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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 4798-4804
Copyright © 2003 by The Endocrine Society

Effect of Ingested Nutrients on the Release of Thrittene into the Human Circulation

John W. Ensinck, Ellen C. Laschansky, Robin E. Vogel and David A. D’Alessio

Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, Washington 98195

Address all correspondence and requests for reprints to: David D’Alessio, M.D., University of Cincinnati Division of Endocrinology, ML 0547 Cincinnati, Ohio 45267-0547. E-mail: dalessd{at}ucmail.uc.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Thrittene is a recently described peptide with a sequence homologous with somatostatin-28 (1–13) but is produced independent of the preprosomatostatin gene. It is localized in epithelial cells in stomach and gut mucosal crypts and in neuronal cell bodies in the myenteric plexus and enteric axons. It is also present in human plasma. The aim of this study was to determine whether the release of thrittene into the circulation was affected by the ingestion of nutrients and, if so, whether the pattern of release was distinct from the closely related peptide somatostatin-28 (S-28). Thrittene was indirectly measured in human plasma by an RIA using antiserum F4. F4 interacts with the Asn5-Pro6 region shared by S-28 and thrittene. The contribution of S-28 to F4 immunoreactivity (F4-IR) was determined using a specific two-site assay, and this measure was subtracted from the total F4-IR to give an estimate of thrittene levels. Plasma for assay was taken from healthy men on 4 separate days before and after intake of: a mixed meal (715 kcal), and meals containing primarily fat (25 g; 225 kcal), carbohydrate (100 g; 454 kcal), and protein (22 g; 100 kcal). After the mixed meal, both S-28 and thrittene rose by 50–100% within 30 min and gradually declined by 4 h. These increments were mimicked after ingestion of fat. By contrast, thrittene levels increased after carbohydrate but not protein intake, whereas S-28 concentrations rose after protein but not carbohydrate ingestion. These findings indicate that thrittene is secreted into the mammalian circulation during food intake and raise the possibility that thrittene may play a role in nutrient disposition. The dichotomy in responses of thrittene and S-28 to ingestion of the major macronutrients suggests that they are secreted from different gastrointestinal cells.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
WE HAVE RECENTLY reported the isolation and identification of a 13-residue peptide from mammalian gut, with a structure homologous with that of somatostatin-28 (1–13) [S-28 (1–13)] (1). Isolation and characterization of this peptide revealed that the eight amino acids that could be determined were identical to those of somatostatin-28 (S-28). Despite its sequence homology with S-28, the novel peptide had a distribution in the gastrointestinal (GI) tract that was distinct from the somatostatins, and occurred in GI neurons that did not contain somatostatin immunoreactivity. As further evidence that this new species is not derived from preprosomatostatin, we were able to identify S-28(1–13) in the GI tissues of mice with a deletion of the somatostatin gene (1). Based on the number of amino acid residues and to distinguish it from prosomatostatin (ProS)-related peptides, we have tentatively named this peptide thrittene. We have detected thrittene in GI enteroendocrine cells and in a widespread network of neurons in the gut using immunocytochemistry (1). We have also identified this peptide from the extracts of pancreas and GI tissues from rodents and nonhuman primates. The gene encoding thrittene has as yet to be identified.

