Published online December 31, 2007
PEDIATRICS Vol. 121 No. 1 January 2008, pp. e180-e186 (doi:10.1542/10.1542/peds.2007-1461)
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ARTICLE

Functional Ontogeny of the Proglucagon-Derived Peptide Axis in the Premature Human Neonate

Harish Amin, MDa, Jens J. Holst, PhDb, Bolette Hartmann, PhDb, Laurie Wallace, BScc, Jim Wright, MD, PhDd and David L. Sigalet, MD, PhDc,e

a Department of Neonatology, Foothills Hospital
c GI Research Group, III Institute
d Departments of Pathology
e Surgery, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
b Department of Physiology, Panum Institute, University of Copenhagen, Copenhagen, Denmark


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND. The regulation of intestinal growth and development in human neonates is incompletely understood, which hinders the provision of nutrients enterally. The "hindgut" hormones glucagon-like peptides 1 and 2 have been shown to play an important role in the regulation of nutrient assimilation, intestinal growth, and function.

OBJECTIVE. Our goal was to investigate the production of glucagon-like peptides 1 and 2 in premature human infants and examine the effects of prematurity and feeding on hormone release.

PATIENTS AND METHODS. With informed consent, premature infants who were admitted to a tertiary neonatal intensive care nursery (gestational age: 28–32 weeks) were monitored with weekly determinations of postprandial glucagon-like peptide 1 and 2 levels. Comparison studies with groups of normal infants and adults were performed. Hormone levels were obtained by using specific radioimmunoassay for glucagon-like peptide 1 (1–36) and glucagon-like peptide 2 (1–33), modified for small sample volumes; accurate monitoring of enteral intake was performed at all of the sampling time points.

RESULTS. Forty-five infants with a mean gestational age of 29.6 ± 1.9 weeks were studied; fasting levels of both glucagon-like peptides 1 and 2 were elevated. There was no correlation between gestational age and glucagon-like peptide 2 output. However, both glucagon-like peptide 1 and 2 levels were correlated with the caloric value of feeds.

CONCLUSIONS. The premature human neonate has significantly higher fasting levels of glucagon-like peptides 1 and 2 compared with adults; feeding increases these levels further. These findings suggest that the proglucagon-derived peptides may have a role in normal intestinal development and nutrient handling.

Key Words: neonatal feeding • GLP-1 • GLP-2 • gut development • necrotizing enterocolitis

Abbreviations: PGDP—proglucagon-derived peptide • GLP—glucagon-like peptide • DPP—dipeptidyl peptidase

Improvements in the general care of premature neonates have resulted in a significant enhancement in outcomes such that survival of infants in the range of 26 to 30 weeks' gestational age is now routine.1 Nevertheless, an ongoing major cause of morbidity and mortality in this population is the difficulties associated with providing adequate nutrients for growth.2–4 At present, clinical nutritional support centers around the provision of nutrients enterally with parenteral nutrition as a backup1; implicit in this strategy is the assumption that the premature neonatal gastrointestinal tract is capable of appropriately assimilating enterally delivered nutrients. For this to occur, signals from nutrient ingestion must be integrated to regulate motility and nutrient absorption. Often, this is not the case, and enteral feeding results in abdominal distension, high gastric residuals, and apparent clinical deterioration, which raises concerns regarding the development of necrotizing enterocolitis.5, 6 The factors that control motility, nutrient absorption, and the integration of nutrient delivery are incompletely understood in the mature intestine.4 Even less is known about the development of these regulatory systems in the human neonate. An improved understanding of these regulatory systems will almost certainly improve the strategies for nutritional support for premature infants.

