jorgensen SM , Windelov JA , Grunddal KV , Schwartz TW , Fuchtbauer EM , Poulsen SS , Holst PJ , Holst JJ . Glucose metabolism is altered after loss of L cells and alpha‐cells but not influenced by loss of K cells. Am J Physiol Endocrinol Metab 304: E60‐E73, 2013.
 326. Pederson RA , Dryburgh JR , Brown JC . The effect of somatostatin on release and insulinotropic action of gastric inhibitory polypeptide. Can J Physiol Pharmacol 53: 1200‐1205, 1975.
 327. Perl SH , Bloch O , Zelnic‐Yuval D , Love I , Mendel‐Cohen L , Flor H , Rapoport MJ . Sepsis‐induced activation of endogenous GLP‐1 system is enhanced in type 2 diabetes. Diabetes Metab Res Rev 34: e2982, 2018.
 328. Perley M , Kipnis DM . Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest 46: 1954‐1962, 1967.
 329. Piche T , des Varannes SB , Sacher‐Huvelin S , Holst JJ , Cuber JC , Galmiche JP . Colonic fermentation influences lower esophageal sphincter function in gastroesophageal reflux disease. Gastroenterology 124: 894‐902, 2003.
 330. Pi‐Sunyer X , Astrup A , Fujioka K , Greenway F , Halpern A , Krempf M , Lau DC , Le Roux CW , Violante OR , Jensen CB , Wilding JP . A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 373: 11‐22, 2015.
 331. Piteau S , Olver A , Kim SJ , Winter K , Pospisilik JA , Lynn F , Manhart S , Demuth HU , Speck M , Pederson RA , McIntosh CH . Reversal of islet GIP receptor down‐regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat. Biochem Biophys Res Commun 362: 1007‐1012, 2007.
 332. Plamboeck A , Holst JJ , Carr RD , Deacon CF . Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon‐like peptide 1 in the anaesthetised pig. Diabetologia 48: 1882‐1890, 2005.
 333. Plamboeck A , Veedfald S , Deacon CF , Hartmann B , Wettergren A , Svendsen LB , Meisner S , Hovendal C , Vilsboll T , Knop FK , Holst JJ . The effect of exogenous GLP‐1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am J Physiol Gastrointest Liver Physiol 304: G1117‐G1127, 2013.
 334. Pocai A , Carrington PE , Adams JR , Wright M , Eiermann G , Zhu L , Du X , Petrov A , Lassman ME , Jiang G , Liu F , Miller C , Tota LM , Zhou G , Zhang X , Sountis MM , Santoprete A , Capito' E , Chicchi GG , Thornberry N , Bianchi E , Pessi A , Marsh DJ , SinhaRoy R . Glucagon‐like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58: 2258‐2266, 2009.
 335. Pohl M , Wank SA . Molecular cloning of the helodermin and exendin‐4 cDNAs in the lizard. Relationship to vasoactive intestinal polypeptide/pituitary adenylate cyclase activating polypeptide and glucagon‐like peptide 1 and evidence against the existence of mammalian homologues. J Biol Chem 273: 9778‐9784, 1998.
 336. Powell DR , Smith M , Greer J , Harris A , Zhao S , DaCosta C , Mseeh F , Shadoan MK , Sands A , Zambrowicz B , Ding ZM . LX4211 increases serum glucagon‐like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)‐mediated absorption of intestinal glucose. J Pharmacol Exp Ther 345: 250‐259, 2013.
 337. Preitner F , Burcelin R , Ibberson M , Hansotia T , Drucker D , Thorens B . Disruption of both GLP‐1 and GIP signalling pathways in the mouse leads to glucose intolerance. Diabetes 51 (Suppl 2): A66, 2002 (Ref Type: Abstract).
 338. Preitner F , Ibberson M , Franklin I , Binnert C , Pende M , Gjinovci A , Hansotia T , Drucker DJ , Wollheim C , Burcelin R , Thorens B . Gluco‐incretins control insulin secretion at multiple levels as revealed in mice lacking GLP‐1 and GIP receptors. J Clin Invest 113 (4): 635‐645, 2004.
 339. Psichas A , Larraufie PF , Goldspink DA , Gribble FM , Reimann F . Chylomicrons stimulate incretin secretion in mouse and human cells. Diabetologia 60: 2475‐2485, 2017.
 340. Pyke C , Heller RS , Kirk RK , Orskov C , Reedtz‐Runge S , Kaastrup P , Hvelplund A , Bardram L , Calatayud D , Knudsen LB . GLP‐1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 155: 1280‐1290, 2014.
 341. Pyke C , Knudsen LB . The glucagon‐like peptide‐1 receptor‐or not. Endocrinology 154: 4‐8, 2013.
 342. Qualmann C , Nauck MA , Holst JJ , Orskov C , Creutzfeldt W . Glucagon‐like peptide 1 (7‐36 amide) secretion in response to luminal sucrose from the upper and lower gut. A study using alpha‐glucosidase inhibition (acarbose). Scand J Gastroenterol 30: 892‐896, 1995.
 343. Raffort J , Lareyre F , Massalou D , Fenichel P , Panaia‐Ferrari P , Chinetti G . Insights on glicentin, a promising peptide of the proglucagon family. Biochem Med (Zagreb) 27: 308‐324, 2017.
 344. Ranganath L , Norris F , Morgan L , Wright J , Marks V . Inhibition of carbohydrate‐mediated glucagon‐like peptide‐1 (7‐36)amide secretion by circulating non‐esterified fatty acids. Clin Sci (Colch) 96: 335‐342, 1999.
 345. Ranganath LR , Beety JM , Morgan LM , Wright JW , Howland R , Marks V . Attenuated GLP‐1 secretion in obesity: cause or consequence? Gut 38: 916‐919, 1996.
 346. Rask E , Olsson T , Soderberg S , Johnson O , Seckl J , Holst JJ , Ahren B . Impaired incretin response after a mixed meal is associated with insulin resistance in nondiabetic men. Diabetes Care 24: 1640‐1645, 2001.
 347. Raufman JP , Singh L , Eng J . Exendin‐3, a novel peptide from Heloderma horridum venom, interacts with vasoactive intestinal peptide receptors and a newly described receptor on dispersed acini from guinea pig pancreas. Description of exendin‐3(9‐39) amide, a specific exendin receptor antagonist. J Biol Chem 266: 2897‐2902, 1991.
 348. Raufman JP , Singh L , Singh G , Eng J . Truncated glucagon‐like peptide‐1 interacts with exendin receptors on dispersed acini from guinea pig pancreas. Identification of a mammalian analogue of the reptilian peptide exendin‐4. J Biol Chem 267: 21432‐21437, 1992.
 349. Ravn P , Madhurantakam C , Kunze S , Matthews E , Priest C , O'Brien S , Collinson A , Papworth M , Fritsch‐Fredin M , Jermutus L , Benthem L , Gruetter M , Jackson RH . Structural and pharmacological characterization of novel potent and selective monoclonal antibody antagonists of glucose‐dependent insulinotropic polypeptide receptor. J Biol Chem 288: 19760‐19772, 2013.
 350. Rehfeld JF . Gastrointestinal hormones and insulin secretion. Scand J Gastroenterol 7: 289‐292, 1972.
 351. Reimann F , Habib AM , Tolhurst G , Parker HE , Rogers GJ , Gribble FM . Glucose sensing in L cells: a primary cell study. Cell Metab 8: 532‐539, 2008.
