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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0409
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6665-6671
Copyright © 2005 by The Endocrine Society

Peptide YY Is Secreted after Oral Glucose Administration in a Gender-Specific Manner

Byung-Joon Kim, Olga D. Carlson, Hyeung-Jin Jang, Dariush Elahi, Carmen Berry and Josephine M. Egan

Diabetes Section, National Institute on Aging, National Institutes of Health (B.-J.K., O.D.C., H.-J.J., C.B., J.M.E.), Baltimore, Maryland 21224; and Department of Surgery, University of Massachusetts (D.E.), Worcester, Massachusetts 01655

Address all correspondence and requests for reprints to: Dr. Josephine M. Egan, Diabetes Section, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, Maryland 21224. E-mail: eganj{at}grc.nia.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Previous studies with small numbers of subjects showed a negative correlation between plasma peptide YY (PYY) levels and obesity. If correct, this would imply that low PYY levels might be involved in the pathogenesis of obesity.

Objective: Our objective was to investigate whether plasma PYY levels were correlated with sex and body mass index (BMI).

Design, Setting, and Patients: We conducted a cross-sectional study of 151 normal volunteers (19–90 yr of age) in the Baltimore Longitudinal Study of Aging.

Interventions: All subjects had an oral glucose tolerance test (75 g) performed.

Main Outcome Measures: Immunostaining of human duodenum, BMI, hemoglobin A1c, plasma glucose, insulin, PYY, glucagon like peptide-1 (GLP-1), ghrelin, and leptin were the main outcome measures.

Results: PYY and GLP-1 colocalized in the same cells in human duodenum. Both hormones reached peak plasma levels by 20 min and had similar secretory patterns. The incremental increases in PYY and GLP-1 during that first 20 min were significantly correlated (r2 = 0.388; P < 0.0001). The areas under the curve from 0–120 min for PYY and GLP-1 were similar in both obese and lean participants. Female participants across the range of BMI had significantly higher PYY area under the curve (17,464 ± 1,240 vs. 14,120 ± 806 pmol/liter·min, female vs. male; P < 0.05) compared with male participants.

Conclusions: Our findings show that PYY and GLP-1 are colocalized and cosecreted from L cells and that total secretion of PYY is higher in females than in males, but fasting PYY levels and PYY secretion in response to oral glucose were not in any way correlated with BMI.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PEPTIDE YY (PYY) and glucagon like peptide-1 (GLP-1) are enteroendocrine hormones that are synthesized and secreted from enteroendocrine L cells. They arise from posttranslational processing of distinct gene products, proglucagon and pro-PYY (1, 2). PYY slows gastric emptying and gastrointestinal (GI) motility, inhibits secretion of gastric acid as well as pancreatic exocrine enzymes, and is thought to be involved in the regulation of food intake (3, 4, 5, 6). GLP-1 stimulates insulin secretion in a glucose-dependent manner and stimulates ß-cell proliferation and differentiation in vivo in rodents (7). Similar to PYY, it inhibits gastric emptying and GI motility as well as inhibits gastric acid and pancreatic secretion (8, 9, 10). In addition, infusions of GLP-1 increase satiety and decrease food intake (11, 12). On immunohistochemical analysis of mouse colonic mucosa, about 37% of L cells showed colocalization of PYY and GLP-1 (13). Rabbit colon was also examined by double Immunogold staining (14), and about 85% of granules of the L cells contained both PYY and GLP-1, with the remaining granules containing either GLP-1 alone or PYY alone. Concentrations of these hormones increased in a parallel manner in the blood of rats after a meal and fatty acid stimulation (15).

Peripheral PYY infusions have been reported to decrease food intake in both rodents (6) and humans (16) and to decrease body weight gain in rodents (6), although the findings in rodents have not been universally replicated (17). Most interestingly, fasting levels of PYY were found to be lower in obese compared with lean humans, with a negative correlation between PYY levels and body mass index (BMI), implicating PYY deficiency in the pathogenesis of obesity. Secretion of PYY after a meal was also lower in obese subjects than in lean subjects (16).