During previously reported studies of the effects of a mixed meal and its macronutrient components on the release of S-28 into the human circulation (2), we observed a discrepancy between concentrations that were measured using a specific two-site assay, and levels detected by RIA using antiserum F4 (3). The F4 antiserum interacts with an epitope shared by both S-28 and thrittene. Therefore, we hypothesized that much of the excess F4 immunoreactivity (F4-IR) beyond what is measured specifically as S-28 was accounted for by thrittene. We report herein a comparison of the levels of F4-IR in peripheral plasma attributed to thrittene and S-28 in response to the intake of a mixed nutrient meal and separate meals containing the majority of calories as fat, carbohydrate, or protein. We observed that both S-28 and thrittene rose significantly following the intake of mixed nutrient and high-fat meals, but that their responses following ingestion of high-carbohydrate and high-protein meals were discordant. These data suggest that the two peptides originate from different GI cells, and that the secretion of thrittene, most likely from GI enteroendocrine cells, is regulated by specific nutrients.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The volunteers included 25 healthy men (aged 22–30 yr) who were within 10% of ideal body weight. None took medications. The subjects gave oral informed consent and signed a form approved by the Institutional Review Board at the University of Washington before participation. After an overnight fast, they were admitted to beds in the University of Washington clinical research center. Blood was withdrawn from an indwelling catheter in an antecubital vein before and up to 4 h after nutrient intake. Ten subjects swallowed 500 ml of a liquid formula meal [Ensure Plus, Ross Laboratories (Columbus, OH) containing 25 g fat (a mixture of canola, corn, and high oleate safflower oils), 100 g carbohydrate (corn syrup, maltodextrin, and sucrose), and 22 g protein (casein hydrolysates and soy protein); 715 kcal]. Groups of five subjects separately ingested the following: 1) whipping cream, 81 g (236 kcal) comprised of 25 g fat (primarily palmitate and oleate), 1.7 g protein (casein), and 2.4 g carbohydrate (lactose); 2) a solution (500 ml) of boiled egg white (100 kcal), consisting of 22 g protein and 2.6 g carbohydrate; 3) boiled rice, 122 g in 500 ml (454 kcal) comprising 100 g carbohydrate (starch), 1.6 g fat (linoleate and linolenate), and 9.8 g protein (primarily glutelin). Ingestion of the meals was started at time 0 and food was consumed within 10 min.

Processing of plasma

To prevent degradation of peptides by plasma endo- and exopeptidases, heparinized blood was collected on ice, the plasma separated within 10 min, and the pH adjusted to 3 with 1 N HCl and stored at -80 C (3, 4). For routine analyses, 5-ml aliquots of acidified plasma were filtered through cartridges containing octadecylsilyl silica (Sep-Pak, Waters Associates, Milford, MA), washed sequentially with 5 ml H2O and 5 ml of 0.1% trifluoroacetic acid (TFA) in H2O and the retained peptides eluted with 5 ml of a solution of 80% methanol and 1% TFA. The eluates were air dried and dissolved in 2 ml of assay buffer. Recoveries of S-28 and S-28(1–13) (50–100 pg) added to 5 ml of acidified plasma were 78 ± 2% (n = 15) and did not differ significantly from each other.

RIA

Details of the separation of S-28 from somatostatin-14 (S-14) and thrittene by immunoadsorption and their measurements in plasma by RIA have been previously published (2, 3, 4). In brief, the retentates from plasma samples applied to Sep-Pak were eluted and passed over a column of agarose coupled with Igs from the F4 antiserum; these antibodies selectively bind to the Asn5-Pro6 sequence in the proximal domain of S-28 and thrittene. F4 interacts with ProS, and S-28 with similar avidity permitting their detection in the femtomolar range. By contrast, F4 has a considerably higher affinity for S-28(1–13), which interacts with F4 80–100 times more avidly than S-28 on a molar basis. The column was washed with 130 mM borate buffer (pH 8.5) in which S-14 was eluted. S-28, ProS, and thrittene were then removed with 0.2 N acetic acid (HAc) containing 0.2% BSA [Miles-Pentex (Kanakaakee, IL)] (pH 3.5) and lyophilized. Samples were reconstituted in 130 mM borate buffer (pH 8.5) and S-28 was quantified by an RIA using antiserum AS-10 that interacts with the Phe7-Trp8-Lys9 residues of S-14 shared by S-28, but does not bind thrittene. Values were corrected for average recoveries of 50%.

Antiserum F4 was also used in a RIA to measure plasma peptides eluted from Sep-Pak and passed over the immunoabsorbent as described above (3). Values were corrected for recoveries of 80%. The lowest limits of detection of thrittene and S-28 in the RIA were 0.2 and 2 fmol per tube, with interassay variances of 15% (n = 10) for each and intraassay variances of 8% and 5% (n = 10), respectively.

Gel permeation chromatography

Chromatography was carried out in columns (1.5 x 90 cm) containing Bio-Gel P-10 (200–400 mesh) (Bio-Rad Chemical Division, Richmond, CA) equilibrated in 50 mM borate buffer (pH 8.5), containing 0.25% BSA (1, 3).The columns were calibrated with blue dextran, molecular size exceeding 1000 kDa; cytochrome c (Sigma, St. Louis, MO), 13 kDa; S-28, 3.1 kDa; S-28(1–13), 1.4 kDa; S-14, 1.6 kDa; and 3H2O. Filtration occurred under gravity at room temperature at 10 ml/h and 1-ml fractions were automatically collected.