 352. Ripken D , van der Wielen N , Wortelboer HM , Meijerink J , Witkamp RF , Hendriks HF . Nutrient‐induced glucagon like peptide‐1 release is modulated by serotonin. J Nutr Biochem 32: 142‐150, 2016.
 353. Roberge JN , Brubaker PL . Regulation of intestinal proglucagon‐derived peptide secretion by glucose‐dependent insulinotropic peptide in a novel enteroendocrine loop. Endocrinology 133: 233‐240, 1993.
 354. Roberts GP , Kay RG , Howard J , Hardwick RH , Reimann F , Gribble FM . Gastrectomy with Roux‐en‐Y reconstruction as a lean model of bariatric surgery. Surg Obes Relat Dis 14: 562‐568, 2018.
 355. Rocca AS , Brubaker PL . Role of the vagus nerve in mediating proximal nutrient‐induced glucagon‐like peptide‐1 secretion. Endocrinology 140: 1687‐1694, 1999.
 356. Roder PV , Geillinger KE , Zietek TS , Thorens B , Koepsell H , Daniel H . The role of SGLT1 and GLUT2 in intestinal glucose transport and sensing. PLoS One 9: e89977, 2014.
 357. Rohde U , Sonne DP , Christensen M , Hansen M , Bronden A , Torang S , Rehfeld JF , Holst JJ , Vilsboll T , Knop FK . Cholecystokinin‐induced gallbladder emptying and metformin elicit additive glucagon‐like peptide‐1 responses. J Clin Endocrinol Metab 101: 2076‐2083, 2016.
 358. Ropert A , Cherbut C , Roze C , Le Quellec A , Holst JJ , Fu‐Cheng X , Bruley d V , Galmiche JP . Colonic fermentation and proximal gastric tone in humans. Gastroenterology 111: 289‐296, 1996.
 359. Rosenquist C , Fledelius C , Christgau S , Pedersen BJ , Bonde M , Qvist P , Christiansen C . Serum CrossLaps one step ELISA. First application of monoclonal antibodies for measurement in serum of bone‐related degradation products from C‐terminal telopeptides of type I collagen. Clin Chem 44: 2281‐2289, 1998.
 360. Rouille Y , Martin S , Steiner DF . Differential processing of proglucagon by the subtilisin‐like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon‐like peptide. J Biol Chem 270: 26488‐26496, 1995.
 361. Ruiz‐Grande C , Alarcon C , Alcantara A , Castilla C , Lopez NJ , Villanueva‐Penacarrillo ML , Valverde I . Renal catabolism of truncated glucagon‐like peptide 1. Horm Metab Res 25: 612‐616, 1993.
 362. Ruttimann EB , Arnold M , Hillebrand JJ , Geary N , Langhans W . Intrameal hepatic portal and intraperitoneal infusions of glucagon‐like peptide‐1 reduce spontaneous meal size in the rat via different mechanisms. Endocrinology 150: 1174‐1181, 2009.
 363. Ryan KK , Tremaroli V , Clemmensen C , Kovatcheva‐Datchary P , Myronovych A , Karns R , Wilson‐Perez HE , Sandoval DA , Kohli R , Backhed F , Seeley RJ . FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509: 183‐188, 2014.
 364. Salehi M , Gastaldelli A , D'Alessio DA . Blockade of glucagon‐like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology 146: 669‐680, 2014.
 365. Salehi M , Vahl TP , D'Alessio DA . Regulation of islet hormone release and gastric emptying by endogenous glucagon‐like peptide 1 after glucose ingestion. J Clin Endocrinol Metab 93: 4909‐4916, 2008.
 366. Saltiel MY , Kuhre RE , Christiansen CB , Eliasen R , Conde‐Frieboes KW , Rosenkilde MM , Holst JJ . Sweet taste receptor activation in the Gut is of limited importance for glucose‐stimulated GLP‐1 and GIP secretion. Nutrients 9, 2017.
 367. Samocha‐Bonet D , Chisholm DJ , Gribble FM , Coster AC , Carpenter KH , Jones GR , Holst JJ , Greenfield JR . Glycemic effects and safety of l‐Glutamine supplementation with or without sitagliptin in type 2 diabetes patients‐a randomized study. PLoS One 9: e113366, 2014.
 368. Sankoda A , Harada N , Iwasaki K , Yamane S , Murata Y , Shibue K , Thewjitcharoen Y , Suzuki K , Harada T , Kanemaru Y , Shimazu‐Kuwahara S , Hirasawa A , Inagaki N . Long‐chain free fatty acid receptor GPR120 mediates oil‐induced GIP secretion through CCK in male mice. Endocrinology 158: 1172‐1180, 2017.
 369. Saxena R , Hivert MF , Langenberg C , Tanaka T , Pankow JS , Vollenweider P , Lyssenko V , Bouatia‐Naji N , Dupuis J , Jackson AU , Kao WH , Li M , Glazer NL , Manning AK , Luan J , Stringham HM , Prokopenko I , Johnson T , Grarup N , Boesgaard TW , Lecoeur C , Shrader P , O'Connell J , Ingelsson E , Couper DJ , Rice K , Song K , Andreasen CH , Dina C , Kottgen A , Le BO , Pattou F , Taneera J , Steinthorsdottir V , Rybin D , Ardlie K , Sampson M , Qi L , van HM , Weedon MN , Aulchenko YS , Voight BF , Grallert H , Balkau B , Bergman RN , Bielinski SJ , Bonnefond A , Bonnycastle LL , Borch‐Johnsen K , Bottcher Y , Brunner E , Buchanan TA , Bumpstead SJ , Cavalcanti‐Proenca C , Charpentier G , Chen YD , Chines PS , Collins FS , Cornelis M , Crawford J , Delplanque J , Doney A , Egan JM , Erdos MR , Firmann M , Forouhi NG , Fox CS , Goodarzi MO , Graessler J , Hingorani A , Isomaa B , Jorgensen T , Kivimaki M , Kovacs P , Krohn K , Kumari M , Lauritzen T , Levy‐Marchal C , Mayor V , McAteer JB , Meyre D , Mitchell BD , Mohlke KL , Morken MA , Narisu N , Palmer CN , Pakyz R , Pascoe L , Payne F , Pearson D , Rathmann W , Sandbaek A , Sayer AA , Scott LJ , Sharp SJ , Sijbrands E , Singleton A , Siscovick DS , Smith NL , Sparso T , Swift AJ , Syddall H , Thorleifsson G , Tonjes A , Tuomi T , Tuomilehto J , Valle TT , Waeber G , Walley A , Waterworth DM , Zeggini E , Zhao JH , Illig T , Wichmann HE , Wilson JF , van DC , Hu FB , Morris AD , Frayling TM , Hattersley AT , Thorsteinsdottir U , Stefansson K , Nilsson P , Syvanen AC , Shuldiner AR , Walker M , Bornstein SR , Schwarz P , Williams GH , Nathan DM , Kuusisto J , Laakso M , Cooper C , Marmot M , Ferrucci L , Mooser V , Stumvoll M , Loos RJ , Altshuler D , Psaty BM , Rotter JI , Boerwinkle E , Hansen T , Pedersen O , Florez JC , McCarthy MI , Boehnke M , Barroso I , Sladek R , Froguel P , Meigs JB , Groop L , Wareham NJ , Watanabe RM . Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 42: 142‐148, 2010.
 370. Schauer PR , Bhatt DL , Kirwan JP , Wolski K , Aminian A , Brethauer SA , Navaneethan SD , Singh RP , Pothier CE , Nissen SE , Kashyap SR . Bariatric surgery versus intensive medical therapy for diabetes – 5‐year outcomes. N Engl J Med 376: 641‐651, 2017.
 371. Schirra J , Goke B . The physiological role of GLP‐1 in human: incretin, ileal brake or more? Regul Pept 128: 109‐115, 2005.