The proglucagon-derived peptides (PGDPs) glucagon-like peptide 1 (GLP-1) and GLP-2 are emerging as having a significant role in the integration of nutrient availability and absorption. GLP-2 and the related PGDP GLP-1 are normally produced in the enteroendocrine L cells, which occur in the mucosa of the distal small intestine and throughout the large intestine. These cells specifically express prohormone convertase 1/3, which processes the translated proglucagon gene product to produce GLP-1 and GLP-2, as well as glicentin and intervening peptide-2 (which have little known biological activity7, 8). In contrast, adult pancreatic {alpha}-cells express prohormone convertase 2, which processes the peptide product of the proglucagon gene into glucagon and the major proglucagon fragment (which is likely inactive; see reviews in refs 9 and 10). In the adult, L cells are stimulated to release GLP-2 (with GLP-1 and PYY) in response to nutrients in the proximal bowel (via a vagal-enteric neuronal pathway) and by direct contact with nutrients, especially fat in the distal small intestine.11–14

During the normal physiologic response to a meal, GLP-1 and GLP-2 act (with the coreleased "hindgut hormone" PYY) to regulate nutrient delivery (via effects on the enteric neuronal system to slow intestinal motility15, 16). GLP-1 acts as an incretin, potentiating the release and activity of insulin, and also affects β-cell growth and survival.9, 17 GLP-1 is metabolized locally, activating sensory neuronal pathways of the gut (including the pancreas and liver) and vagus, with very little intact GLP-1 reaching the systemic circulation.10 In contrast, GLP-2 acts to increase intestinal epithelial absorptive capacity and mucosal growth, primarily acting by a classical endocrine pathway, activating enteric neurons.18–23 Both GLP-1 and GLP-2 are inactivated by cleavage at the N terminus by the ubiquitous enzyme dipeptidyl peptidase (DPP)-IV; the half-life of GLP-1 is <2 minutes, whereas the half-life of GLP-2 is 7 minutes in adults.10, 24 The importance of GLP-2 in controlling the absorptive capacity of the proximal bowel is demonstrated by studies that have shown that, after resection, the increased nutrient load to the residual bowel stimulates the release of increased amounts of GLP-2; this is tightly correlated with the process of intestinal adaptation.19, 20

In the context of the developing fetus, studies examining the effects of GLP-1 are limited; it seems to be a potential mediator of pancreatic β-cell mass.9, 10, 25, 26 In contrast, the GLP-2 axis is active in the developing intestine, with peak lifetime levels of GLP-2 in the late weaning period.27, 28 Although the specific functions of GLP-2 in controlling gut development are not clear, the high level of expression of both the ligand and the receptor for this system suggests a role in controlling gut growth and mucosal development, both of which would be expected to be important in the response of the developing neonatal gut. No studies to date have examined the development of the PGDP system in the premature human infant; previous studies were performed by examining the levels of enteroglucagon, which is related to GLP-1 and GLP-2 but has much different kinetics and effects than GLP-1 and GLP-2.9, 29, 30

Accordingly, the present studies were undertaken to examine the activity of the PGDP axis in premature human neonates. Specifically, we sought to determine whether GLP-1 and GLP-2 were produced in the human neonate in response to feeds, whether there was a relationship between their production and gestational age, and whether there is a release response that is related to the amount of nutrients delivered. Because of the small volumes of blood available for sampling, we chose to examine amidated GLP-1 (1–36 and 7–36), reflecting total GLP-131 and GLP-2 (1–33) to examine the endocrinologically active hormone.9, 32 The results demonstrate that the PGDP axis is very active in the fed premature human; these findings have prompted ongoing studies to determine the source of these peptides and their role in controlling gut development.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This study was approved by the Conjoint Health Research Ethics Board of the Faculty of Medicine and affiliated teaching institutions of the University of Calgary. The parents of premature infants with a gestational age of 24 to 32 weeks were approached for informed consent. Gestational age was determined by the last maternal menstrual period and the Ballard scoring system.33 All of the neonates were cared for in the Foothills Hospital NICU from May 2004 through February 2006. Baseline data collected included antenatal history, details of drug exposure, infant's length and weight, and coexisting diseases. Infants having identified syndromes, chromosomal abnormalities, congenital nonbacterial infection, evidence of intraventricular hemorrhage at or more than grade II on cranial ultrasound scan during the first week of life, evidence of an inborn error of metabolism, or renal failure (urine output of <0.5 mL/kg per hour for >8 hours) were excluded. Primary end points were the gestational age, weight, caloric content of feeds, and postprandial serum levels of GLP-1 and GLP-2. Infants were followed until they achieved full enteral feeds or were discharged from the NICU. To examine the response of normal infants to feeding, control subjects were solicited from infants (term delivery, age <6 months) admitted for nongastrointestinal-related treatment to the Alberta Children's Hospital. School-aged children and adult control patients were solicited from local schools and staff.