Because the relationship between PYY and GLP-1 secretion is not clear in humans, we examined their secretion after an oral glucose tolerance test with multiple blood samplings. We also examined human duodenum by immunofluorescent staining to look for colocalization of the two hormones.


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

We screened the Baltimore Longitudinal Study on Aging (BLSA) participants from 2001 forward who were not taking glucose-lowering medications and who had an oral glucose tolerance testing with the standard 75-g glucose load during their most recent visit. From those, we analyzed all 151 (mean age, 57.1 ± 17.0 yr; 93 women and 58 men; BMI, 28.4 ± 5.5 kg/m2) with normal fasting and 2-h glucose levels [fasting plasma glucose, <100 mg/dl (5.6 mmol/liter); 2-h plasma glucose after 75 g oral glucose, <140 mg/dl (7.8 mmol/liter)]). The committee on human investigation of Medstar Research Institute approved the study. All volunteers were informed about the nature of the study, and all provided written informed consent in accordance with the Helsinki II Declaration.

Modified oral glucose tolerance test in BLSA participants

Participants fasted overnight. Blood was obtained for hemoglobin A1c (HbA1c) as well as for fasting plasma glucose, insulin, GLP-1, PYY, ghrelin, and leptin measurements (time zero). Participants then drank 75 g glucose (SunDex, Fisherbrand, Pittsburgh, PA), and nine more blood samples were subsequently drawn at 5, 10, 15, 20, 40, 60, 80, 100, and 120 min for plasma glucose, insulin, GLP-1, and PYY determinations. Blood was collected into EDTA-coated tubes (1.5 µg/ml blood), containing aprotinin (40 µl/ml blood; Trasylol, Serological Proteins, Kankakee, IL) and an inhibitor of dipeptidyl-peptidase IV (DDP4; 10 µl/ml blood; Linco Research, Inc., St. Charles, MO). The body weights and heights of participants were measured manually using a medical scale (SECA Corp., Hanover, MD), and BMI was calculated as body weight in kilograms divided by the square of the height in meters.

Plasma hormone and biochemical assays

We measured plasma glucose levels with a glucose analyzer (Beckman Instruments, Brea, CA). We assayed plasma samples for insulin by ELISA (ALPCO Diagnostics, Windham, NH) with a detection limit of 1 µU/ml. The cross-reactivity of the insulin antibody for C peptide and vice versa were less than 0.1%. We measured active GLP-1 by ELISA (Linco Research, Inc.) with a detection limit of 5 pmol/liter. We assayed PYY using an RIA (Linco Research, Inc.). The PYY antibody recognizes both 1–36 and 3–36 forms of human PYY. The limit of sensitivity and the limit of linearity of the PYY assay are 10 and 1280 pg/ml, respectively (100 µl plasma). Quality control specimens (QC1, 38.4–79.7 pg/ml; QC2, 156.0–324.1 pg/ml; interassay variation, <5%) were always run with each standard curve, and their results were within the levels of expectation. In addition, we checked the cross-reactivity of the PYY antibody with pancreatic polypeptide (PP) and neuropeptide Y (NPY) by assay of serial dilutions of PYY-(1–36), PP, and NPY synthetic peptides (Bachem Bioscience, Inc., King of Prussia, PA; 2.5, 5, 10, 20, 40, 80, 160, 320, and 640 pmol/liter) in human plasma with the same kit and did not find any cross-reactivity between PYY and either PP or NPY. We measured plasma leptin levels by ELISA (Linco Research, Inc.), plasma ghrelin levels by RIA (Phoenix Pharmaceuticals, Inc., Belmont, CA), and HbA1c with an automated DiaSTAT analyzer (Bio-Rad Laboratories, Hercules, CA).