 372. Schirra J , Nicolaus M , Roggel R , Katschinski M , Storr M , Woerle HJ , Goke B . Endogenous glucagon‐like peptide 1 controls endocrine pancreatic secretion and antro‐pyloro‐duodenal motility in humans. Gut 55: 243‐251, 2006.
 373. Schirra J , Sturm K , Leicht P , Arnold R , Goke B , Katschinski M . Exendin(9‐39)amide is an antagonist of glucagon‐like peptide‐1(7‐36)amide in humans. J Clin Invest 101: 1421‐1430, 1998.
 374. Schmidt JB , Gregersen NT , Pedersen SD , Arentoft JL , Ritz C , Schwartz TW , Holst JJ , Astrup A , Sjodin A . Effects of PYY3‐36 and GLP‐1 on energy intake, energy expenditure, and appetite in overweight men. Am J Physiol Endocrinol Metab 306: E1248‐E1256, 2014.
 375. Schmidt JB , Pedersen SD , Gregersen NT , Vestergaard L , Nielsen MS , Ritz C , Madsbad S , Worm D , Hansen DL , Clausen TR , Rehfeld JF , Astrup A , Holst JJ , Sjodin A . Effects of RYGB on energy expenditure, appetite and glycaemic control: a randomized controlled clinical trial. Int J Obes (Lond) 40: 281‐290, 2016.
 376. Schmidt P , Rasmussen TN , Holst JJ . Release of immunoreactive somatostatin, vasoactive intestinal polypeptide (VIP), and galanin during propulsive complexes in isolated pig ileum. Peptides 14: 215‐220, 1993.
 377. Schmidt PT , Ljung T , Hartmann B , Hare KJ , Holst JJ , Hellstrom PM . Tissue levels and post‐prandial secretion of the intestinal growth factor, glucagon‐like peptide‐2, in controls and inflammatory bowel disease: comparison with peptide YY. Eur J Gastroenterol Hepatol 17: 207‐212, 2005.
 378. Schmidt PT , Rickelt LF , Holst JJ . Tachykinins stimulate release of peptide hormones (glucagon‐like peptide‐1) and paracrine (somatostatin) and neurotransmitter (vasoactive intestinal polypeptide) from porcine ileum through NK‐1 receptors. Dig Dis Sci 44: 1273‐1281, 1999.
 379. Schmidt WE , Siegel EG , Creutzfeldt W . Glucagon‐like peptide‐1 but not glucagon‐like peptide‐2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia 28: 704‐707, 1985.
 380. Schubert MM , Sabapathy S , Leveritt M , Desbrow B . Acute exercise and hormones related to appetite regulation: a meta‐analysis. Sports Med 44: 387‐403, 2014.
 381. Schwartz TW , Holst JJ , Fahrenkrug J , Jensen SL , Nielsen OV , Rehfeld JF , de Muckadell OB , Stadil F . Vagal, cholinergic regulation of pancreatic polypeptide secretion. J Clin Invest 61: 781‐789, 1978.
 382. Scrocchi LA , Brown TJ , MaClusky N , Brubaker PL , Auerbach AB , Joyner AL , Drucker DJ . Glucose intolerance but normal satiety in mice with a null mutation in the glucagon‐like peptide 1 receptor gene. Nat Med 2: 1254‐1258, 1996.
 383. Secher A , Jelsing J , Baquero AF , Hecksher‐Sorensen J , Cowley MA , Dalboge LS , Hansen G , Grove KL , Pyke C , Raun K , Schaffer L , Tang‐Christensen M , Verma S , Witgen BM , Vrang N , Bjerre KL . The arcuate nucleus mediates GLP‐1 receptor agonist liraglutide‐dependent weight loss. J Clin Invest 124: 4473‐4488, 2014.
 384. Seferovic PM , Petrie MC , Filippatos GS , Anker SD , Rosano G , Bauersachs J , Paulus WJ , Komajda M , Cosentino F , de Boer RA , Farmakis D , Doehner W , Lambrinou E , Lopatin Y , Piepoli MF , Theodorakis MJ , Wiggers H , Lekakis J , Mebazaa A , Mamas MA , Tschope C , Hoes AW , Seferovic JP , Logue J , McDonagh T , Riley JP , Milinkovic I , Polovina M , van Veldhuisen DJ , Lainscak M , Maggioni AP , Ruschitzka F , McMurray JJV . Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 20 (5): 853‐872, 2018.
 385. Seghieri M , Rebelos E , Gastaldelli A , Astiarraga BD , Casolaro A , Barsotti E , Pocai A , Nauck M , Muscelli E , Ferrannini E . Direct effect of GLP‐1 infusion on endogenous glucose production in humans. Diabetologia 56: 156‐161, 2013.
 386. Serre V , Dolci W , Schaerer E , Scrocchi L , Drucker D , Efrat S , Thorens B . Exendin‐(9‐39) is an inverse agonist of the murine glucagon‐like peptide‐1 receptor: implications for basal intracellular cyclic adenosine 3',5'‐monophosphate levels and beta‐cell glucose competence [In Process Citation]. Endocrinology 139: 4448‐4454, 1998.
 387. Shi YC , Loh K , Bensellam M , Lee K , Zhai L , Lau J , Cantley J , Luzuriaga J , Laybutt DR , Herzog H . Pancreatic PYY is critical in the control of insulin secretion and glucose homeostasis in female mice. Endocrinology 156: 3122‐3136, 2015.
 388. Shimotoyodome A , Fukuoka D , Suzuki J , Fujii Y , Mizuno T , Meguro S , Tokimitsu I , Hase T . Coingestion of acylglycerols differentially affects glucose‐induced insulin secretion via glucose‐dependent insulinotropic polypeptide in C57BL/6J mice. Endocrinology 150: 2118‐2126, 2009.
 389. Sisley S , Gutierrez‐Aguilar R , Scott M , D'Alessio DA , Sandoval DA , Seeley RJ . Neuronal GLP1R mediates liraglutide's anorectic but not glucose‐lowering effect. J Clin Invest 124: 2456‐2463, 2014.
 390. Sjoberg KA , Holst JJ , Rattigan S , Richter EA , Kiens B . GLP‐1 increases microvascular recruitment but not glucose uptake in human and rat skeletal muscle. Am J Physiol Endocrinol Metab 306: E355‐E362, 2014.
 391. Sjoberg KA , Rattigan S , Jeppesen JF , Lundsgaard AM , Holst JJ , Kiens B . Differential effects of glucagon‐like peptide‐1 on microvascular recruitment and glucose metabolism in short‐ and long‐term insulin resistance. J Physiol 593: 2185‐2198, 2015.
 392. Sjolund K , Sanden G , Hakanson R , Sundler F . Endocrine cells in human intestine: an immunocytochemical study. Gastroenterology 85: 1120‐1130, 1983.
 393. Skak‐Nielsen T , Holst JJ , Baldissera FG , Poulsen SS . Localization in the gastrointestinal tract of immunoreactive prosomatostatin. Regul Pept 19: 183‐195, 1987.
 394. Skov J , Dejgaard A , Frokiaer J , Holst JJ , Jonassen T , Rittig S , Christiansen JS . Glucagon‐like peptide‐1 (GLP‐1): effect on kidney hemodynamics and renin‐angiotensin‐aldosterone system in healthy men. J Clin Endocrinol Metab 98: E664‐E671, 2013.
 395. Sloth B , Holst JJ , Flint A , Gregersen NT , Astrup A . Effects of PYY1‐36 and PYY3‐36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects. Am J Physiol Endocrinol Metab 292: E1062‐E1068, 2007.
 396. Sparre‐Ulrich AH , Gabe MN , Gasbjerg LS , Christiansen CB , Svendsen B , Hartmann B , Holst JJ , Rosenkilde MM . GIP(3‐30)NH2 is a potent competitive antagonist of the GIP receptor and effectively inhibits GIP‐mediated insulin, glucagon, and somatostatin release. Biochem Pharmacol 131: 78‐88, 2017.