Data analyses

The data for plasma peptide measurements in the various groups are expressed as means ± SE. To compare the relative amounts of peptide released by the individual nutrients, the incremental responses above baseline were calculated as areas under the curves by the trapezoid method. Postprandial changes in S-28 and thrittene were compared with basal levels using repeated measures ANOVA. The integrated responses of these peptides to meals were compared using paired t tests.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Plasma levels of S-28, measured with the specific two-site assay, and total F4-IR are shown in Figure 1Go. Mean basal levels of S-28 of 22 ± 2 pg/ml rose to 35 ± 4 pg/ml by 30 min, reached a zenith of 45 ± 6 pg/ml at 120 min and remained elevated even at 180 min after meal ingestion. By contrast, when expressed as pg equivalents of S-28/ml, the mean levels of the combined peptides measured as total F4 immunoreactivity (F4-IR) were 170 ± 16 pg equiv S-28/ml at baseline and ascended to 208 ± 28 pg equiv S-28/ml by 30 min, before reaching a maximum of 280 ± 22 pg equiv S-28/ml by 180 min.



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  		FIG. 1. Plasma levels of S-28 and F4-IR in 10 healthy men before and after intake of a liquid meal (Ensure Plus, 715 kcal). Peptides from plasma (5 ml), absorbed and eluted from Sep-Pak, were applied to a column of agarose linked to Igs reacting with Asp5-Pro6 residues of S-28. The retained peptides subsequently eluted with HAc were measured with an antiserum (AS-10) reacting with the Phe7-Trp8-Lys9 sequence of somatostatin-14. The two-site assay quantified S-28 levels in picograms per milliliter. All peptides in the eluates from the immunoadsorbent were also measured by the F-4 immunoassay with S-28 as standard. Because of heterogeneity, values are recorded as pg equiv per ml S-28. *, Values that were significantly greater than basal levels (P < 0.05). Values are mean ± SEM.

 
Because the discordance in values between those of S-28 and total F4-IR, suggested that the latter reflected heterogeneity of substances measured by F4 RIA, 70 ml of plasma from six men was submitted to immunoadsorption on F4-linked agarose followed by gel filtration in attempt to distinguish among the putative peptides. The profiles of the peptides in separated in this manner and measured by the F4 RIA before and at 120 min after ingestion of Ensure Plus are displayed in Fig. 2Go. Mean values of the F4 reactive peaks eluting at the cytochrome c marker were not significantly different from one another at baseline and 120 min after food intake. We believe that this peak represents ProS as it was detected by AS-10 RIA which recognizes the C-terminal region of the propeptide and also coincided with the behavior of prosomatostatin (3). By contrast, at 120 min after food intake when the amplitudes were increased, the diffuse F4 immunoreactive peak bridging both the S-28(1–13) and S-28 standards at baseline became more distinct as two separate peaks. The larger F-4 reacting peak, eluted at 70–105 ml preceding the S-28 standard, coincided with the S-28(1–13) standard and did not react in the AS-10 RIA (data not shown) indicating that the peptide lacked the C-terminal domain of the somatostatins (ProS, S-28, and S-14). The S-28 standard eluted at approximately 95 ml, a position that was associated with a peak of F4-IR in the postprandial plasma. We confirmed that S-28 and thrittene were present in the 80–90 ml and 90–100 ml peaks, respectively, by submitting aliquots to HPLC and demonstrating that they coeluted with their respective synthetic standards (1).



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  		FIG. 2. Profiles of F4 immunoreactive peptides from six healthy men at 0 min (open circles) and 120 min (closed circles) after ingestion of Ensure Plus. Plasma (70 ml) from each subject was adsorbed onto Sep-Pak, eluted with methanol and TFA, and the dried eluates dissolved in borate buffer were subjected to immunoadsorption on F-4 agarose. The retained peptides were eluted with 2 N HAc, lyophilized, and reconstituted in 1.0 ml borate buffer for application to the column. Filtration was carried out in a 1.5 x 90-cm column of BioGel P-10 in 50 mM borate buffer (pH 8.5) containing 0.25% BSA. RIA measurements were performed using S-28 as standard. Arrows designate peaks where markers of known composition were eluted. Vo, Void volume detected by blue dextran and cytochrome c has a molecular mass of 13 Da.