Immunofluorescent staining

Antibodies used were to GLP-1 (goat antihuman GLP-1 C-terminal antibody; Santa Cruz Biotechnology, Inc., Santa Cruz, CA; 1:200) antibody, PYY (rabbit polyclonal antihuman PYY antibody; gift from Dr. Gordon Ohning, Cure/Digestive Disease Research Center, University of California, Los Angeles, CA; 1:200) (18) and chromogranin A (mouse monoclonal antihuman chromogranin antibody; Abcam, Inc., Cambridge, MA; 1:200). The GLP-1 and PYY antibodies were preincubated with their respective antigens to block staining and then were also preincubated with one another as well as with chromogranin A. Human paraffin-embedded duodenal sections (anonymous postmortem samples from a woman, aged 28 yr, and a man, aged 64 yr) were obtained from Histology Control Systems. After deparaffinization with xylene, human duodenal sections were permeabilized in Triton X (0.1%) on ice and blocked for 1 h at room temperature in 5% BSA and 0.1% Tween in PBS. For triple-immunofluorescent staining, sections were incubated overnight at 4 C with primary antibodies, washed, incubated with secondary antibodies (Alexa 568 donkey antigoat antibody for GLP-1, Alexa 488 donkey antirabbit antibody for PYY, and Alexa 633 goat antimouse antibody for chromogranin A) for 1 h, washed, and mounted with fluorescence mounting medium (Vector Laboratories, Inc., Burlingame, CA). Immunofluorescent control sections were stained using isotype controls, with omission of primary antibodies and primary antibodies had been blocked with their respective antigens. After single staining (to prove the blocking), we performed triple-indirect immunofluorescent staining, and we made photomicrograph images using a confocal microscope (LSM-410, Carl Zeiss, Inc., New York, NY). We also made images using filters only at the correct wavelengths (without antibodies added) to exclude autofluorescence in enteroendocrine cells.

Statistical analysis

All values are expressed as the mean ± SEM. To estimate the incremental changes in plasma glucose, insulin, PYY, and GLP-1 levels between 0 and 120 min after challenge, we calculated the area under the curve (AUC) for the plasma hormone concentrations vs. time by the trapezoidal rule. Unpaired Student’s t tests were used to compare mean values of glucose and hormone levels, the homeostasis model assessment of insulin resistance (HOMAIR) (19), BMI, HbA1c, incremental changes in hormones (0–20 min after oral glucose tolerance test for plasma GLP-1 and PYY), and total AUC of plasma hormone levels among the participants. All data were normally distributed (Kolmogorov and Smirnov test). Simple Pearson correlation was performed between BMI and hormone levels. All significance tests for the comparisons were two-sided, and P < 0.05 was regarded as indicating statistical significance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
PYY and GLP-1 were colocalized and cosecreted from intestinal L cells

Omission of primary antibodies (PYY, GLP-1, and chromogranin A), the use of isotype controls, and the use of filters at the wavelengths of the three secondary antibodies revealed no positive staining and no autofluorescence in enteroendocrine cells (Fig. 1AGo). Triple-immunofluorescent staining of human duodenal sections generally showed PYY (green), GLP-1 (red), and chromogranin A (blue) to be colocalized (white) in human intestinal mucosa with just an occasional granule containing either PYY or GLP-1 (Fig. 1BGo). All duodenal L cells from the female specimen, having examined over 1000 cells, contained both hormones. In the male specimen there was an occasional L cell, which contained only GLP-1. There were no PYY-positive only cells in either specimen. After the glucose load, both hormones peaked at 20 min and returned toward the fasting level during the next 2 h (Fig. 2AGo). We calculated the incremental rise during the first 20 min of PYY ({Delta}PYY) and GLP-1 ({Delta}GLP-1). {Delta}PYY was positively correlated with {Delta}GLP-1 (r2 = 0.3381; P < 0.0001; Fig. 2BGo). We did not find any correlation between fasting PYY and GLP-1 levels and total PYY (PYYAUC (0–120 min), 3831 ± 1422 pmol/liter·min) and GLP-1 (GLP-1AUC (0–120 min), 1133 ± 797 pmol/liter·min) secretion (Fig. 2Go, C and D).