 397. Sparre‐Ulrich AH , Hansen LS , Svendsen B , Christensen M , Knop FK , Hartmann B , Holst JJ , Rosenkilde MM . Species‐specific action of (Pro3). Br J Pharmacol 173: 27‐38, 2016.
 398. Steiner DF , Patzelt C , Chan SJ , Quinn PS , Tager HS , Nielsen D , Lernmark A , Noyes BE , Agarwal KL , Gabbay KH , Rubenstein AH . Formation of biologically active peptides. Proc R Soc Lond B Biol Sci 210: 45‐59, 1980.
 399. Steiner DF , Smeekens SP , Ohagi S , Chan SJ . The new enzymology of precursor processing endoproteases. J Biol Chem 267: 23435‐23438, 1992.
 400. Steinert RE , Feinle‐Bisset C , Asarian L , Horowitz M , Beglinger C , Geary N . Ghrelin, CCK, GLP‐1, and PYY(3‐36): secretory controls and physiological roles in eating and glycemia in health, obesity, and after RYGB. Physiol Rev 97: 411‐463, 2017.
 401. Steinert RE , Gerspach AC , Gutmann H , Asarian L , Drewe J , Beglinger C . The functional involvement of gut‐expressed sweet taste receptors in glucose‐stimulated secretion of glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY). Clin Nutr 30: 524‐532, 2011.
 402. Sundstrom L , Myhre S , Sundqvist M , Ahnmark A , McCoull W , Raubo P , Groombridge SD , Polla M , Nystrom AC , Kristensson L , Nagard M , Winzell MS . The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon‐like peptide 1. PLoS One 12: e0189060, 2017.
 403. Svane MS , Bojsen‐Moller KN , Nielsen S , Jorgensen NB , Dirksen C , Bendtsen F , Kristiansen VB , Hartmann B , Holst JJ , Madsbad S . Effects of endogenous GLP‐1 and GIP on glucose tolerance after Roux‐en‐Y gastric bypass surgery. Am J Physiol Endocrinol Metab 310: E505‐E514, 2016.
 404. Svane MS , Jorgensen NB , Bojsen‐Moller KN , Dirksen C , Nielsen S , Kristiansen VB , Torang S , Wewer Albrechtsen NJ , Rehfeld JF , Hartmann B , Madsbad S , Holst JJ . Peptide YY and glucagon‐like peptide‐1 contribute to decreased food intake after Roux‐en‐Y gastric bypass surgery. Int J Obes (Lond) 40: 1699‐1706, 2016.
 405. Svendsen B , Holst JJ . Regulation of gut hormone secretion. Studies using isolated perfused intestines. Peptides 77: 47‐53, 2016.
 406. Svendsen B , Larsen O , Gabe MBN , Christiansen CB , Rosenkilde MM , Drucker DJ , Holst JJ . Insulin secretion depends on intra‐islet glucagon signaling. Cell Rep 25: 1127‐1134, 2018.
 407. Svendsen B , Pais R , Engelstoft MS , Milev NB , Richards P , Christiansen CB , Habib A , Egerod KL , Jensen SM , Gribble F , Schwartz TW , Reimann F , Holst JJ . GLP1 and GIP cells rarely overlap and differ by bombesin receptor‐2 expression and responsiveness. J Endocrinol 228: 39‐48, 2015.
 408. Svendsen B , Pedersen J , Albrechtsen NJ , Hartmann B , Torang S , Rehfeld JF , Poulsen SS , Holst JJ . An analysis of cosecretion and coexpression of gut hormones from male rat proximal and distal small intestine. Endocrinology 156: 847‐857, 2015.
 409. Takebayashi K , Inukai T . Effect of sodium glucose cotransporter 2 inhibitors with low SGLT2/SGLT1 selectivity on circulating glucagon‐like peptide 1 levels in type 2 diabetes mellitus. J Clin Med Res 9: 745‐753, 2017.
 410. Takeda J , Seino Y , Tanaka K , Fukumoto H , Kayano T , Takahashi H , Mitani T , Kurono M , Suzuki T , Tobe T . Sequence of an intestinal cDNA encoding human gastric inhibitory polypeptide precursor. Proc Natl Acad Sci U S A 84: 7005‐7008, 1987.
 411. Ten Kulve JS , Veltman DJ , van BL , Barkhof F , Deacon CF , Holst JJ , Konrad RJ , Sloan JH , Drent ML , Diamant M , IJzerman RG . Endogenous GLP‐1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes. Diabetologia 58: 2688‐2698, 2015.
 412. Tharakan G , Behary P , Wewer Albrechtsen NJ , Chahal H , Kenkre J , Miras AD , Ahmed AR , Holst JJ , Bloom SR , Tan T . Roles of increased glycaemic variability, GLP‐1 and glucagon in hypoglycaemia after Roux‐en‐Y gastric bypass. Eur J Endocrinol 177: 455‐464, 2017.
 413. Thomsen C , Rasmussen O , Lousen T , Holst JJ , Fenselau S , Schrezenmeir J , Hermansen K . Differential effects of saturated and monounsaturated fatty acids on postprandial lipemia and incretin responses in healthy subjects. Am J Clin Nutr 69: 1135‐1143, 1999.
 414. Thorens B . Expression cloning of the pancreatic beta cell receptor for the gluco‐incretin hormone glucagon‐like peptide 1. Proc Natl Acad Sci USA 89: 8641‐8645, 1992.
 415. Thorens B , Porret A , Buhler L , Deng SP , Morel P , Widmann C . Cloning and functional expression of the human islet GLP‐1 receptor. Demonstration that exendin‐4 is an agonist and exendin‐(9‐39) an antagonist of the receptor. Diabetes 42: 1678‐1682, 1993.
 416. Tiengo A , Bessioud M , Valverde I , Tabbi‐Anneni A , Delprato S , Alexandre J , Assan R . Absence of islet alpha cell function in pancreatectomized patients. Diabetologia 22: 25‐32, 1982.
 417. Toft‐Nielsen M , Madsbad S , Holst JJ . The effect of glucagon‐like peptide I (GLP‐I) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones. Diabetes 45: 552‐556, 1996.
 418. Toft‐Nielsen M , Madsbad S , Holst JJ . Exaggerated secretion of glucagon‐like peptide‐1 (GLP‐1) could cause reactive hypoglycaemia. Diabetologia 41: 1180‐1186, 1998.
 419. Toft‐Nielsen MB , Damholt MB , Madsbad S , Hilsted LM , Hughes TE , Michelsen BK , Holst JJ . Determinants of the impaired secretion of glucagon‐like peptide‐1 in type 2 diabetic patients. J Clin Endocrinol Metab 86: 3717‐3723, 2001.
 420. Toft‐Nielsen MB , Madsbad S , Holst JJ . Determinants of the effectiveness of glucagon‐like peptide‐1 in type 2 diabetes. J Clin Endocrinol Metab 86: 3853‐3860, 2001.
 421. Torekov SS , Harslof T , Rejnmark L , Eiken P , Jensen JB , Herman AP , Hansen T , Pedersen O , Holst JJ , Langdahl BL . A functional amino acid substitution in the glucose‐dependent insulinotropic polypeptide receptor (GIPR) gene is associated with lower bone mineral density and increased fracture risk. J Clin Endocrinol Metab 99: E729‐E733, 2014.
 422. Trahair LG , Horowitz M , Rayner CK , Gentilcore D , Lange K , Wishart JM , Jones KL . Comparative effects of variations in duodenal glucose load on glycemic, insulinemic, and incretin responses in healthy young and older subjects. J Clin Endocrinol Metab 97: 844‐851, 2012.