Infants were enrolled when feeds were started, typically at 10 mL/kg per day. Studies were not performed before this because of concerns regarding the volume of blood sampling in these small, critically ill infants. Feeds were increased by 10 to 25 mL/kg per day as tolerated to a maximum of 180 mL/kg per day; all of the infants received L-arginine supplementation (1.5 mmol/kg per day) via the parenteral or enteral route.34 Feeds were typically given as a bolus feed, every 2 to 3 hours by gavage, with expressed breast milk or Similac special care infant formula via gastric feeding tube until >32 weeks' gestational age. In a few older infants, feeds were given by bottle. All of the patients were monitored with at least twice weekly serum glucose measurements and daily bedside glucose checks. In neonates, blood was collected as part of routine monitoring for parenteral nutrition once per week, timed at 50 to 60 minutes after feeds. A 500-µL sample was drawn and placed immediately in an iced heparinized tube containing 10% for volume of Trasylol (5000 kallikrein inhibitor U/mL, diproprotin A, 34 mg/mL; Becton Dickinson, Toronto, Ontario, Canada). Samples were centrifuged within 20 minutes, and the serum was frozen and stored for batched analysis. GLP-1 (amidated GLP-1 1–36 and 7–36) levels were obtained by radioimmunoassay using synthetic unlabeled and 125I-labeled GLP-1 (7–36) amide (Peninsula, St Helens, United Kingdom) and antiserum 89390 (C-terminal specific for amidated GLP-1 1–36 and 7–36).31, 35 The experimental detection limit was 1 pmol/L, and the intra-assay coefficient of variation was 6%. GLP-2 levels were obtained by using a radioimmunoassay for the N terminus of intact human GLP-2 (1–33; antibody code 92160), with a sensitivity of ~1 pmol/L and an interassay variation of 5% at a GLP-2 concentration of 40 pmol/L.36 Each sample was analyzed in duplicate.

In premature infants, the feeding rate was determined by the clinician caring for the infant, independent of the study. The initial caloric stimulation was low but increased as the infant matured. Accordingly, to examine the relationship between gestational age, days of life, and the caloric content of each feed, each parameter was plotted as the independent variable, with GLP-2 levels as the dependent variable in a linear correlation analysis. Once infants were tolerating >21 kJ/kg (5 kcal/kg) per feed (the threshold for mixed meal stimulated GLP-2 response in adults37), results were pooled into 2 groups: 21 to 42 kJ/kg (5–10 kcal/kg) and 42 to 63 kJ/kg (10–15 kcal/kg) per feed.

Control term infants were sampled after a regular bottle feed using an identical protocol. Older children and adults had fasting blood samples drawn, and on different days had 1 hour postprandial GLP-2 levels measured after a 25.2 kJ/kg (6 kcal/kg) meal (Carnation Instant Breakfast; Nestle Corp, Toronto, Ontario, Canada; composition: total calories: carbohydrate, 64%; protein, 21%; fat, 18%) or a large mixed meal (>50.4 kJ/kg [12 kcal/kg]; typical composition: carbohydrate, 55%; protein, 18%; fat, 27%).

Comparisons between specific groups' GLP-2 levels were compared by using Student's t test (unpaired) or analysis of variance using Tukey's posthoc comparison tests as appropriate. Pearson linear correlation coefficients were calculated by using Prism software (GraphPad Corp, San Francisco, CA).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
During the study period, 111 infants of 24 to 32 weeks' gestational age were admitted to the NICU. Of these, 51 infants had coexisting morbidities, and 15 parents could not be reached because of logistic reasons. Forty-five families were approached for consent, all agreed, and their infants were enrolled.

In total, 45 infants were studied, sampling ≥2 values of GLP-1 or GLP-2; their gestational age and weight were typical of this population (Table 1). Nineteen were studied for GLP-1 levels and 43 had studies for GLP-2. In addition, 6 term infants were recruited from patients admitted to the newborn ward for nongastrointestinal reasons. Eight older children (aged 6–12 years) and 6 adults (aged 24–44 years) were recruited from families of staff. There were no differences between the older children and adults in any of the hormonal responses, and so the results are presented as the pooled averages.