 
To quantify the contribution of thrittene to increments in total F4-IR after food intake, we reasoned that since the peak coinciding with the behavior of the cytochrome c marker during gel filtration, attributed to proS, was unchanged at 120 min compared with the values in the fasting state, only S-28 and thrittene were increased after food intake. Because S-28 levels were accurately measured by combining F4 immunoadsorption with measurement with a C-terminal antibody (AS-10) for RIA, they could be subtracted from the postprandial F-4 levels leaving an estimate of thrittene levels that could be quantified by comparison of the displacement obtained with a synthetic S-28(1–13) standard. The responses of S-28 and thrittene following the mixed meal were 1530 ± 351 pM·min and 1630 ± 261 pM·min, respectively.

To determine whether the nutrient stimuli for S-28 release and thrittene release were similar, we compared the plasma profiles of each peptide after ingestion of meals of distinct nutrient composition. These meals were chosen to provide the majority of calories as either carbohydrate, lipid, or protein although each of them contained a mixture of nutrients. Following the ingestion of 25 g of whipping cream, the high-fat meal, concentrations of both S-28 and thrittene rose in parallel from 30–120 min, achieving a zenith between 60 and 120 min and declining gradually thereafter. The postprandial responses were indistinguishable from one another at any time point (Fig. 3AGo). In contrast, there were marked differences in the responses the high carbohydrate meal, and the high protein meal. Figure 3BGo depicts the responses of S-28 and thrittene to 100 g of carbohydrate in rice. While there was a significant increase in plasma thrittene, S-28 levels did not change. The responses to egg whites, consisting mainly of protein, were completely reversed with a significant elevation of S-28 and no change in plasma thrittene (Fig. 3CGo). Figure 4Go shows the areas under the curves S-28 and thrittene in the five subjects who consumed the mixed nutrient, fat, carbohydrate, and protein meals.



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  		FIG. 3. Levels of S-28 (filled circles) and thrittene (open circles) in plasma from healthy men after intake of whipping cream containing 25 g fat (A), boiled rice containing 100 g of glucose equivalents (B), and a solution of egg white containing 22 g of protein (C). The results are shown as increments above baseline for each peptide. Vertical lines refer to SEMs.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Thrittene is a novel GI peptide sharing sequence homology with prosomatostatin that is apparently the product of a separate gene. Similar to many gut peptides, thrittene is synthesized in mucosal endocrine cells and neurons. In the present study, we have demonstrated that plasma levels of thrittene increase following the ingestion of meals, and that there is nutrient specificity in this process. Of importance, the nutrients that stimulate thrittene release differ from those inducing S-28 release. High-fat meals stimulate the release of both peptides whereas a meal containing predominantly carbohydrate elevates thrittene but not S-28 levels. Conversely, ingestion of a mostly protein meal evokes an increase in S-28 but not thrittene. The distinct pattern of release of these two peptides to carbohydrate and protein is not only in keeping with their origins from different genes but also implies that that they are not cosecreted from a common cell. Although a physiologic role for thrittene has not been established, the secretion of this peptide in response to meal consumption is similar to many other GI hormones that regulate nutrient assimilation.

The opposite responses of thrittene and S-28 to protein and carbohydrate containing meals add further support to the independence of these two peptides. In our previous study, we observed F4-IR in cells that did not stain with AS-10, our antiserum binding the C-terminus common to ProS, S-28, and S-14 (1). In addition, we noted that levels of F4-IR were greatest in extracts of the lower intestine, whereas the ProS-derived peptides were most prevalent in the upper intestine. Most convincingly, we were able to demonstrate F4-IR in mucosal cells and neurons from the stomach and intestine of mice with a deletion of the somatostatin gene (1), and peaks coeluting with thrittene standard from gastric, intestinal, and pancreatic extracts from these animals. Taken together, these data indicate that thrittene and the somatostatins originate from different genes and likely different cells.