 423. Traub S , Meier DT , Schulze F , Dror E , Nordmann TM , Goetz N , Koch N , Dalmas E , Stawiski M , Makshana V , Thorel F , Herrera PL , Boni‐Schnetzler M , Donath MY . Pancreatic alpha cell‐derived glucagon‐related peptides are required for beta cell adaptation and glucose homeostasis. Cell Rep 18: 3192‐3203, 2017.
 424. Tsukiyama K , Yamada Y , Yamada C , Harada N , Kawasaki Y , Ogura M , Bessho K , Li M , Amizuka N , Sato M , Udagawa N , Takahashi N , Tanaka K , Oiso Y , Seino Y . Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion. Mol Endocrinol 20: 1644‐1651, 2006.
 425. Ugleholdt R , Pedersen J , Bassi MR , Fuchtbauer EM , Jorgensen SM , Kissow HL , Nytofte N , Poulsen SS , Rosenkilde MM , Seino Y , Thams P , Holst PJ , Holst JJ . Transgenic rescue of adipocyte glucose‐dependent insulinotropic polypeptide receptor expression restores high fat diet‐induced body weight gain. J Biol Chem 286: 44632‐44645, 2011.
 426. Ugleholdt R , Poulsen ML , Holst PJ , Irminger JC , Orskov C , Pedersen J , Rosenkilde MM , Zhu X , Steiner DF , Holst JJ . Prohormone convertase 1/3 is essential for processing of the glucose‐dependent insulinotropic polypeptide precursor. J Biol Chem 281: 11050‐11057, 2006.
 427. Vaag AA , Holst JJ , Volund A , Beck‐Nielsen HB . Gut incretin hormones in identical twins discordant for non‐ insulin‐ dependent diabetes mellitus (NIDDM)‐‐evidence for decreased glucagon‐ like peptide 1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol 135: 425‐432, 1996.
 428. Vahl TP , Drazen DL , Seeley RJ , D'Alessio DA , Woods SC . Meal‐anticipatory glucagon‐like peptide‐1 secretion in rats. Endocrinology 151: 569‐575, 2010.
 429. van der Beek CM , Canfora EE , Lenaerts K , Troost FJ , Olde Damink SWM , Holst JJ , Masclee AA , Dejong CH , Blaak EE . Distal, not proximal, colonic acetate infusions promote fat oxidation and improve metabolic markers in overweight/obese men. Clin Sci (Lond) 130: 2073‐2082, 2016.
 430. Vardarli I , Arndt E , Deacon CF , Holst JJ , Nauck MA . Effects of sitagliptin and metformin treatment on incretin hormone and insulin secretory responses to oral and “isoglycemic” intravenous glucose. Diabetes 63: 663‐674, 2014.
 431. Varndell IM , Bishop AE , Sikri KL , Uttenthal LO , Bloom SR , Polak JM . Localization of glucagon‐like peptide (GLP) immunoreactants in human gut and pancreas using light and electron microscopic immunocytochemistry. J Histochem Cytochem 33: 1080‐1086, 1985.
 432. Veedfald S , Plamboeck A , Deacon CF , Hartmann B , Knop FK , Vilsboll T , Holst JJ . Cephalic phase secretion of insulin and other enteropancreatic hormones in humans. Am J Physiol Gastrointest Liver Physiol 310: G43‐G51, 2016.
 433. Veedfald S , Wu T , Bound M , Grivell J , Hartmann B , Rehfeld JF , Deacon CF , Horowitz M , Holst JJ , Rayner CK . Hyperosmolar duodenal saline infusion lowers circulating ghrelin and stimulates intestinal hormone release in young men. J Clin Endocrinol Metab 103: 4409‐4418, 2018.
 434. Verdich C , Toubro S , Buemann B , Lysgard MJ , Juul HJ , Astrup A . The role of postprandial releases of insulin and incretin hormones in meal‐induced satiety‐effect of obesity and weight reduction. Int J Obes Relat Metab Disord 25: 1206‐1214, 2001.
 435. Vilsboll T , Agerso H , Krarup T , Holst JJ . Similar elimination rates of glucagon‐like peptide‐1 in obese type 2 diabetic patients and healthy subjects. J Clin Endocrinol Metab 88: 220‐224, 2003.
 436. Vilsboll T , Agerso H , Lauritsen T , Deacon CF , Aaboe K , Madsbad S , Krarup T , Holst JJ . The elimination rates of intact GIP as well as its primary metabolite, GIP 3‐42, are similar in type 2 diabetic patients and healthy subjects. Regul Pept 137: 168‐172, 2006.
 437. Vilsboll T , Knop FK , Krarup T , Johansen A , Madsbad S , Larsen S , Hansen T , Pedersen O , Holst JJ . The pathophysiology of diabetes involves a defective amplification of the late‐phase insulin response to glucose by glucose‐dependent insulinotropic polypeptide‐regardless of etiology and phenotype. J Clin Endocrinol Metab 88: 4897‐4903, 2003.
 438. Vilsboll T , Krarup T , Deacon CF , Madsbad S , Holst JJ . Reduced postprandial concentrations of intact biologically active glucagon‐like peptide 1 in type 2 diabetic patients. Diabetes 50: 609‐613, 2001.
 439. Vilsboll T , Krarup T , Madsbad S , Holst JJ . No reactive hypoglycaemia in Type 2 diabetic patients after subcutaneous administration of GLP‐1 and intravenous glucose. Diabet Med 18: 144‐149, 2001.
 440. Vilsboll T , Krarup T , Madsbad S , Holst JJ . Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia 45: 1111‐1119, 2002.
 441. Vilsboll T , Krarup T , Madsbad S , Holst JJ . Both GLP‐1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept 114: 115‐121, 2003.
 442. Vilsboll T , Krarup T , Sonne J , Madsbad S , Volund A , Juul AG , Holst JJ . Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. J Clin Endocrinol Metab 88: 2706‐2713, 2003.
 443. Waget A , Cabou C , Masseboeuf M , Cattan P , Armanet M , Karaca M , Castel J , Garret C , Payros G , Maida A , Sulpice T , Holst JJ , Drucker DJ , Magnan C , Burcelin R . Physiological and pharmacological mechanisms through which the DPP‐4 inhibitor sitagliptin regulates glycemia in mice. Endocrinology 152: 3018‐3029, 2011.
 444. Wang N , Zhang JP , Xing XY , Yang ZJ , Zhang B , Wang X , Yang WY . Associations between changes in glucagon‐like peptide‐1 and bodyweight reduction in patients receiving acarbose or metformin treatment. J Diabetes 9: 728‐737, 2017.
 445. Wang S , Oestricker LZ , Wallendorf MJ , Sterl K , Dunai J , Kilpatrick CR , Patterson BW , Reeds DN , Wice BM . Cholinergic signaling mediates the effects of xenin‐25 on secretion of pancreatic polypeptide but not insulin or glucagon in humans with impaired glucose tolerance. PLoS One 13: e0192441, 2018.
 446. Wasada T , McCorkle K , Harris V , Kawai K , Howard B , Unger RH . Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs. J Clin Invest 68: 1106‐1107, 1981.
 447. Wettergren A , Maina P , Boesby S , Holst JJ . Glucagon‐like peptide‐1 7‐36 amide and peptide YY have additive inhibitory effect on gastric acid secretion in man. Scand J Gastroenterol 32: 552‐555, 1997.