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  		TABLE 1 Demographics of Subjects

 
Fasting and fed measures of serum GLP-1 levels of the different study groups are presented in Fig 1 and Table 2. Premature infants showed a significant elevation in both fasting and fed GLP-1 levels, with fasting levels approximately twofold higher than those of the adult patients (Table 2). There was a relationship between the caloric content of feeds and the postprandial levels of GLP-1 observed (Fig 1; Pearson correlation coefficient: r2 = 0.42; P < .0006 [GraphPad]). The number of observations was not adequate to detect a relationship between gestational age or postnatal development and GLP-1 levels (data not shown). Especially at lower feeding values (<37.8 kJ/kg [9 kcal/kg]), all of the patients were receiving supplemental intravenous glucose as part of parenteral nutrition while GLP-1 blood samples were being drawn. No patient had documented hypoglycemia (serum glucose <3 mmol/L) during the study period.


Figure 1
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  		FIGURE 1 Caloric values of meals (kcal/kg [1 kcal = 4.2 kJ] body weight) versus postprandial GLP-1 levels (pmol/L) by radioimmunoassay during initial feeding of human premature infants (gestational age: 26–32 weeks) (Pearson correlation coefficient: r2 = 0.42; P < .006 [GraphPad Corp]).

 

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  		TABLE 2 Fasting and Postprandial GLP-1 Levels

 
Fasting and fed production of GLP-2 of the different study groups is presented in Fig 2 and Table 3. Premature infants showed a significant elevation in both fasting and fed GLP-2 levels, with fasting levels approximately twofold and maximal fed levels approaching a fivefold increase compared with adults (P < .02 for all comparisons; Table 3). In older children and adults, subgroup analysis of the responses between the school-aged children (aged 5–12 years; n = 7) and the adults (aged 28–44 years) showed no differences, and so the results were pooled. In premature infants fed <21 kJ/kg (5 kcal/kg) per feed, there was a highly significant relationship between calories fed and the GLP-2 response (Fig 2; Pearson correlation coefficient: r2 = 0.48; P < .0001). However, at feeding levels >21 kJ/kg (5 kcal/kg) per feed, the GLP-2 response seemed to become more variable; there was no increase in the GLP-2 response in the premature infants between feeds averaging 29.4 kJ/kg (7 kcal/kg) versus those of 58.4 kJ/kg (13.9 kcal/kg) (Table 3). Overall, there was still a significant correlation between the caloric value of all feeds and the GLP-2 output (r2 = 0.38; P < .0001). There was no significant relationship between GLP-2 production and gestational age (or days of life) or days feeding in premature infants fed ≥21 kJ/kg (5 kcal/kg) per feed in the patients studied (data not shown). However, in term infants fed a high-caloric content meal, the meal-stimulated levels of GLP-2 were significantly lower than those seen in premature infants and not significantly different from those seen in older children or adults (Table 3).


Figure 2
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  		FIGURE 2 Caloric values of meal (kcal/kg [1 kcal = 4.2 kJ] body weight) versus postprandial GLP-2 (1–33) levels (pmol/L) by radioimmunoassay, during initial feeding of human premature infants (gestational age: 26–32 weeks) (Pearson correlation coefficient: r2 = 0.38; P < .0001).

 

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  		TABLE 3 Fasting- and Meal-Stimulated GLP-2 Levels

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
These results clearly demonstrate a remarkable activity of the PGDP axis in both fasting and fed premature human neonates. These findings build on previous studies, which have shown in fed premature infants a significant increase in total GLP-2 and PYY levels38, 39 compared with adult values. The present study shows that both fasting and postfeeding levels of GLP-1 and GLP-2 in premature neonates are significantly higher than in older infants and adults. These findings may be explained by either an increase in production or a decrease in metabolism.