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  		FIG. 1. Immunofluorescent staining and confocal imaging of human duodenum. A, Omission of primary antibodies (PYY, GLP-1, and chromogranin A), the use of isotype controls, and the use of filters at the wavelengths of the three secondary antibodies of human duodenum from a 28-yr-old woman and a 64-yr-old man show no positive staining and no autofluorescence in enteroendocrine cells. B, Immunofluorescent staining using primary antibodies (PYY, GLP-1, and chromogranin A) shows PYY (green), GLP-1 (red), and chromogranin A (blue) staining and a merged image. Scale bar, 15 µm.

 


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  		FIG. 2. Cosecretion of PYY and GLP-1 after administration of 75 g oral glucose in BLSA participants (n = 54). A, Plasma PYY and GLP-1 secretory profiles after administration of 75 g oral glucose. B, Incremental changes in PYY ({Delta}PYY) and GLP-1 ({Delta}GLP-1) during the first 20 min after oral glucose. C and D, Correlation between fasting plasma PYY and GLP-1 levels (C) and correlation between PYYAUC (0–120 min) and GLP-1AUC (0–120 min) (D) after oral glucose.

 
Fasting plasma PYY levels were not correlated with BMI

We found no correlation between either fasting PYY (r2 = 0.00002; P = 0.568) or GLP-1 (r2 = 0.0007; P = 0.909) levels across the range of BMI (19–47 kg/m2) of participants (Fig. 3Go, A and B). Sorting our participants by age (≤50 yr or >50 yr) also did not alter the finding (data not shown). Fasting ghrelin and leptin levels have been shown in previous studies to be correlated with BMI (20, 21). This study confirmed those findings, because fasting ghrelin (r2 = 0.089; P < 0.0001) and leptin (r2 = 0.2726; P < 0.0001) levels correlated with BMI (Fig. 3Go, C and D) in our participants.



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  		FIG. 3. Correlation of fasting plasma PYY (A), GLP-1 (B), ghrelin (C), and leptin (D) levels with BMI (19–47 kg/m2) in BLSA participants (n = 151).

 
Factors affecting PYY secretion after oral glucose tolerance testing

We analyzed the secretory profiles of PYY as well as GLP-1 and insulin in obese participants with BMI of 30 kg/m2 or higher (n = 19; BMI, 31.6 ± 1.6 kg/m2) and in lean participants with BMI less than 25 kg/m2 (n = 19; BMI, 22.8 ± 1.7 kg/m2), who were aged-matched (50.6 ± 18.5 vs. 57.8 ± 16.3 yr, lean vs. obese; P = 0.211). The glucose profile, total AUC of glucose [glucoseAUC (0–120 min); Fig. 4AGo] and HbA1c (5.2 ± 0.4 vs. 5.2 ± 0.3%, lean vs. obese; P = 0.755) were similar in the two groups. Total insulin secretion was significantly higher in obese participants [insulinAUC (0–120 min), 7660 ± 1400 vs. 3917 ± 403 µU/ml·min, obese vs. lean; P = 0.011; Fig. 4Go, B and F]. As expected, obese participants were more insulin resistant than lean participants, as quantified by HOMAIR (2.21 ± 0.99 vs. 1.35 ± 0.68 mmol/liter·µU/ml, obese vs. lean; P = 0.004; Fig. 4FGo). However, total secretion of GLP-1 [GLP-1AUC (0–120 min)] and that of PYY [PYYAUC (0–120 min)] were similar in obese and lean participants (Fig. 4Go, C–E).



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  		FIG. 4. Plasma glucose, insulin, PYY, and GLP-1 concentration profiles after administration of 75 g oral glucose in lean (n = 19; BMI, <25 kg/m2) and obese (n = 19; BMI, ≥30 kg/m2) BLSA participants (A–D). E, Integrated concentrations of PYY [PYYAUC (0–120 min)] and GLP-1 [GLP-1AUC (0–120 min)] in lean vs. obese participants. F, Integrated concentrations of insulin [insulinAUC (0–120 min)] and HOMAIR in lean vs. obese participants. Each value is expressed as the mean ± SEM. *, P < 0.05; **, P < 0.01. Conversion from metric to Systeme International units: glucose: mg/dl x 0.056 = mmol/liter; insulin: µU/ml x 7.175 = pmol/liter; PYY: pg/ml x 0.25 = pmol/liter; GLP-1: pg/ml x 0.3 = pmol/liter.