 448. Wettergren A , Petersen H , Orskov C , Christiansen J , Sheikh SP , Holst JJ . Glucagon‐like peptide‐1 7‐36 amide and peptide YY from the L‐ cell of the ileal mucosa are potent inhibitors of vagally induced gastric acid secretion in man. Scand J Gastroenterol 29: 501‐505, 1994.
 449. Wettergren A , Pridal L , Wojdemann M , Holst JJ . Amidated and non‐amidated glucagon‐like peptide‐1 (GLP‐1): non‐pancreatic effects (cephalic phase acid secretion) and stability in plasma in humans. Regul Pept 77: 83‐87, 1998.
 450. Wettergren A , Wojdemann M , Holst JJ . Glucagon‐like peptide‐1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol 275: G984‐G992, 1998.
 451. Wettergren A , Wojdemann M , Holst JJ . The inhibitory effect of glucagon‐like peptide‐1 (7‐36)amide on antral motility is antagonized by its N‐terminally truncated primary metabolite GLP‐1 (9‐36)amide [In Process Citation]. Peptides 19: 877‐882, 1998.
 452. Wewer Albrechtsen NJ , Asmar A , Jensen F , Torang S , Simonsen L , Kuhre RE , Asmar M , Veedfald S , Plamboeck A , Knop FK , Vilsboll T , Madsbad S , Nauck MA , Deacon CF , Bulow J , Holst JJ , Hartmann B . A sandwich ELISA for measurement of the primary glucagon‐like peptide‐1 metabolite. Am J Physiol Endocrinol Metab 313: E284‐E291, 2017.
 453. Wewer Albrechtsen NJ , Hornburg D , Albrechtsen R , Svendsen B , Torang S , Jepsen SL , Kuhre RE , Hansen M , Janus C , Floyd A , Lund A , Vilsboll T , Knop FK , Vestergaard H , Deacon CF , Meissner F , Mann M , Holst JJ , Hartmann B . Oxyntomodulin identified as a marker of Type 2 diabetes and gastric bypass surgery by mass‐spectrometry based profiling of human plasma. EBioMedicine 7: 112‐120, 2016.
 454. Wewer Albrechtsen NJ , Kuhre RE , Hornburg D , Jensen CZ , Hornum M , Dirksen C , Svane M , Gasbjerg LS , Jorgensen NB , Gabe MN , Balk‐Moller E , Albrechtsen R , Winther‐Sorensen M , Galsgaard KD , Meissner F , Jorsal T , Lund A , Vilsboll T , Eliasen R , Bojsen‐Moller KN , Idorn T , Deacon CF , Knop FK , Rosenkilde MM , Hartmann B , Feldt‐Rasmussen B , Mann M , Madsbad S , Holst JJ . Circulating glucagon 1‐61 regulates blood glucose by increasing insulin secretion and hepatic glucose production. Cell Rep 21: 1452‐1460, 2017.
 455. Wewer Albrechtsen NJ , Kuhre RE , Pedersen J , Knop FK , Holst JJ . The biology of glucagon and the consequences of hyperglucagonemia. Biomark Med 10: 1141‐1151, 2016.
 456. Whalley NM , Pritchard LE , Smith DM , White A . Processing of proglucagon to GLP‐1 in pancreatic alpha‐cells: is this a paracrine mechanism enabling GLP‐1 to act on beta‐cells? J Endocrinol 211: 99‐106, 2011.
 457. Wideman RD , Yu IL , Webber TD , Verchere CB , Johnson JD , Cheung AT , Kieffer TJ . Improving function and survival of pancreatic islets by endogenous production of glucagon‐like peptide 1 (GLP‐1). Proc Natl Acad Sci USA 103: 13468‐13473, 2006.
 458. Widmann C , Dolci W , Thorens B . Internalization and homologous desensitization of the GLP‐1 receptor depend on phosphorylation of the receptor carboxyl tail at the same three sites. Mol Endocrinol 11: 1094‐1102, 1997.
 459. Willard JR , Barrow BM , Zraika S . Improved glycaemia in high‐fat‐fed neprilysin‐deficient mice is associated with reduced DPP‐4 activity and increased active GLP‐1 levels. Diabetologia 60: 701‐708, 2017.
 460. Wilson ME , Kalamaras JA , German MS . Expression pattern of IAPP and prohormone convertase 1/3 reveals a distinctive set of endocrine cells in the embryonic pancreas. Mech Dev 115: 171‐176, 2002.
 461. Windelov JA , Wewer Albrechtsen NJ , Kuhre RE , Jepsen SL , Hornburg D , Pedersen J , Jensen EP , Galsgaard KD , Winther‐Sorensen M , Orgaard A , Deacon CF , Mann M , Kissow H , Hartmann B , Holst JJ . Why is it so difficult to measure glucagon‐like peptide‐1 in a mouse? Diabetologia 60: 2066‐2075, 2017.
 462. Wynne K , Park AJ , Small CJ , Patterson M , Ellis SM , Murphy KG , Wren AM , Frost GS , Meeran K , Ghatei MA , Bloom SR . Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double‐blind, randomized, controlled trial. Diabetes 54: 2390‐2395, 2005.
 463. Xie D , Cheng H , Hamrick M , Zhong Q , Ding KH , Correa D , Williams S , Mulloy A , Bollag W , Bollag RJ , Runner RR , McPherson JC , Insogna K , Isales CM . Glucose‐dependent insulinotropic polypeptide receptor knockout mice have altered bone turnover. Bone 37: 759‐769, 2005.
 464. Xu G , Kaneto H , Laybutt DR , Duvivier‐Kali VF , Trivedi N , Suzuma K , King GL , Weir GC , Bonner‐Weir S . Downregulation of GLP‐1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes. Diabetes 56: 1551‐1558, 2007.
 465. Yamada Y , Seino Y . Physiology of GIP – a lesson from GIP receptor knockout mice. Horm Metab Res 36: 771‐774, 2004.
 466. Yanagimachi T , Fujita Y , Takeda Y , Honjo J , Atageldiyeva KK , Takiyama Y , Abiko A , Makino Y , Kieffer TJ , Haneda M . Pancreatic glucose‐dependent insulinotropic polypeptide (GIP) (1‐30) expression is upregulated in diabetes and PEGylated GIP(1‐30) can suppress the progression of low‐dose‐STZ‐induced hyperglycaemia in mice. Diabetologia 59: 533‐541, 2016.
 467. Yasuda N , Inoue T , Nagakura T , Yamazaki K , Kira K , Saeki T , Tanaka I . Enhanced secretion of glucagon‐like peptide 1 by biguanide compounds. Biochem Biophys Res Commun 298: 779‐784, 2002.
 468. Yusta B , Baggio LL , Koehler J , Holland D , Cao X , Pinnell LJ , Johnson‐Henry KC , Yeung W , Surette MG , Bang KW , Sherman PM , Drucker DJ . GLP‐1R agonists modulate enteric immune responses through the intestinal intraepithelial lymphocyte GLP‐1R. Diabetes 64: 2537‐2549, 2015.
 469. Zander M , Madsbad S , Deacon CF , Holst JJ . The metabolite generated by dipeptidyl‐peptidase 4 metabolism of glucagon‐like peptide‐1 has no influence on plasma glucose levels in patients with type 2 diabetes. Diabetologia 49: 369‐374, 2006.
 470. Zhong Q , Itokawa T , Sridhar S , Ding KH , Xie D , Kang B , Bollag WB , Bollag RJ , Hamrick M , Insogna K , Isales CM . Effects of glucose‐dependent insulinotropic peptide on osteoclast function. Am J Physiol Endocrinol Metab 292: E543‐E548, 2007.
 471. Zunz E , LaBarre J . Contributions a l'etude des variation physiologiques de la secretion interne de pancreas: relations entre les secretions externe et interne du pancreas. Archs Int Physiol Biochim 31: 20‐44, 1929.