The increase in plasma thrittene in response to meals containing predominantly fat and carbohydrate, but not protein, is in keeping with the general nutrient specific release of more completely understood GI hormones. For example, cholecystokinin (CCK) is released primarily in response to protein and fat in the gut (5), whereas glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are stimulated by lipid and carbohydrate, but not protein meals (6, 7). Our data support the importance of specific substrates in triggering the release of thrittene, and S-28, in that all the meals were taken with water in amounts to produce similar gastric volumes, but all did not stimulate peptide release. It is important to note that the meals used in this study were heterogeneous in the nutrients they contained so that we were unable to determine the specific compounds stimulating the enteroendocrine cells. It is possible that our observations on thrittene release were specific to the particular constituents that were fed and are not representative of the general nutrient classes—carbohydrate, fat, and protein—that we designated. Furthermore, because we did not have a control for the osmolalities of the meals, we cannot rule out variation in this factor as accounting for differences in thrittene release. Determining the specific nutrients responsible for the release of thrittene and the mechanism of stimulus-secretion coupling may provide useful insight into the physiology of the peptide.

Although we are unable to measure thrittene specifically, our chromatographic data support the contention that much of the non-S-28 portion of F4-IR is thrittene. Both fasting and postprandial plasma had significant F4 peaks coeluting with authentic thrittene. Because of its greater avidity for F4, it is likely that the amount of thrittene relative to S-28 is exaggerated when assayed against an S-28 standard. However, even when read against a thrittene standard the amounts of peptide present in the plasma were similar to concentrations of S-28. The similar profile of thrittene compared with S-28, a peptide with an established role as a hormone (4, 8, 9), suggests that this novel peptide may also be an endocrine factor.

The thrittene secreted into plasma following meal ingestion is likely to originate in mucosal cells of the stomach or intestine. Based on our immunocytochemical studies (1), thrittene is localized not only in enteroendocrine cells in the stomach and gut mucosa but also in a widespread network of neurons in all layers of the intestinal wall with greatest abundance in the mucosa. It is traditionally held that peptides released from cells within GI tissues in response to nutrient ingestion originate in cells of epithelial origin (10). Examples include gastrin, secretin, CCK, GIP, GLP-1, and S-28, all of which act as hormones interacting with receptors on distant cells (4, 5, 10, 11, 12). Thus, it seems probably that, like other GI hormones, thrittene, originates in specialized endocrine epithelial cells, and their counterparts in the gastric mucosa, and is secreted into the circulation in response to selected nutrients. Whether or not thrittene localized in GI neurons (1) contributes to circulating levels of this peptide is unknown, however, based on studies of vasoactive intestinal polypeptide, calcitonin gene-related peptide, gastrin-releasing peptide, S-14, and galanin, which are of neuronal origin (13, 14, 15, 16), it seems likely that spillover of thrittene from neuronal axons accounts for only a minor portion of plasma F4-IR. Thus, we postulate that thrittene is secreted from enteroendocrine cells in response to the introduction of nutrients into the GI tract and acts on distant targets, whereas the peptide detected in the neuronal plexus serves as an interneuronal transmitter within the local milieu.

At present, we have not confirmed a physiologic role for thrittene either as a purported hormone or neurotransmitter. It might be construed from the postprandial rise affected by fat and carbohydrate that thrittene would most likely be involved in fuel homeostasis. Because it shares the sequence of the proximal thirteen residues of S-28, it is possible that it interacts with the somatostatin receptor-5 to which S-28 binds with a higher affinity than S-14, presumably due in part to the tertiary structure conferred by the additional amino acids. Somatostatin receptor-5 is found in pancreas, intestine, heart, brain, and pituitary (17). We have added thrittene to isolated rat islet cell cultures where it neither stimulates nor inhibits the release of insulin, glucagon or somatostatin (Ensinck, J. W., and D. D’Alessio, unpublished data). We have not as yet assessed its possible effect on pancreatic exocrine secretions or GI function. Noteworthy, when it was instilled into the cerebral ventricles of rats, thrittene decreased food intake in a dose-dependent manner without evoking an aversive effect, implying that it may serve a role in the regulation of appetite (18).

In summary, in the present studies, we have determined that a novel peptide we have termed thrittene, which shares the proximal structure of S-28 but is derived from a separate gene is released into the human circulation during food intake. Presumably originating in the GI tract, thrittene is preferentially secreted in response to dietary carbohydrate and fat but not protein. These data suggest that thrittene may be involved in the regulation of fuel homeostasis.



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  		FIG. 4. Comparison of the integrated responses of S-28 (filled bars) and thrittene (open bars) to the intake of mixed fat, carbohydrate, and protein meals in five healthy men. Each bar represents the mean ± SEM.