 
We also analyzed data from 54 age-, sex-, and BMI-matched participants to examine gender effects on hormone secretion (Table 1Go). Secretory profiles and total secretion of insulin and GLP-1 were similar in both sexes (Fig. 5Go, A, B, D, and E). Interestingly, however, female participants had significantly higher plasma PYY levels by 15 and 20 min after oral glucose (Fig. 5CGo). Total secretion of PYY [PYYAUC (0–120 min), 17,464 ± 1,240 vs. 14,120 ± 806 pmol/liter·min, female vs. male; P < 0.05] was also significantly higher in females (Fig. 5EGo). Confirming other reports (22, 23), fasting leptin levels were higher in females than males, but fasting ghrelin levels were similar in females and males (Table 1Go).


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  		TABLE 1. Characteristics of subjects stratified by sex

 


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  		FIG. 5. Plasma glucose, insulin, PYY, and GLP-1 concentration profiles after administration of 75 g oral glucose in female and male (27 women and 27 men; mean age, 55.4 ± 18.6 yr) BLSA participants (A–D). E, Integrated concentrations of insulin [insulinAUC (0–120 min)], PYY [PYYAUC (0–120 min)], and GLP-1 [GLP-1AUC (0–120 min)] in female vs. male subjects. Each value is expressed as the mean ± SEM. *, P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Islet amyloid polypeptide (IAPP) and insulin are cosecreted from granules in islet ß-cells (24), and various modulators that stimulate or inhibit insulin secretion have similar effects on IAPP secretion (25). Inhibin/activin ß-subunit and LH or FSH are copackaged and coreleased from gonadotrophs in anterior pituitary gland (26). In this study we show that PYY and GLP-1, products of two separate genes, are located in the same human duodenal L cells and that these hormones have similar secretory patterns after oral glucose loading. It is common to find two or three distinct hormones present during early differentiation processes in progenitor cells (27) and dedifferentiated tissues, i.e. cancer, but the secretory response to physiological secretagogues in these cells is not regulated. Although all enteroendocrine cells are short-lived cells (28), the synthesis and secretion of their hormone products are controlled by physiological stimuli. The simultaneous release of both PYY and GLP-1 from L cells is controlled by foods containing glucose and fat. It is likely that the expression of proglucagon and pro-PYY are also regulated by some of the same transcription factors, analogous to the effect of the pax4 transcription factor on proinsulin and IAPP promoters (29). It is interesting to speculate as to why two distinct hormones are synthesized and secreted simultaneously from the same cell. They have overlapping functions (both decrease gastric secretion and emptying, both decrease GI motility, both decrease pancreatic secretion, and both have effects on food intake and satiety), but only GLP-1 has an effect on ß-cells of the pancreas. All of these functions are in harmony during the postprandial state, during which time both hormones are acting in a complementary manner; therefore, there is a physiological rationale for their colocalization. Whether PYY and GLP-1 have effects on one another’s synthesis and/or secretion is not clear. Intravenous injection of GLP-1 to humans decreased both basal and stimulated secretion of PYY (30), strongly suggesting a negative feedback of GLP-1 on PYY secretion.

Infusions of PYY to animals and humans are reported to regulate appetite and cause a decrease in food intake (6, 16). Its anorectic effect appears to be through the Y2 receptor in the arcuate nucleus of the hypothalamus in rodents (31). Several NPY receptor subtypes (Y1, Y2, Y4, and Y5) exist in brain, and PYY is thought to be a ligand of the Y2 receptor (32). However, the effects of PYY infusions on food intake, leading to decreases in body weight in rodents, have not been universally replicated (17). Of importance to elucidating the pathogenesis of obesity and diabetes, fasting levels of PYY were found to be lower in obese compared with lean humans, with a negative correlation between PYY levels and BMI (16). We found no correlation between BMI and GLP-1 levels, in agreement with previous reports (16), but, in contrast, we did not find a correlation between BMI and PYY levels. The original report (16) was based on 24 participants with an age range of 18–50 yr. In an attempt to evaluate a similar population in this report, analyses of age-matched participants (19–50 yr) were performed; however, this subset of our data still did not reveal any correlation. Similarly, our data serve to confirm a recent report that did not find any correlation between fasting PYY and BMI in obese, control, and anorectic adolescents (33). The PYY profiles of the BLSA participants after oral glucose loading are slightly blunted compared with the profiles reported by Stock et al. (33). This difference is probably due to the 20% fat content in liquid mixed meal that they used as a stimulus for PYY secretion. Also, the time to peak PYY and GLP-1 plasma levels of BLSA participants is quicker then generally reported (16, 33), and again, this is probably due to a slowing of the transit time of nutrients due to the fat in the mixed meals. As generally reported, we found that fasting ghrelin and leptin levels were negatively and positively correlated, respectively, with BMI in our study population.