 

Teaching Material

J. J. Holst, N. J. Wewer Albrechtsen, M. M. Rosenkilde, C. F. Deacon. Physiology of the Incretin Hormones, GIP and GLP-1—Regulation of Release and Posttranslational Modifications.Compr Physiol 9: 2019, 1339-1381.

Didactic Synopsis

Major Teaching Points:

  • GLP-1 and GIP are important incretin hormones, responsible for a major part of postprandial insulin secretion and, therefore, for glucose tolerance.
  • The insulinotropic action of GLP-1 is preserved in type 2 diabetes (T2DM), while that of GIP is lost. GLP-1 receptor agonists are, therefore, utilized for T2DM treatment.
  • Because of their (patho)physiological role, knowledge of their secretion and metabolism is important.
  • Their secretion is mainly prandial, and all macronutrients stimulate their secretion, often secondary to their absorption.
  • Studies of their physiological role in metabolism are greatly facilitated by the use of receptor antagonists, exendin 9-39 for the GLP-1 receptor and, more recently, GIP 3-30amide for the GIP receptor.
  • Both hormones are rapidly metabolized by the ubiquitous enzyme, dipeptidyl peptidase-4, which truncates and inactivates the peptides.
  • The extremely rapid degradation of GLP-1 suggests that the endogenous peptide mainly acts via neuronal signaling.
  • Inhibitors of DPP-4 significantly enhance the survival of GIP and GLP-1 and are used to treat T2DM.
  • Incretin hormone posttranslational processing and their metabolism create considerable molecular heterogeneity, which not only impacts upon their spectrum of biological activities, but also complicates their measurement in plasma.
  • In general, secretion is best studied using assays that codetermine the intact hormone as well as any metabolites (total hormone levels).

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1 The incretin effect and its impairment in type 2 diabetes. Patients with type 2 diabetes and matched healthy controls received 50 g of glucose orally (black circles). On a subsequent day, they received an intravenous infusion of glucose (white circles), which was adjusted so that the plasma glucose concentrations were similar to those obtained on the day with the oral glucose administration. Subsequently, insulin and C-peptide concentrations were measured in peripheral blood. Asterisks indicate significant (p < 0.05) differences. Didactic explanation. The figure illustrates the classical method of investigating the incretin effect: isoglycemic oral and intravenous glucose administration. In the control subjects, much more insulin is secreted during the oral compared to the intravenous administration. The difference is the incretin effect. C-peptide measurements show about the same difference between oral and intravenous glucose, but the changes are more accurately related to the actual insulin secretion rate, since C-peptide is not extracted in the liver. In the people with type 2 diabetes, the differences between responses to oral and intravenous glucose are much smaller, and for C-peptide, the difference is not significant. This indicates the lack of incretin effect. From Nauck et al. (290).

Figure 2 A schematic representation of the differential processing of proglucagon in the pancreas and in the intestine. The numbers refer to the numbering of the amino acid residues of proglucagon, counting from the N-terminus. GRPP, Glicentin-related pancreatic polypeptide; IP-1, intervening peptide-1; IP-2, intervening peptide-2. GLP-1 (glucagon-like peptide-1) thus corresponds to proglucagon 78-107NH2 (meaning that its carboxyterminus is amidated). Didatic explanation. It is seen that in the (human) pancreas, proglucagon is cleaved (by the prohormone convertase PC-2) to the pancreatic glicentin-related peptide (GRPP) corresponding to proglucagon (PG) 1-30; glucagon (PG 33-61); a small intervening peptide; and the major proglucagon fragment (MPF) consisting of amino acid residues PG 72-158. In the gut, the processing products (PC1/3) are glicentin (PG1-69), about 1/3 is processed further to GRPP and oxyntomodulin (PG 33-69); GLP-1 (PG 78-107amide) and GLP-2 (PG 126-158) (the missing amino acids are cleaved off by the processing enzymes).

Figure 3 Healthy subjects were given glucose orally with or without a concomitant infusion of exendin 9-39, and had insulin and glucagon concentrations measured in their peripheral blood. Didactic explanation. During exendin infusions, insulin and C-peptide responses to glucose were clearly reduced, whereas glucagon responses increased. The interpretation is that GLP-1 secreted from the gut in response to glucose normally acts to enhance insulin secretion but also to inhibit glucagon secretion, and that both responses are prevented or even reversed by exendin 9-39. From Salehi et al. (367).

Figure 4 Total GLP-1 responses to a mixed meal (538 kcal) in 54 patients with type 2 diabetes (HbA1c 8.4%—black circles), 33 matched controls with normal glucose tolerance (white circles), and 15 subjects with impaired glucose tolerance (white squares). Asterisks indicate significant differences between patients and controls. Didactic explanation. The study shows that in these cohorts of patients and controls (which were carefully matched for body weight, age, and gender), there was a significantly impaired GLP-1 response to the mixed meal in the patients with T2DM. Interestingly, the fasting concentrations in the patients were significantly higher than that of the other groups, and it is clear that the impaired response occurs rather late, with the curves separating around 1 h after meal intake. Note the tendency to a rise already after 10 min. A biphasic response has been mentioned in the literature, but clearly is not seen here. The figure shows “total GLP-1” responses (see text for explanation). In younger and leaner populations, greater meal responses may be seen (322). From Toft-Nielsen et al. (422).

Figure 5 Glucose absorption and GLP-1 secretion from isolated perfused rat upper small intestine. (A) Effluent concentrations of glucose (blue) and GLP-1 (black) during brief luminal administration of a 20% glucose solution in saline. Bombesin (BBS), a Gq-activating ligand of the bombesin 2 receptor, was infused toward the end of the experiment as a positive control. (B) Correlation between GLP-1 and glucose concentrations in the venous effluent. (C and D) Responses to repeated stimulations with 20% glucose. (D and F) Effect of the SGLT-1 inhibitor, phloridzin, on GLP-1 responses to glucose. Didactic explanation. The experiments illustrate the effect of luminal administration of glucose on the secretion of GLP-1 from the gut. The gut preparation also absorbs the luminal glucose load, measured as increasing glucose concentrations in the venous effluent from the perfused segment. Not only are GLP-1 secretion and glucose absorption highly correlated (panel B), but the powerful sodium-glucose cotransporter (SGLT-1) inhibitor, phloridzin, nearly completely blocked the GLP-1 response. This indicates that the glucose absorption is required for GLP-1 secretion, and suggests that it is the glucose entry into the L-cell that is responsible for stimulation of secretion. Further details may be found in Kuhre et al. (230).

Figure 6 Diagrammatic representation of the gastrointestinal anatomy after a Roux-en-Y gastric bypass operation. Didactic explanation. Importantly, the gastric pouch is very small (~30 mL), which means that there is no reservoir for retention of food, which therefore passes directly on to a more distal segment of the small intestine. The so-called alimentary limb draining the pouch does not receive any of the digestive secretions (bile, gastric, and pancreatic secretion) and, therefore, depends entirely on its brush-border enzymes for digestive capacity. Digestion requiring the digestive secretions can only begin distal to the entero-entero-anastomosis between the secretory limb and the alimentary limb, together forming the “common limb,” but this where the density of, for instance, the L-cells is high.