 

   Footnotes
 
Portions of this work were carried out in the General Clinical Research Center (Grant NIH RR-00037) at the University of Washington. Support was also provided through United States Public Health Service Grant DK34397, the Diabetes and Endocrinology Research Center (Grant DK17047), and grants from the American Diabetes Association and Juvenile Diabetes Foundation.

Abbreviations: F4-IR, F4 immunoreactivity; GI, gastrointestinal; HAc, acetic acid; ProS, prosomatostatin; S-14, somatostatin-14; S-28, somatostatin-28; TFA, trifluoroacetic acid.

Received January 13, 2003.

Accepted July 14, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Ensinck JW, Baskin DG, Vahl TP, Vogel RE, Laschansky EC, Francis BH, Hoffman RC, Krakover JD, Stamm MR, Low MJ, Rubinstein M, Otero-Corchon V, D’Alessio DA 2002 Thrittene, homologous with somatostatin-28((1–13)), is a novel peptide in mammalian gut and circulation. Endocrinology 143:2599–2609[Abstract/Free Full Text]
  2. Ensinck JW, Vogel RE, Laschansky EC, Francis BH 1990 Effect of ingested carbohydrate, fat, and protein on the release of somatostatin-28 in humans. Gastroenterology 98:633–638[Medline]
  3. Ensinck JW, Laschansky EC, Vogel RE, Simonowitz DA, Roos BA, Francis BH 1989 Circulating prosomatostatin-derived peptides. Differential responses to food ingestion. J Clin Invest 83:1580–1589
  4. D’Alessio DA, Sieber C, Beglinger C, Ensinck JW 1989 A physiologic role for somatostatin 28 as a regulator of insulin secretion. J Clin Invest 84:857–862
  5. Liddle RA, Goldfine ID, Rosen MS, Taplitz RA, Williams JA 1985 Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. J Clin Invest 75:1144–1152
  6. Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V 1993 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[Abstract/Free Full Text]
  7. D’Alessio DA, Thirlby R, Laschansky EC, Zebroski H, Ensinck JW 1993 Response of tGLP-1 to nutrients in humans. Digestion 54:377–379
  8. Hildebrand P, Ensinck JW, Gyr K, Mossi S, Leuppi J, Eggenberger C, Beglinger C 1992 Evidence for hormonal inhibition of exocrine pancreatic function by somatostatin 28 in humans. Gastroenterology 103:240–247[Medline]
  9. Hildebrand P, Ensinck JW, Buettiker J, Drewe J, Burckhardt B, Gyr K, Beglinger C 1994 Circulating somatostatin-28 is not a physiologic regulator of gastric acid production in man. Eur J Clin Invest 24:50–56
  10. Rehfeld JF 1998 The new biology of gastrointestinal hormones. Physiol Rev 78:1087–1108[Abstract/Free Full Text]
  11. Pederson R 1995 Gastric inhibitory polypeptide. In: Walsh JH, Dockray GJ, eds. Gut peptides. New York: Raven Press; 217–260
  12. Kieffer TJ, Habener JF 1999 The glucagon-like peptides. Endocr Rev 20:876–913[Abstract/Free Full Text]
  13. Bitar KN, Said SI, Weir GC, Saffouri B, Makhlouf GM 1980 Neural release of vasoactive intestinal peptide from the gut. Gastroenterology 79:1288–1294[Medline]
  14. Bloom SR, Edwards AV, Ghatei MA 1984 Neuroendocrine responses to stimulation of the splanchnic nerves in bursts in the conscious adrenalectomized calf. J Physiol 346:519–531[Abstract/Free Full Text]
  15. Geppetti P, Tramontana M, Evangelista S, Renzi D, Maggi CA, Fusco BM, Del Bianco E 1991 Differential effect on neuropeptide release of different concentrations of hydrogen ions on afferent and intrinsic neurons of the rat stomach. Gastroenterology 101:1505–1511[Medline]
  16. Kowalyk S, Veith R, Boyle M, Taborsky Jr GJ 1992 Liver releases galanin during sympathetic nerve stimulation. Am J Physiol 262:E671–E678
  17. Patel YC 1999 Somatostatin and its receptor family. Front Neuroendocrinol 20:157–198[CrossRef][Medline]
  18. D’Alessio DA, Rushing PA, Blake K, Ensinck JW, Seeley RA 2000 Suppression of food intake by Somatostatin-28(1–13) a novel gut peptide. Diabetes 49:A260




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