In animal models, during this same developmental period, there is a significant expression of GLP-1 in the pancreas; in the late-gestation rat, fetal pancreas GLP-1 represents 40% of glucagon like reactivity, whereas in the adult animal, it is <1%.25 In these animal studies, the fetal intestinal content of GLP-1 was very low and increased markedly with weaning. In the present studies, we have shown that, in fasting premature infants, the serum levels of GLP-1 are double normal adult levels; given the rapid metabolism of this hormone, this suggests a high rate of endogenous production by the pancreas (Table 2). Together, these findings support further work to determine whether a similar population of transient GLP-1-expressing cells in the pancreas exists in the human. The role of GLP-1 in affecting early (neonatal) and late (adult) pancreatic development and β-cell mass has been extensively reviewed17, 40; it seems to be an important stimulus for cell division and differentiation into the β-cell lineage. In the present study, insulin levels were not obtained, and significant episodes of hypoglycemia were not noted. However, hypoglycemia is a relatively common problem in neonates, and the role of GLP-1 has not been investigated in these clinical situations.

The high fasting levels of GLP-2 seen in these infants (Table 3) would also be expected to have effects on the developing gut, acting as a stimulus for the normal development of the intestine. The present results corroborate the 1 previous report in the literature and demonstrate that the elevated total GLP-2 levels noted are caused by an increase in the active form of the hormone, GLP-2 (1–33).38 The relevance of these levels may be extrapolated from work performed in animal models, which demonstrated moderate-to-high levels of expression of GLP-2 and the GLP-2 receptor in the late-developing rat fetus and weanling pups.27, 41 The GLP-2 protein content in the intestine increases over the first 3 weeks of life to approximate adult levels in the rat,27 but as the tissue content increases, plasma levels decrease, similar to that seen in the present human studies. The trophic effects of GLP-2 are well described27, 42, 43; thus, GLP-2 may be exerting a physiologic trophic effect in the normal-developing human fetus during this phase of rapid intestinal growth.44 The time course of this developmental effect cannot be directly determined from this study, but the observation that normal infants, with an average corrected gestational age of 48 weeks, had much lower postprandial levels of GLP-2 suggests that this maturation occurs around the time of normal delivery (40 weeks; Table 3). This also corresponds with the time of the most rapid growth of bowel length in the fetus, from 30 to 40 weeks of development.44 An important issue in this consideration is the sensitivity of the developing infant gut to GLP-2; this will require additional direct study.

This potential developmental role in the nonfed fetus does not explain the second major observation from the present study; feeding of the premature neonate resulted in very significant increases in GLP-1 and GLP-2 production, far beyond the norms for term infants or older children and adults (see Table 3). Although the absolute levels of both GLP-1 and GLP-2 were much higher than in adults, there seemed to be an intact regulatory system, especially at lower levels of feed stimulation. This was clearly shown in the significant correlation between hormone levels and nutrient load per feed exhibited throughout the premature age range (Figs 1 and 2). It is also interesting to note that the majority of the infants in the present study were being fed by a nasogastric tube and, thus, would not be expected to have activation of cephalic vagal tone; the likely stimulus for hormone release was local, enteric pathways (which could also involve the vagus). It seems most likely that the observed high levels of GLP-1 and GLP-2 after feeding were because of release from a population of developing endocrine cells in the neonatal pancreas and intestine, with an increased mass of cells and/or increased sensitivity to stimulation producing such high levels. The decline in observed GLP-2 levels in the term infants suggests that gestational age may have an impact on this relationship, but the study was limited by the initial design to include infants only up to age 32 weeks. The understanding of the effects of maturation from 32 to 40 weeks on this system will require additional direct study.

An alternative explanation for the high levels of hormones observed would be decreased degradation after release. As noted, GLP-1 and GLP-2 initial metabolism involves specific N-terminal cleavage of the His-Ala sequence by the ubiquitous enzyme DPP-IV; in adults, there are high levels of DPP-IV activity in the kidney and intestinal epithelium; however, very little is known about maturational changes in the human infant.45 This enzyme does metabolize the breakdown of a wide range of cytokines and peptide hormones, including PYY, GLP-1, GLP-2, and glucose-dependent inhibitory peptide. Reduced activity of this common pathway could be a cause of the elevation in levels of active (1–33) GLP-2 seen in this study. Given the very high levels of DPP-IV activity in the placenta,45 the in utero levels of hormones metabolized by this pathway would be expected to be lower than the postnatal levels. This may also explain the low levels of GLP-2 seen in cord blood samples in previous studies.46 Direct study of these pathways is indicated, examining both for possible cell populations producing these hormones and variations in their metabolism in the developing neonate.