Figure 7 A diagrammatic representation of the degradation of GLP-1 by dipeptidyl peptidase-4 (DPP-4). Didactic explanation. The figure shows a (very enlarged) intestinal villus with a single yellow open type L-cell. Newly secreted GLP-1 is indicated by black dots. Upon stimulation, GLP-1 is released by exocytosis and diffuses across the lamina propria of the mucosa until it finds and enters a capillary. Here, the GLP-1 molecules meet DPP-4 expressed on the luminal surface of the endothelial cells lining the capillary. As a result, only about 33%-25% of what leaves the gut remains in the intact form. In the liver, there is also the DPP-4 activity degrading about half of what the liver receives. This means that only about 10%-15% of what was released makes it to the systemic circulation in the intact form. In plasma, there is soluble DPP-4 causing further degradation, and it has been calculated that only about 8% of what was originally released reaches the target organs (e.g. the pancreas) in the intact form (170).

Figure 8 Degradation of GLP-1 by DPP-4. (A) DPP-4 mediated degradation of the GLP-1 molecule. The diagram shows that the enzyme cleaves off the two N-terminal amino acids leaving the inactive metabolite, GLP-1 9-36/37, and that this occurs rapidly (resulting in a plasma half-life in humans of about 2 min) and with a high plasma clearance. If DPP-4 is blocked, it can be determined that the kidneys alone are responsible for a high plasma clearance, resulting in a plasma half-life of 4-5 min. (B) Concentrations in plasma of intact GLP-1 and total GLP-1 (intact GLP-1 7-36amide + the metabolite GLP-1 9-36amide) after i.v. injection of the maximally tolerated dose of GLP-1 (1.5 nmol/kg) in patients with type 2 diabetes. In spite of the high dose injected, very little GLP-1 survives in the intact form (from Deacon et al. (83)).

Figure 9 An alternative signaling pathway for GLP-1 via sensory afferent of the vagus nerve. Didactic explanation. Confer with Figure 7. During the diffusion across the lamina propria, newly secreted GLP-1, which is still intact, has the chance of binding to GLP-1 receptors expressed on nerve fibers of sensory afferents of the parasympathetic nervous system (f). Indeed, such receptors are synthesized in the cell bodies of these neurons in the nodose ganglion (c). The neurons project to the nucleus of the solitary tract (a) where they may interact with other neurons, projecting to the hypothalamus or to the dorsal vagal motor nuclei (b), eventually leading to stimulation of efferent nerve fibers reaching the peripheral organs (g, h) via the vagus (from Holst and Deacon (173)).

Figure 10 Processing of proglucagon and antigenic determinants utilized for antibody generation allowing specific measurement of the various circulating components. The processing scheme is identical to the one shown in Figure 2, but also shows the various molecular forms of GLP-1 resulting from the differential pancreatic and intestinal processing, the absence or presence of amidation, and DPP-4-mediated degradation products. Didactic explanation. Obviously, the black antibodies, directed against a mid-region of GLP-1 (the so-called side-viewing), will react with all of the molecular forms of GLP-1 regardless of the origin (including the major proglucagon fragment), and therefore completely lack specificity. The C-terminal antibodies (terminal wrapping) will react with GLP-1 1-36NH2, 7-36NH2, and 9-36NH2, and have therefore been used for measuring “total GLP-1” (although the cross-reaction with GLP-1 1-36NH2, which is derived from the pancreas, represents a problem). Similar results may be obtained with a sandwich ELISA combination of black and red antibodies, which currently is the combination used in commercial ELISAs for “total GLP-1.” For specific measurement of the Gly-extended molecular forms, a terminal wrapping antibody against the free acid in position 37 is required (yellow antibody). For specific measurement of the individual molecular forms, a combination of the C-terminally wrapping antibodies and N-terminally wrapping antibodies may be used. Thus, for intact GLP-1 sandwich ELISAs, blue and red antibodies or blue and yellow antibodies may be used. It is clear that specific measurement of GLP-1 in the circulation is challenging, and not many assays are sufficiently specific. Indeed, most antibodies claimed to be truly terminal are somewhat “side-viewing” and, therefore, suffer from lack of specificity.

Figure 11 Secretion of GLP-1 and GIP in patients with type 2 diabetes (blue curves) and in healthy control subjects (green curves) in response to increasing doses of glucose (25, 75, and 125 g) and in response to intravenous infusions of glucose resulting in similar glucose excursions (isoglycemia). Color tones indicate each set of OGTT and IGII [light, 25-g OGTT (closed symbols) and corresponding IIGI (open symbols); medium, 75-g OGTT (closed symbols) and corresponding IIGI (open symbols); and dark, 125-g OGTT (closed symbols) and corresponding IIGI (open symbols)]. Didactic explanation. In these experiments, none of the intravenous infusions resulted in any changes in hormone secretion, as expected. The responses to oral administration were clearly dependent on the dose, with short-lived increases in GIP secretion after the low glucose dose and more protracted responses to the larger doses, although reaching almost the same peak or plateau levels. For GLP-1, a similar pattern was observed for the two larger doses, whereas the response to the low dose was clearly smaller. These responses are readily explained by the markedly different rates of gastric emptying associated with the three doses, as shown in the bottom panel. The nutrient regulation of gastric emptying ensures that a rather constant amount of nutrients (in kcal per min) is delivered to the small intestine as long as there is something left in the gastric reservoir. The hormone responses, which are generated by the presentation and absorption of the nutrients, therefore follow the gastric emptying rate. From Bagger et al. (19).

Figure 12 The relationship between the intestinal somatostatin cells and the L-cells. Didactic explanation. The diagram shows three cells, an L-cell, a somatostatin producing D-cell, and an interspaced enterocyte. Both the D-cell and the L-cell are of the “open” type with a projection with microvilli reaching the gut lumen, but the D-cell has the characteristic basal cytoplasmic process of the paracrine cells, which, in this case, contacts the L-cells. The L-cell expresses somatostatin receptors, and the D-cell expresses GLP-1 receptors, so that GLP-1 reaching the D-cells stimulates somatostatin secretion, which in turn restrains L-cell secretion. If the feedback cycle is interrupted with receptor antagonists, GLP-1 secretion increases markedly (based on Hansen et al. (146)).

Figure 13 ProGIP and its intestinal processing. Didactic explanation. Once the signal peptide of Prepro-GIP is cleaved off in the Golgi apparatus, the remaining proGIP is processed further in the granules by the prohormone convertase 1/3 to release full-length GIP 1-42 (proGIP 52-93). In the circulation, about half of circulating GIP is degraded by dipeptidyl peptidase-4 (DPP-4) to generate GIP 3-42 (whereas GIP, unlike GLP-1, does not seem to be degraded locally in the gut). Small amounts of a C-terminally truncated and amidated form, GIP 1-30NH2, which is a full agonist on the GIP receptor, may also be formed and, upon DPP-4 digestion, this form may be degraded to generate GIP 3-30NH2, which is a potent GIP receptor antagonist. The figure also indicates how antibodies against specific regions of the molecules may be used to measure the various molecular forms identified in the circulation.

 


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Article Title: Physiology of the Incretin Hormones, GIP and GLP‐1—Regulation of Release and Posttranslational Modifications
 

How to Cite

Jens J. Holst, Nicolai J. Wewer Albrechtsen, Mette M. Rosenkilde, Carolyn F. Deacon. Physiology of the Incretin Hormones, GIP and GLP‐1—Regulation of Release and Posttranslational Modifications. Compr Physiol 2019, 9: 1339-1381. doi: 10.1002/cphy.c180013