It has also been reported that PYY secretion is lower in obese than in lean participants (16). However, PYY secretion after oral glucose was similar in our obese and lean participants. The design of the Batterham et al. study (16) was different, in that they examined the PYY response to a mixed meal, not glucose. Recently, it has been clearly shown that fat components directly stimulate L cell secretion through activation of gpr120 receptors (34). It is possible that in obesity, grp120 receptors are down-regulated to fat stimulation, and as a consequence, pro-PYY expression and secretion are decreased in response to fats, but that glucose-stimulated hormone secretion is not altered, which would explain why obese and lean participants respond similarly to glucose, but not to a mixed meal. In this regard, it has been shown that the PYY response was blunted after a mixed meal in obese adolescents (33), which seems to be in agreement with the findings of Batterham et al. (16). However, in the adolescents, PYY levels were decreased only at the 180-min point after their mixed meal, whereas in the obese subjects reported by Batterham et al. (16), PYY levels were decreased at all time points studied after their mixed meal. Obese BLSA participants displayed the expected changes in insulin secretion and insulin resistance, again demonstrating that they conform to known metabolic consequences of their obesity.

Plasma levels of some hormones show sex differences. It has been reported in 24 subjects (13 males and 11 females) that fasting plasma levels of ghrelin, a potent GH secretagogue that plays a role in feeding behavior, are higher in females than in males (35).

Our findings were not consistent with that report, which had a much smaller sample size. Leptin (22, 23) and agouti signal protein (36), expressed in adipose tissue, are reported to be higher in females than in males, and our findings confirm this observation.

Although the time to peak PYY concentration was similar in male and females, in that they both attained peak levels by 20 min, females reached significantly higher levels, and the total PYY AUC remained higher in females. Delayed GI motility (37), decreased gall bladder contraction (38), and increased colonic transit and gastric emptying time (39) in women have all been reported. Also, females sense gastric fullness earlier than males (40). Slow movement of foods through the GI tract may provide more contact time for the food material with intestinal mucosa, which might lead to increased PYY secretion and synthesis. PYY decreases GI motility and inhibits pancreatic exocrine secretion through inhibition of cholecystokinin- and secretin-modulated pathways in the area postrema of the brain (41, 42), which might, in turn, modulate its own secretion.

We conclude that PYY and GLP-1 are colocalized and cosecreted from L cells in response to physiological stimuli. Fasting PYY levels and PYY secretion in response to oral glucose were not correlated with BMI. Interestingly, the total secretion of PYY was higher in females than in males. Although PYY analogs are under development as therapeutic targets for obesity because of reports that PYY deficiency is involved in the pathogenesis of obesity, our findings do not support their development.


   Footnotes
 
This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging.

First Published Online September 20, 2005

Abbreviations: AUC, Area under the curve; BLSA, Baltimore Longitudinal Study on Aging; BMI, body mass index; {Delta}, incremental rise; GI, gastrointestinal; GLP-1, glucagon like peptide-1; HbA1c, glycosylated hemoglobin; HOMAIR, homeostasis model assessment of insulin resistance; IAPP, islet amyloid polypeptide; NPY, neuropeptide Y; PP, pancreatic polypeptide; PYY, peptide YY.

Received February 24, 2005.

Accepted September 13, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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