Having described these high levels of GLP-1 and GLP-2 in the fed human neonate, what are the potential consequences? It would seem logical that both hormones will stimulate additional growth and perhaps earlier maturation in their respective target organs, the pancreas and small intestine.19, 40, 42, 44 There is evidence that, in low birth weight individuals, there is a lifelong impairment in β-cell responsiveness, which may be caused by alterations in pancreatic development affected by GLP-1 levels.47

An aspect of gut metabolism that may be affected by these high levels of GLP-2 is intestinal blood flow. It has been shown that exogenous GLP-2, at levels similar to those noted in these patients, caused a significant increase in blood flow to the proximal gut in the neonatal pig.48 However, there was a concomitant decrease in blood flow to the distal small intestine, colon, kidneys, and stomach, as well as exaggerated perfusion of the serosa versus the mucosa. Although an increase in blood flow to the gut is generally considered to be protective, it is possible that increased flow to proximal regions could result in a relative "steal phenomenon" and could potentiate alterations in mucosal barrier function, which could lead to necrotizing enterocolitis.1, 3 This mechanism may explain some of the "random" cases of necrotizing enterocolitis, which seem to occur in otherwise thriving neonates.4

This is the opposite of our initial hypothesis; we had expected that only low levels of GLP-2 would correlate with gut dysfunction. During this study, 2 patients developed feeding intolerance or necrotizing enterocolitis; both had relatively low levels of GLP-2 in the week before development of overt difficulties. During the phase of gut dysfunction, both had low levels when compared with normal fasting levels (Table 3). Overall, these findings suggest that additional work in the human neonate to clarify the relationship between the enteral "load" of nutrients and the intestinal hormonal response elicited is required and may well lead to novel methods of monitoring feeding tolerance.

Finally, these findings do support the consideration of the use of GLP-2 to increase nutrient absorptive capacity in the human neonate. The PGDP axis is clearly very active in these patients and is temporally associated with a phase of active intestinal growth and mucosal development. However, given the high levels of intrinsic GLP-2 production, specific assessments of the doses appropriate for this age group would be required. These findings demonstrate for the first time a previously unappreciated ontogeny of GLP-1 and GLP-2 activity in the human neonate. Given the developmental changes in the intestine over the last trimester, these findings are perhaps to be expected; what is truly remarkable is the ability of the premature neonatal intestine to function as well as it typically does, up to 15 weeks before its expected start date.


   ACKNOWLEDGMENTS
 
This work was supported financially by the Alberta Children's Hospital Research Foundation and the Research Fund of the Department of Surgery, University of Calgary, with infrastructure support of the Sigalet laboratory from the Crohn's and Colitis Foundation of Canada and of the Holst laboratory from the Danish Medical Council.

We give special thanks to the nurses and dieticians of the Foothill's Hospital NICU and "N" cluster of the Alberta Children's Hospital for helpful care of the patients. We also thank Viona Lam and Dragan Kravarusic for technical support. The expert secretarial support of Gail Wright-Wilson is gratefully acknowledged. Finally, the enthusiasm and understanding of the parents of these infants was instrumental in allowing the project to proceed; their generous sharing at a time of great personal distress was truly inspiring.


   FOOTNOTES
 
Accepted Jul 19, 2007.

Address correspondence to David L. Sigalet, MD, PhD, Department of Surgery, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, Canada T3B 6A8. E-mail: sigalet{at}ucalgary.ca

Financial Disclosure: Dr Sigalet has acted as a paid consultant for NPS Pharmaceuticals and Centocor Pharmaceuticals. The other authors have indicated they have no financial relationships relevant to this article to disclose.


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R. Padidela, M. Patterson, N. Sharief, M. Ghatei, and K. Hussain
Elevated basal and post-feed glucagon-like peptide 1 (GLP-1) concentrations in the neonatal period
Eur. J. Endocrinol., January 1, 2009; 160(1): 53 - 58.
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